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    Clinical Trial Results:
    An open-label, international, multicenter, single-arm, uncontrolled, phase IIIb study of riociguat in patients with PAH who demonstrate an insufficient response to treatment with phosphodiesterase-5 inhibitors (PDE-5i)

    Summary
    EudraCT number
    2013-001759-10
    Trial protocol
    DE   CZ   IT   BE   GB   FR  
    Global end of trial date
    29 Dec 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    13 Mar 2019
    First version publication date
    15 Dec 2017
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY63-2521/16719
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02007629
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen D-51368, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether it was safe, feasible and beneficial to replace phosphodiesterase-5 inhibitors (PDE-5i) therapy with Riociguat (BAY63-2521) in pulmonary arterial hypertension (PAH) subjects demonstrating insufficient response to PDE-5 inhibition.
    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 Council for 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. 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
    18 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 3
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    61
    EEA total number of subjects
    56
    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)
    46
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted in 20 study centers in Belgium, Czech Republic, France, Germany, Italy, Switzerland, United Kingdom, Canada, United States, Germany, between 18 February 2014 (first subject first visit) and 29 December 2016 (last subject last visit).

    Pre-assignment
    Screening details
    Overall, 79 subject were screened, of them 17 were screen failure and 1 withdrew consent; total 61 were assigned to pre-treatment phase (approximately 2 weeks) and treatment phase (titration phase [8 weeks] and maintenance phase [16 weeks]). Of 61 subjects, 51 completed treatment phase and 28 of them entered in an extended drug supply phase (EDSP).

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

    Arms
    Arm title
    Riociguat up to 2.5 mg tid (Main Phase)
    Arm description
    Subjects received riociguat film coated immediate-release (IR) tablet 3 times a day (tid) with or without food at a starting dose of 1.0 milligram (mg) and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase). An optimal dose was determined based on systolic blood pressure (SBP) and well-being. Thereafter, riociguat continued at the optimal individual dose until Week 24 (Main phase). Dose reductions or stop of study medication for safety reasons were allowed at any time. Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) were possible at the investigator’s discretion weighing the benefit with potential risks implied.
    Arm type
    Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received riociguat film coated IR tablet 3 tid with or without food at a starting dose of 1.0 mg and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase).

    Number of subjects in period 1
    Riociguat up to 2.5 mg tid (Main Phase)
    Started
    61
    Completed
    51
    Not completed
    10
         Death
    1
         Physician decision
    1
         Adverse event
    4
         Lack of efficacy
    1
         Consent withdrawn by subject
    3
    Period 2
    Period 2 title
    Extended Drug Supply Phase (EDSP)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Riociguat up to 2.5 mg tid EDSP
    Arm description
    Subjects were offered participation in EDSP and received riociguat 2.5 mg film coated IR tablet 3 tid with or without food for 18 months or until reimbursement.
    Arm type
    Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were offered participation in EDSP and received riociguat 2.5 mg film coated IR tablet 3 tid with or without food for 18 months or until reimbursement.

    Number of subjects in period 2 [1]
    Riociguat up to 2.5 mg tid EDSP
    Started
    28
    Completed
    28
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all subjects who completed the main phase were enrolled in EDSP. Subjects may continue to participate in EDSP of the study at the discretion of the investigator. The study drug was provided free of charge until market approval and reimbursement or at the longest for 18 months, whatever date occurs earlier.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat up to 2.5 mg tid (Main Phase)
    Reporting group description
    Subjects received riociguat film coated immediate-release (IR) tablet 3 times a day (tid) with or without food at a starting dose of 1.0 milligram (mg) and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase). An optimal dose was determined based on systolic blood pressure (SBP) and well-being. Thereafter, riociguat continued at the optimal individual dose until Week 24 (Main phase). Dose reductions or stop of study medication for safety reasons were allowed at any time. Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) were possible at the investigator’s discretion weighing the benefit with potential risks implied.

    Reporting group values
    Riociguat up to 2.5 mg tid (Main Phase) Total
    Number of subjects
    61 61
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.9 ± 13.8 -
    Gender categorical
    Units: Subjects
        Female
    45 45
        Male
    16 16
    World Health Organization Functional Class (WHO FC)
    WHO FC assessment of PAH ranged from functional class I (subjects with pulmonary hypertension [PH] but without resulting limitation of physical activity); class II (subjects with PH resulting in slight limitation of physical activity); class III (subjects with PH resulting in marked limitation of physical activity); class IV (subjects with PH with inability to carry out any physical activity without symptoms); and class V death. Changes to a lower WHO FC resemble improvement; changes to a higher functional class resemble deterioration of PAH.
    Units: Subjects
        Class I
    0 0
        Class II
    0 0
        Class III
    61 61
        Class IV
    0 0
        Class V
    0 0
    Number of subjects with and without idiopathic PAH
    Number of subjects with and without idiopathic PAH at baseline were reported.
    Units: Subjects
        With idiopathic PAH
    56 56
        Without idiopathic PAH
    5 5
    Number of subjects receiving sildenafil and tadalafil
    Number of subjects receiving sildenafil and tadalafil before entering RESPITE were reported.
    Units: Subjects
        Subjects receiving sildenafil
    40 40
        Subjects receiving tadalafil
    21 21
    Number of subjects with and without endothelin receptor antagonists (ERAs) therapy
    Number of subjects with