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 are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   36619   clinical trials with a EudraCT protocol, of which   6046   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).
     
    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 multicenter, non-randomized, non-blinded, non-controlled study to investigate the impact of multiple doses of BAY 63-2521 on safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with pulmonary hypertension in a 12 week 3 times a day individual dose titration scheme

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2006-003520-10
    Trial protocol
    DE  
    Global end of trial date
    12 Sep 2014

    Results information
    Results version number
    v1
    This version publication date
    23 Jun 2016
    First version publication date
    23 Jun 2016
    Other versions
    v2

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    BAY63-2521/12166
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00454558
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer HealthCare AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Scientific contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety, tolerability, and feasibility of individual titration of riociguat according to peripheral systolic blood pressure. In addition, long-term safety and tolerability of riociguat were investigated during the optional open-label extension period.
    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. Before entering the study, the informed consent form was read by and explained to all 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. Before entering the extension part of this study, the subject had to sign an additional informed consent form. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug. Before entering the extension part of this study, the subject had to sign an additional informed consent form.
    Background therapy
    Basic pulmonary hypertension medications such as diuretics, oral anticoagulants, digitalis, calcium channel blockers given up to the approved dose in arterial hypertension, and oxygen supplementation, as well as an extended basic therapy with oral bosentan were allowed.
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Feb 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 75
    Worldwide total number of subjects
    75
    EEA total number of subjects
    75
    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)
    42
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study was conducted at 16 centres in Germany between 12 February 2007 (first subject first visit) and 29 July 2014 (last subject last visit).

    Pre-assignment
    Screening details
    Of the 78 subjects enrolled in the main study, 3 were screening failures. A total of 75 subjects received study drug and valid for the safety analysis in the main study, 3 prematurely discontinued study drug treatment due to adverse events. Only 68 subjects participated in the optional open-label extension period after Day 84 of the main study.

    Period 1
    Period 1 title
    Main Study
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Riociguat (Adempas, BAY63-2521) Main Study
    Arm description
    Subjects received Riociguat (Adempas, BAY63-2521) immediate release (IR) tablets with biweekly titrations of doses starting from 1.0 milligram (mg) thrice in a day (TID) up to 2.5 mg TID in steps of plus (+) 0.5 mg according to safety and tolerability (mainly peripheral systolic blood pressure) for 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Adempas
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Riociguat (Adempas, BAY63-2521) IR tablets with biweekly titrations of doses starting from 1.0 mg TID up to 2.5 mg TID in steps of +0.5 mg according to safety and tolerability (mainly peripheral systolic blood pressure) for 12 weeks.

    Number of subjects in period 1
    Riociguat (Adempas, BAY63-2521) Main Study
    Started
    75
    Completed
    72
    Not completed
    3
         Adverse event
    3
    Period 2
    Period 2 title
    Long-term Extension (LTE) Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Riociguat (Adempas, BAY63-2521) LTE Phase
    Arm description
    Subjects who were willing to continue, entered the optional 84-month LTE phase until the premature termination of product development or until official approval and commercial availability of BAY63-2521 at a minimum dose of 0.5 mg TID and maximum dose of 2.5 mg TID.
    Arm type
    Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Adempas
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects who were willing to continue, entered the optional 84month LTE phase until the premature termination of product development or until official approval and commercial availability of BAY63-2521 at a minimum dose of 0.5 mg TID and maximum dose of 2.5 mg TID.

    Number of subjects in period 2
    Riociguat (Adempas, BAY63-2521) LTE Phase
    Started
    68
    Completed
    36
    Not completed
    32
         Death
    11
         Investigator decision, not protocol driven
    8
         Non-compliant with study drug
    1
         Adverse event
    6
         Insufficient therapeutic effect
    1
         Consent withdrawn by subject
    4
         Lost to follow-up
    1

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521) Main Study
    Reporting group description
    Subjects received Riociguat (Adempas, BAY63-2521) immediate release (IR) tablets with biweekly titrations of doses starting from 1.0 milligram (mg) thrice in a day (TID) up to 2.5 mg TID in steps of plus (+) 0.5 mg according to safety and tolerability (mainly peripheral systolic blood pressure) for 12 weeks.

    Reporting group values
    Riociguat (Adempas, BAY63-2521) Main Study Total
    Number of subjects
    75
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.3 ± 11.8 -
    Gender Categorical
    Units: Subjects
        Female
    41 41
        Male
    34 34

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521) Main Study
    Reporting group description
    Subjects received Riociguat (Adempas, BAY63-2521) immediate release (IR) tablets with biweekly titrations of doses starting from 1.0 milligram (mg) thrice in a day (TID) up to 2.5 mg TID in steps of plus (+) 0.5 mg according to safety and tolerability (mainly peripheral systolic blood pressure) for 12 weeks.
    Reporting group title
    Riociguat (Adempas, BAY63-2521) LTE Phase
    Reporting group description
    Subjects who were willing to continue, entered the optional 84-month LTE phase until the premature termination of product development or until official approval and commercial availability of BAY63-2521 at a minimum dose of 0.5 mg TID and maximum dose of 2.5 mg TID.

    Subject analysis set title
    Safety set (Main Study)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety set (N=75) included all subjects who received 1 dose of the study drug in the main study.

    Subject analysis set title
    Pharmacokinetic (PK)/Pharmacodynamic (PD) set (Main Study)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    PK/PD set (N=72) included all subjects who completed the 12-week treatment without major changes versus protocol in the main study.

    Primary: Number of Subjects With Systolic Blood Pressure Less Than 90 Millimeter of Mercury in the Long-term Extension Phase

    Close Top of page
    End point title
    Number of Subjects With Systolic Blood Pressure Less Than 90 Millimeter of Mercury in the Long-term Extension Phase [1]
    End point description
    End point type
    Primary
    End point timeframe
    From Day 84 (end of main study) until up to 7.25 years (87 months) of the 84-month LTE
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done and inferential statistics were not planned as this is an open, single-group study.
    End point values
    Riociguat (Adempas, BAY63-2521) LTE Phase
    Number of subjects analysed
    68 [2]
    Units: Subjects
    16
    Notes
    [2] - All subjects who entered the LTE phase.
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-emergent Adverse Events Related to Heart Rate and Blood Pressure in the Main Study

    Close Top of page
    End point title
    Number of Subjects With Treatment-emergent Adverse Events Related to Heart Rate and Blood Pressure in the Main Study [3]
    End point description
    An adverse event (AE) is any untoward medical occurrence (that is, any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. Treatment-emergent AEs (TEAE) were AEs that began while the subject was taking study treatment or up to 2 days after the end of study treatment. TEAEs with regard to heart rate and blood pressure included tachycardia/sinus tachycardia, hypotension, and syncope.
    End point type
    Primary
    End point timeframe
    From initiation of study treatment until 12 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done and inferential statistics were not planned as this is an open, single-group study.
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    75 [4]
    Units: Subjects
        Tachycardia/sinus tachycardia
    11
        Hypotension
    11
        Syncope
    4
    Notes
    [4] - Safety set (main study).
    No statistical analyses for this end point

    Primary: Number of Subjects Categorized According to Their Absolute QTc Values (Bazett and Fridericia) at Specified Time Points in the Main Study

    Close Top of page
    End point title
    Number of Subjects Categorized According to Their Absolute QTc Values (Bazett and Fridericia) at Specified Time Points in the Main Study [5]
    End point description
    Subjects were categorized (less than or equal to [<=] 450, greater than [>] 450 to 500 and >500 milliseconds [msec]) and distributed according to their absolute QTc values, calculated by Bazett and Fridericia formulae.
    End point type
    Primary
    End point timeframe
    Pre-study and Days 0, 1, 14, 28, 42, 56, 70, 84, and 85
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done and inferential statistics were not planned as this is an open, single-group study.
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    40 [6]
    Units: Subjects
        Bazett: <=450 msec at pre-study
    36
        Bazett: >450-500 msec at pre-study
    1
        Bazett: >500 msec at pre-study
    0
        Bazett: <=450 msec on Day 0
    36
        Bazett: >450-500 msec on Day 0
    3
        Bazett: >500 msec on Day 0
    0
        Bazett: <=450 msec on Day 1
    29
        Bazett: >450-500 msec on Day 1
    6
        Bazett: >500 msec on Day 1
    0
        Bazett: <=450 msec on Day 14
    34
        Bazett: >450-500 msec on Day 14
    5
        Bazett: >500 msec on Day 14
    0
        Bazett: <=450 msec on Day 28
    35
        Bazett: >450-500 msec on Day 28
    4
        Bazett: >500 msec on Day 28
    0
        Bazett: <=450 msec on Day 42
    31
        Bazett: >450-500 msec on Day 42
    6
        Bazett: >500 msec on Day 42
    0
        Bazett: <=450 msec on Day 56
    34
        Bazett: >450-500 msec on Day 56
    3
        Bazett: >500 msec on Day 56
    0
        Bazett: <=450 msec on Day 70
    34
        Bazett: >450-500 msec on Day 70
    4
        Bazett: >500 msec on Day 70
    0
        Bazett: <=450 msec on Day 84
    31
        Bazett: >450-500 msec on Day 84
    5
        Bazett: >500 msec on Day 84
    0
        Bazett: <=450 msec on Day 85
    13
        Bazett: >450-500 msec on Day 85
    0
        Bazett: >500 msec on Day 85
    0
        Fridericia: <=450 msec at pre-study
    37
        Fridericia: >450-500 msec at pre-study
    0
        Fridericia: >500 msec at pre-study
    0
        Fridericia: <=450 msec on Day 0
    39
        Fridericia: >450-500 msec on Day 0
    0
        Fridericia: >500 msec on Day 0
    0
        Fridericia: <=450 msec on Day 1
    35
        Fridericia: >450-500 msec on Day 1
    0
        Fridericia: >500 msec on Day 1
    0
        Fridericia: <=450 msec on Day 14
    38
        Fridericia: >450-500 msec on Day 14
    1
        Fridericia: >500 msec on Day 14
    0
        Fridericia: <=450 msec on Day 28
    37
        Fridericia: >450-500 msec on Day 28
    2
        Fridericia: >500 msec on Day 28
    0
        Fridericia: <=450 msec on Day 42
    37
        Fridericia: >450-500 msec on Day 42
    0
        Fridericia: >500 msec on Day 42
    0
        Fridericia: <=450 msec on Day 56
    37
        Fridericia: >450-500 msec on Day 56
    0
        Fridericia: >500 msec on Day 56
    0
        Fridericia: <=450 msec on Day 70
    37
        Fridericia: >450-500 msec on Day 70
    1
        Fridericia: >500 msec on Day 70
    0
        Fridericia: <=450 msec on Day 84
    34
        Fridericia: >450-500 msec on Day 84
    2
        Fridericia: >500 msec on Day 84
    0
        Fridericia: <=450 msec on Day 85
    13
        Fridericia: >450-500 msec on Day 85
    0
        Fridericia: >500 msec on Day 85
    0
    Notes
    [6] - Safety set (main study) with electrocardiogram valid for QT/QTc evaluation at all time points.
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-emergent Adverse Events Leading to Discontinuation of Study Drug in the Main Study and the Long-term Extension Phase

    Close Top of page
    End point title
    Number of Subjects With Treatment-emergent Adverse Events Leading to Discontinuation of Study Drug in the Main Study and the Long-term Extension Phase [7]
    End point description
    An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. TEAEs were AEs that began while the subject was taking study treatment or up to 2 days after the end of study treatment. Here n = number of subjects evaluable at the specific period.
    End point type
    Primary
    End point timeframe
    From the start of main study (12 weeks) until the end of LTE phase (84 months)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done and inferential statistics were not planned as this is an open, single-group study.
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    75
    Units: Subjects
        Main Study (n = 75)
    0
        LTE Phase (n = 68)
    13
    No statistical analyses for this end point

    Secondary: Change From Baseline in 6-minute Walk Time Distance (6MWD) at Specified Time Points

    Close Top of page
    End point title
    Change From Baseline in 6-minute Walk Time Distance (6MWD) at Specified Time Points
    End point description
    6MWD is a measure for the objective evaluation of a subject's functional exercise capacity. In the below table,'n' signifies the number of subjects evaluable for the corresponding time points. '99999' in the table below indicates that value could not be estimated since there was only 1 subject evaluable at LTE Month 84.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of main study), Day 84 (end of main study), LTE Months 12, 24, 36, 48, 60, 72, and 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    68 [8]
    Units: Meters
    arithmetic mean (standard deviation)
        Baseline (n=68)
    364.9 ± 103.3
        Change at Day 84 (n=66)
    66.3 ± 71
        Change at LTE Month 12 (n=52)
    58.3 ± 78.8
        Change at LTE Month 24 (n=48)
    72.7 ± 94.4
        Change at LTE Month 36 (n=49)
    64.2 ± 93.3
        Change at LTE Month 48 (n=42)
    69.1 ± 104.5
        Change at LTE Month 60 (n=40)
    55.1 ± 102.2
        Change at LTE Month 72 (n=36)
    57.8 ± 103.6
        Change at LTE Month 84 (n=1)
    297 ± 99999
    Notes
    [8] - All subjects who entered the LTE phase.
    No statistical analyses for this end point

    Secondary: Number of Subjects With World Health Organization (WHO) Functional Class Assessment at Specified Time Points

    Close Top of page
    End point title
    Number of Subjects With World Health Organization (WHO) Functional Class Assessment at Specified Time Points
    End point description
    The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (subjects with pulmonary hypertension but without resulting limitation of physical activity) to class IV (subjects with pulmonary hypertension with inability to carry out any physical activity without symptoms. These subjects manifest signs of right-heart failure). In the below table, 'n' signifies the number of subjects evaluable for the corresponding time points.
    End point type
    Secondary
    End point timeframe
    Pre-study (<=1 week prior to start of study), Day 84 (end of main study), LTE Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, and 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    68 [9]
    Units: Subjects
        Pre-study: WHO Functional Class I (n=68)
    0
        Pre-study: WHO Functional Class II (n=68)
    14
        Pre-study: WHO Functional Class III (n=68)
    53
        Pre-study: WHO Functional Class IV (n=68)
    1
        Day 84: WHO Functional Class I (n=68)
    2
        Day 84: WHO Functional Class II (n=68)
    30
        Day 84: WHO Functional Class III (n=68)
    36
        Day 84: WHO Functional Class IV (n=68)
    0
        LTE Month 3: WHO Functional Class I (n=62)
    2
        LTE Month 3: WHO Functional Class II (n=62)
    31
        LTE Month 3: WHO Functional Class III (n=62)
    28
        LTE Month 3: WHO Functional Class IV (n=62)
    1
        LTE Month 6: WHO Functional Class I (n=56)
    2
        LTE Month 6: WHO Functional Class II (n=56)
    29
        LTE Month 6: WHO Functional Class III (n=56)
    25
        LTE Month 6: WHO Functional Class IV (n=56)
    0
        LTE Month 9: WHO Functional Class I (n=52)
    4
        LTE Month 9: WHO Functional Class II (n=52)
    27
        LTE Month 9: WHO Functional Class III (n=52)
    21
        LTE Month 9: WHO Functional Class IV (n=52)
    0
        LTE Month 12: WHO Functional Class I (n=53)
    3
        LTE Month 12: WHO Functional Class II (n=53)
    27
        LTE Month 12: WHO Functional Class III (n=53)
    23
        LTE Month 12: WHO Functional Class IV (n=53)
    0
        LTE Month 15: WHO Functional Class I (n=53)
    3
        LTE Month 15: WHO Functional Class II (n=53)
    26
        LTE Month 15: WHO Functional Class III (n=53)
    24
        LTE Month 15: WHO Functional Class IV (n=53)
    0
        LTE Month 18: WHO Functional Class I (n=52)
    3
        LTE Month 18: WHO Functional Class II (n=52)
    25
        LTE Month 18: WHO Functional Class III (n=52)
    24
        LTE Month 18: WHO Functional Class IV (n=52)
    0
        LTE Month 21: WHO Functional Class I (n=51)
    3
        LTE Month 21: WHO Functional Class II (n=51)
    28
        LTE Month 21: WHO Functional Class III (n=51)
    18
        LTE Month 21: WHO Functional Class IV (n=51)
    2
        LTE Month 24: WHO Functional Class I (n=49)
    3
        LTE Month 24: WHO Functional Class II (n=49)
    29
        LTE Month 24: WHO Functional Class III (n=49)
    17
        LTE Month 24: WHO Functional Class IV (n=49)
    0
        LTE Month 27: WHO Functional Class I (n=51)
    3
        LTE Month 27: WHO Functional Class II (n=51)
    29
        LTE Month 27: WHO Functional Class III (n=51)
    19
        LTE Month 27: WHO Functional Class IV (n=51)
    0
        LTE Month 30: WHO Functional Class I (n=51)
    2
        LTE Month 30: WHO Functional Class II (n=51)
    29
        LTE Month 30: WHO Functional Class III (n=51)
    20
        LTE Month 30: WHO Functional Class IV (n=51)
    0
        LTE Month 33: WHO Functional Class I (n=50)
    2
        LTE Month 33: WHO Functional Class II (n=50)
    31
        LTE Month 33: WHO Functional Class III (n=50)
    17
        LTE Month 33: WHO Functional Class IV (n=50)
    0
        LTE Month 36: WHO Functional Class I (n=50)
    3
        LTE Month 36: WHO Functional Class II (n=50)
    30
        LTE Month 36: WHO Functional Class III (n=50)
    17
        LTE Month 36: WHO Functional Class IV (n=50)
    0
        LTE Month 39: WHO Functional Class I (n=50)
    3
        LTE Month 39: WHO Functional Class II (n=50)
    25
        LTE Month 39: WHO Functional Class III (n=50)
    22
        LTE Month 39: WHO Functional Class IV (n=50)
    0
        LTE Month 42: WHO Functional Class I (n=48)
    3
        LTE Month 42: WHO Functional Class II (n=48)
    23
        LTE Month 42: WHO Functional Class III (n=48)
    22
        LTE Month 42: WHO Functional Class IV (n=48)
    0
        LTE Month 45: WHO Functional Class I (n=47)
    3
        LTE Month 45: WHO Functional Class II (n=47)
    25
        LTE Month 45: WHO Functional Class III (n=47)
    18
        LTE Month 45: WHO Functional Class IV (n=47)
    1
        LTE Month 48: WHO Functional Class I (n=44)
    3
        LTE Month 48: WHO Functional Class II (n=44)
    25
        LTE Month 48: WHO Functional Class III (n=44)
    16
        LTE Month 48: WHO Functional Class IV (n=44)
    0
        LTE Month 51: WHO Functional Class I (n=44)
    3
        LTE Month 51: WHO Functional Class II (n=44)
    27
        LTE Month 51: WHO Functional Class III (n=44)
    14
        LTE Month 51: WHO Functional Class IV (n=44)
    0
        LTE Month 54: WHO Functional Class I (n=42)
    4
        LTE Month 54: WHO Functional Class II (n=42)
    25
        LTE Month 54: WHO Functional Class III (n=42)
    13
        LTE Month 54: WHO Functional Class IV (n=42)
    0
        LTE Month 57: WHO Functional Class I (n=42)
    4
        LTE Month 57: WHO Functional Class II (n=42)
    23
        LTE Month 57: WHO Functional Class III (n=42)
    14
        LTE Month 57: WHO Functional Class IV (n=42)
    1
        LTE Month 60: WHO Functional Class I (n=41)
    3
        LTE Month 60: WHO Functional Class II (n=41)
    23
        LTE Month 60: WHO Functional Class III (n=41)
    15
        LTE Month 60: WHO Functional Class IV (n=41)
    0
        LTE Month 63: WHO Functional Class I (n=41)
    3
        LTE Month 63: WHO Functional Class II (n=41)
    22
        LTE Month 63: WHO Functional Class III (n=41)
    15
        LTE Month 63: WHO Functional Class IV (n=41)
    1
        LTE Month 66: WHO Functional Class I (n=39)
    4
        LTE Month 66: WHO Functional Class II (n=39)
    21
        LTE Month 66: WHO Functional Class III (n=39)
    14
        LTE Month 66: WHO Functional Class IV (n=39)
    0
        LTE Month 69: WHO Functional Class I (n=38)
    3
        LTE Month 69: WHO Functional Class II (n=38)
    23
        LTE Month 69: WHO Functional Class III (n=38)
    12
        LTE Month 69: WHO Functional Class IV (n=38)
    0
        LTE Month 72: WHO Functional Class I (n=37)
    3
        LTE Month 72: WHO Functional Class II (n=37)
    21
        LTE Month 72: WHO Functional Class III (n=37)
    13
        LTE Month 72: WHO Functional Class IV (n=37)
    0
        LTE Month 75: WHO Functional Class I (n=33)
    4
        LTE Month 75: WHO Functional Class II (n=33)
    18
        LTE Month 75: WHO Functional Class III (n=33)
    11
        LTE Month 75: WHO Functional Class IV (n=33)
    0
        LTE Month 78: WHO Functional Class I (n=19)
    1
        LTE Month 78: WHO Functional Class II (n=19)
    7
        LTE Month 78: WHO Functional Class III (n=19)
    11
        LTE Month 78: WHO Functional Class IV (n=19)
    0
        LTE Month 81: WHO Functional Class I (n=10)
    1
        LTE Month 81: WHO Functional Class II (n=10)
    4
        LTE Month 81: WHO Functional Class III (n=10)
    5
        LTE Month 81: WHO Functional Class IV (n=10)
    0
        LTE Month 84: WHO Functional Class I (n=2)
    1
        LTE Month 84: WHO Functional Class II (n=2)
    0
        LTE Month 84: WHO Functional Class III (n=2)
    1
        LTE Month 84: WHO Functional Class IV (n=2)
    0
    Notes
    [9] - All subjects who entered the LTE phase.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Echocardiographic Results - Tei Index at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Echocardiographic Results - Tei Index at Day 84 in the Main Study
    End point description
    Tei index = myocardial performance index (isovolumic contraction time plus isovolumic relaxation time divided by right ventricular ejection time). In the below table, 'n' signifies the number of subjects evaluable for the corresponding time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    72 [10]
    Units: Ratio
    arithmetic mean (standard deviation)
        Baseline (n=46)
    0.708 ± 0.341
        Change at Day 84 (n=35)
    -0.176 ± 0.28
    Notes
    [10] - PK/PD set (main study).
    No statistical analyses for this end point

    Secondary: Change From Baseline in Echocardiographic Results - Pulmonary Arterial Systolic Pressure (PASP) at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Echocardiographic Results - Pulmonary Arterial Systolic Pressure (PASP) at Day 84 in the Main Study
    End point description
    PASP is composed of the right ventricular systolic pressure as measured over the tricuspid regurgitation jet (4xtricuspid regurgitation jet peak velocity) plus the systolic venous pressure according to width of the vena cava inferior measured in M-mode. In the below table, 'n' signifies the number of subjects evaluable for the corresponding time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    72 [11]
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n=65)
    73.6 ± 20.6
        Change at Day 84 (n=58)
    -6.9 ± 16.7
    Notes
    [11] - PK/PD set (main study).
    No statistical analyses for this end point

    Secondary: Change From Baseline in Echocardiographic Results - Tricuspid Annular Plane Systolic Excursion (TAPSE) at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Echocardiographic Results - Tricuspid Annular Plane Systolic Excursion (TAPSE) at Day 84 in the Main Study
    End point description
    In a modified apical 4-chamber view, the excursions of the tricuspid annular plane were measured by positioning the M-mode cursor on the lateral portion of the tricuspid annulus; this movement reflected the base to apex shortening of the right ventricle in systole; movement >2 centimeters (cm) indicates good contraction, 12 cm indicate poor contraction, and less than (<) 1 cm indicates heart failure. In the below table, 'n' signifies the number of subjects evaluable for the corresponding time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    72 [12]
    Units: centimeters
    arithmetic mean (standard deviation)
        Baseline (n=64)
    1.741 ± 0.586
        Change at Day 84 (n=59)
    0.276 ± 0.491
    Notes
    [12] - PK/PD set (main study).
    No statistical analyses for this end point

    Secondary: Change From Baseline in Swan-Ganz Hemodynamic Parameters - Blood/Artery/Atrial/Capillary Pressure at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Swan-Ganz Hemodynamic Parameters - Blood/Artery/Atrial/Capillary Pressure at Day 84 in the Main Study
    End point description
    The following Swan-Ganz hemodynamic parameters related to blood/artery/atrial/capillary pressure during right heart catheterization were measured: mean right atrial pressure (RAPmean), systolic pulmonary artery pressure (PAPsyst), diastolic pulmonary artery pressure (PAPdiast), mean pulmonary artery pressure (PAPmean), pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP). In the below table, 'n' signifies the number of subjects evaluable for the respective outcomes at that time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    50 [13]
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline: RAPmean (n=50)
    6.6 ± 4.3
        Change at Day 84: RAPmean (n=50)
    0.3 ± 5.2
        Baseline: PAPsyst (n=50)
    77.5 ± 15.1
        Change at Day 84: PAPsyst (n=48)
    -7.3 ± 14.1
        Baseline: PAPdiast (n=50)
    27.5 ± 10.9
        Change at Day 84: PAPdiast (n=48)
    -4.8 ± 9.2
        Baseline: PAPmean (n=50)
    45.3 ± 10.8
        Change at Day 84: PAPmean (n=50)
    -5.3 ± 8.6
        Baseline: PCWP (n=50)
    8 ± 4.2
        Change at Day 84: PCWP (n=50)
    1.2 ± 4.4
        Baseline: SBP (n=47)
    129.3 ± 19.3
        Change at Day 84: SBP (n=47)
    -7.5 ± 18.2
        Baseline: DBP (n=47)
    78.4 ± 12.8
        Change at Day 84: DBP (n=47)
    -7.2 ± 14.2
        Baseline: MAP (n=45)
    95.5 ± 16.6
        Change at Day 84: MAP (n=45)
    -5.3 ± 17.7
    Notes
    [13] - PK/PD population (main study) with available measurements for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Swan-Ganz Hemodynamic Parameters - Heart Rate at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Swan-Ganz Hemodynamic Parameters - Heart Rate at Day 84 in the Main Study
    End point description
    Heart rate was measured during right heart catheterization. In the below table, 'n' signifies the number of subjects evaluable at the corresponding time points.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    50 [14]
    Units: beats per minute
    arithmetic mean (standard deviation)
        Baseline (n=49)
    77 ± 12.1
        Change at Day 84 (n=50)
    0.9 ± 11.8
    Notes
    [14] - PK/PD population (main study) with available measurements for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Swan-Ganz Hemodynamic Parameters - Vascular Resistance at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Swan-Ganz Hemodynamic Parameters - Vascular Resistance at Day 84 in the Main Study
    End point description
    Systemic and pulmonary vascular resistance parameters were calculated as follows: Systemic vascular resistance (SVR)=80*(MAP RAPmean)/cardiac output, and pulmonary vascular resistance (PVR)=80*(PAPmean PCWP)/cardiac output. SVR and PVR were expressed in dyne*second*centimeter^5. 1 dyne=1 gram*centimeter*second^2= 10^5 Newton. In the below table, 'n' signifies the number of subjects evaluable for the respective outcomes at that time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    50 [15]
    Units: dyne*second*centimeter^5
    arithmetic mean (standard deviation)
        Baseline: SVR (n=45)
    1815 ± 638
        Change at Day 84: SVR (n=44)
    -399 ± 589
        Baseline: PVR (n=50)
    778 ± 351
        Change at Day 84: PVR (n=48
    -253 ± 209
    Notes
    [15] - PK/PD population (main study) with available measurements for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Swan-Ganz Hemodynamic Parameters - Percentage Vascular Resistance Ratio at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Swan-Ganz Hemodynamic Parameters - Percentage Vascular Resistance Ratio at Day 84 in the Main Study
    End point description
    Ratio of PVR/SVR was reported in terms of percentage. SVR=80*(MAP-RAPmean)/cardiac output, and PVR=80*(PAPmean-PCWP)/cardiac output. In the below table, 'n' signifies the number of subjects evaluable at the corresponding time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    50 [16]
    Units: Percentage of Ratio
    arithmetic mean (standard deviation)
        Baseline (n=45)
    45.2 ± 15.8
        Change at Day 84 (n=44)
    -6.2 ± 14.5
    Notes
    [16] - PK/PD population (main study) with available measurements for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Swan-Ganz Hemodynamic Parameters - Vascular Resistance Index at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Swan-Ganz Hemodynamic Parameters - Vascular Resistance Index at Day 84 in the Main Study
    End point description
    Systemic and pulmonary vascular resistance indices were calculated as follows: SVR index (SVRI)=80*(MAP-RAPmean)/cardiac output*body surface area, and PVR index (PVRI)=80*(PAPmean PCWP)/cardiac output*body surface area. SVRI and PVRI were expressed in dyne*second*centimeter^5*square meter. 1 dyne=1 gram*centimeter*second^2= 10^5 Newton. In the below table, 'n' signifies the number of subjects evaluable for the respective outcomes at that time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    50 [17]
    Units: dyne*second*centimeter^5* square meter
    arithmetic mean (standard deviation)
        Baseline: SVRI (n=45)
    3380 ± 1081
        Change at Day 84: SVRI (n=44)
    -736 ± 1125
        Baseline: PVRI (n=50)
    1436 ± 615
        Change at Day 84: PVRI (n=48)
    -466 ± 385
    Notes
    [17] - PK/PD population (main study) with available measurements for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Swan-Ganz Hemodynamic Parameters - Cardiac Output at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Swan-Ganz Hemodynamic Parameters - Cardiac Output at Day 84 in the Main Study
    End point description
    Cardiac output was measured in triplicate, performed and calculated by cardiac output device. In the below table, 'n' signifies the number of subjects evaluable at the corresponding time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    50 [18]
    Units: liter per minute
    arithmetic mean (standard deviation)
        Baseline (n=50)
    4.2 ± 1.2
        Change at Day 84 (n=48)
    0.88 ± 0.98
    Notes
    [18] - PK/PD population (main study) with available measurements for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Swan-Ganz Hemodynamic Parameters - Cardiac Index at Day 84 in the Main Study

    Close Top of page
    End point title
    Change From Baseline in Swan-Ganz Hemodynamic Parameters - Cardiac Index at Day 84 in the Main Study
    End point description
    Cardiac index = cardiac output / body surface area. In the below table, 'n' signifies the number of subjects evaluable at the corresponding time points. Please find the statistical analyses in the attachment below.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of study) and Day 84
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    50 [19]
    Units: liter per minute per square meter
    arithmetic mean (standard deviation)
        Baseline (n=50)
    2.24 ± 0.59
        Change at Day 84 (n=48)
    0.48 ± 0.51
    Notes
    [19] - PK/PD population (main study) with available measurements for this endpoint.
    No statistical analyses for this end point

    Secondary: Change From Baseline in N-terminal Pro-hormone B-type Natriuretic Peptide (NT-proBNP) Levels at Specified Time Points

    Close Top of page
    End point title
    Change From Baseline in N-terminal Pro-hormone B-type Natriuretic Peptide (NT-proBNP) Levels at Specified Time Points
    End point description
    In the below table, 'n' signifies the number of subjects evaluable for the respective outcomes at that time points.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-study defined as <=1 week prior to start of main study), Day 84 (end of main study), LTE Months 12, 24, 36, 48, 60, and 69
    End point values
    Riociguat (Adempas, BAY63-2521) Main Study
    Number of subjects analysed
    72 [20]
    Units: picogram per milliliter
    arithmetic mean (standard deviation)
        Baseline (n=53)
    9081 ± 5204
        Change at Day 84 (n=51)
    -1736 ± 2952
        Change at LTE Month 12 (n=36)
    -1334 ± 4138
        Change at LTE Month 24 (n=37)
    -214 ± 3342
        Change at LTE Month 36 (n=37)
    305 ± 5305
        Change at LTE Month 48 (n=34)
    2169 ± 8072
        Change at LTE Month 60 (n=24)
    2636 ± 7277
        Change at LTE Month 69 (n=0)
    99999 ± 99999
    Notes
    [20] - PK/PD set (main study).
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From time of an AE that began while the subject was taking study treatment or up to 2 days after the end of study treatment
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Riociguat (Adempas, BAY63-2521)
    Reporting group description
    Subjects received Riociguat (Adempas, BAY63-2521) immediate release (IR) tablets with biweekly titrations of doses starting from 1.0 milligram (mg) thrice in a day (TID) up to 2.5 mg TID in steps of plus (+) 0.5 mg according to safety and tolerability (mainly peripheral systolic blood pressure) for 12 weeks. Subjects who were willing to continue, entered the long-term extension (LTE) phase until the premature termination of product development or until official approval and commercial availability of BAY63-2521 at a minimum dose of 0.5 mg TID and maximum dose of 2.5 mg TID.

    Serious adverse events
    Riociguat (Adempas, BAY63-2521)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    54 / 68 (79.41%)
         number of deaths (all causes)
    13
         number of deaths resulting from adverse events
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Abscess drainage
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angioplasty
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lung transplant
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bilevel positive airway pressure
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Large intestinal polypectomy
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mechanical ventilation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary endarterectomy
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Uterine leiomyoma
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hernia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorder postoperative
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal column injury
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheterisation cardiac
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular resistance pulmonary increased
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic right ventricular failure
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences causally related to treatment / all
    2 / 14
         deaths causally related to treatment / all
    0 / 1
    Right ventricular failure
         subjects affected / exposed
    13 / 68 (19.12%)
         occurrences causally related to treatment / all
    0 / 20
         deaths causally related to treatment / all
    0 / 5
    Cor pulmonale
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 68 (4.41%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    9 / 68 (13.24%)
         occurrences causally related to treatment / all
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    13 / 68 (19.12%)
         occurrences causally related to treatment / all
    2 / 14
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    14 / 68 (20.59%)
         occurrences causally related to treatment / all
    6 / 36
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Crohn's disease
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Gingival bleeding
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cardiac cirrhosis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Riociguat (Adempas, BAY63-2521)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 68 (94.12%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Hypotension
         subjects affected / exposed
    24 / 68 (35.29%)
         occurrences all number
    32
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    6
    Fatigue
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    11
    Oedema
         subjects affected / exposed
    19 / 68 (27.94%)
         occurrences all number
    29
    Oedema peripheral
         subjects affected / exposed
    30 / 68 (44.12%)
         occurrences all number
    59
    Peripheral swelling
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    9
    Depression
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Muscle strain
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Fall
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    9
    Atrial fibrillation
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    8
    Right ventricular failure
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Tachycardia
         subjects affected / exposed
    12 / 68 (17.65%)
         occurrences all number
    16
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 68 (17.65%)
         occurrences all number
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 68 (27.94%)
         occurrences all number
    22
    Dysphonia
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    5
    Dyspnoea
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    11
    Epistaxis
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    12
    Pleural effusion
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Pulmonary arterial hypertension
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Nasal congestion
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Pulmonary hypertension
         subjects affected / exposed
    13 / 68 (19.12%)
         occurrences all number
    16
    Respiratory failure
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    26 / 68 (38.24%)
         occurrences all number
    38
    Head discomfort
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Sciatica
         subjects affected / exposed
    7 / 68 (10.29%)
         occurrences all number
    7
    Headache
         subjects affected / exposed
    15 / 68 (22.06%)
         occurrences all number
    23
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    7 / 68 (10.29%)
         occurrences all number
    7
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    6
    Constipation
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    12
    Abdominal distension
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Abdominal pain
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Abdominal pain upper
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    11
    Gastritis
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    5
    Dyspepsia
         subjects affected / exposed
    23 / 68 (33.82%)
         occurrences all number
    33
    Diarrhoea
         subjects affected / exposed
    16 / 68 (23.53%)
         occurrences all number
    22
    Gastrooesophageal reflux disease
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    14
    Vomiting
         subjects affected / exposed
    14 / 68 (20.59%)
         occurrences all number
    18
    Nausea
         subjects affected / exposed
    12 / 68 (17.65%)
         occurrences all number
    16
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    6
    Rash
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 68 (10.29%)
         occurrences all number
    9
    Back pain
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences all number
    11
    Myalgia
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Osteoarthritis
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Musculoskeletal pain
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Muscle spasms
         subjects affected / exposed
    9 / 68 (13.24%)
         occurrences all number
    10
    Pain in extremity
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    11 / 68 (16.18%)
         occurrences all number
    13
    Iron deficiency
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Infections and infestations
    Gastrointestinal infection
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    10
    Gastroenteritis
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences all number
    12
    Bronchitis
         subjects affected / exposed
    13 / 68 (19.12%)
         occurrences all number
    20
    Nasopharyngitis
         subjects affected / exposed
    41 / 68 (60.29%)
         occurrences all number
    111
    Pneumonia
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Influenza
         subjects affected / exposed
    9 / 68 (13.24%)
         occurrences all number
    20
    Urinary tract infection
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    16
    Sinusitis
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    9
    Respiratory tract infection
         subjects affected / exposed
    15 / 68 (22.06%)
         occurrences all number
    35

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jan 2007
    After 2 subjects were enrolled, protocol was corrected for consistent requirements for biomarker samples.
    28 Mar 2007
    1. Further allowed concomitant medications added (and corresponding exclusion criterion deleted): calcium channel blockers given up to the dose approved for arterial hypertension, such as nifedipine up to 120 milligram per day (mg/day), diltiazem up to 360 mg/day, amlodipine up to 10 mg/day. 2. Additional laboratories for safety laboratory added due to new study centers. 3. PAPmean reduced from 30 to 25 millimeter of mercury as inclusion criterion. 4. Change in exclusion criteria: resting heart rate less than 55 beats per minute or more than 105 beats per minute. 5. Number of valid subjects to be treated increased to 25. 6. Optional openlabel extension phase introduced for subjects willing to stay on riociguat following the initial 12week treatment phase. 7. Cancellation of fasting period on Day 0. 8. Addition of troponin I as additional cardiac marker.
    08 May 2007
    1. Change of clinical phase to "clinical pharmacology study phase I/II". 2. Inclusion criteria: change of upper age limit from 65 to 75 years of age. 3. Inclusion criteria: change of upper limit of body mass index from 30 to 35 kilogram per square meter. 4. Exclusion criteria: increase of PCWP limit to >15 millimeter of mercury. 5. Correction of the Borg modified dyspnea score rating scale. 6. Shortening of final study visit procedures in subjects participating in the extension phase.
    16 Oct 2007
    1. Number of subjects to be treated increased to 60. 2. Interim analysis after 25 subjects completed the 12-week treatment phase. 3. Further allowed concomitant medications added (and corresponding exclusion criterion deleted): Bosentan. 4. After the availability of all data an unplanned analysis was performed including all subjects of the 12-week dose titration period to supply the most important information as soon as possible. 5. Box-Whisker-Plots are displayed instead of profile curves for PK concentrations.
    29 May 2008
    1. Supply of new riociguat tablets at doses of 1.0, 1.5, and 2.0 mg. 2. Introduction of the optional openlabel extension period to assess the longterm safety and tolerability of riociguat in subjects having completed the main study as study objective. 3. Introduction of end of optional open label extension period visit and 6-monthly follow-up. 4. Introduction of events of special interests (death, heart/lung transplantation, arterial septostomy, pulmonary endarterectomy, start of new pulmonary hypertensionspecific treatment. 5. Subjects were to be withdrawn from the study in case of use of the following medications : – Unspecific phosphodiesterase (PDE) inhibitors, such as dipyridamole, theophylline, pentoxyfilline, enoximone, milrinone, or pimobendan. – Specific PDE inhibitors such as sildenafil, vardenafil, or tadalafil. – No donors, such as nitrates. 6. Introduction of additional warnings based on the results of clinical pharmacological studies: – Due to possible PK interactions between riociguat and strong cytochrome P450 3A4 inhibitors, such as ketoconazole, concomitant treatment was to be applied with caution, such as additional blood pressure monitoring. – Antacids like aluminum hydroxide/magnesium hydroxide, such as maaloxan, were not to be taken simultaneously with riociguat because a negative impact on the bioavailability of the study drug had been observed. To avoid such interaction, antacids were to be taken not before 1 hour after intake of riociguat.
    25 Mar 2010
    1. Smoking status questioning added to the protocol as riociguat clearance is increased in smokers compared to nonsmokers. 2. “Syncope” was defined as a safetyrelevant event of special interest and thus was to be reported as a serious adverse event. 3. Subject participation in another clinical trial was added as criterion for removal. 4. In the extension part of the study, the dose titration scheme was identical to that of the main study; however, in case that the 1 mg TID dose was not tolerated, the riociguat dose could be reduced to a minimum dose of 0.5 mg TID.
    13 Dec 2012
    1. Optional Open Label Extension Period (OOLEP) procedures were changed to facilitate studyrelated activities as follows: A separate subject information and informed consent form was added and was signed by all subjects participating in this period. Deviation of +/-14 days from the scheduled every 3 months visit added as permissible. Every 3 months visits no longer required smoking status, but a physical exam was performed and status of concomitant medication was determined 1 hour before study treatment. Laboratory sampling and electrocardiogram (ECG) were only to be performed locally at the investigator's discretion. Vital signs, modified Borg dyspnea score, PK sampling, and AE questioning were reduced. Return of all unused medication by the subject and dispensing of a 3-month supply of study medication was performed. The End of OOLEP Visit was 30 (+5) days after the last dose. WHO functional class, 6MWT, ECG, safety laboratory, troponin I, prohormone, modified Borg dyspnea score, and smoking status were no longer required at this visit; physical exam results, heart rate and blood pressure, and pregnancy test data if applicable were captured, and AEs and events of special interest were documented. Subjects who permanently stopped riociguat in the OOLEP due to reasons other than consent withdrawal were no longer required to be followed up; subjects were to return to the hospital for the End of OOLEP Visit. 2. ECG and laboratory test abnormalities as well as change in modified Borg dyspnea score was not to be analyzed due to data for these procedures in this trial period no longer being captured. 3. Premature termination of study or closure of center criterion added: “If subjects can be transferred to another trial or therapy program with riociguat which ensures that subjects benefit can be treated until the drug receives official approval and will be commercially available.” 4. A routine right heart catheterization was considered.
    03 Apr 2013
    After all subjects had already been enrolled, the following changes were made which concerned the Optional Extension Period and End of Open Label Extension Period Visit: 1. Recording of events of special interest (death, heart/lung transplantation, atrial septostomy, pulmonary endarterectomy, start of new PH specific treatment [endothelin antagonists, prostacyclin analogues, PDE type 5-inhibitors]) in this period was clarified as “With the exception of death (to be recorded on the end of study page), the first occurrence of each of the events of special interest was to be captured at each visit of the optional open label extension period and end of open label extension period visit (safety visit)”. 2. For the estimation of the combined endpoint “time to clinical worsening” in this period, the following clarifications were added: the first occurrence of events of special interest was to be considered and incidence tables of the overall rate were to be presented, together with the Kaplan-Meier survival curve. 3. Safety analyses in this period were clarified as “change-from-baseline analyses”.

    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.
    Decimal places were automatically truncated if last decimal equals zero.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA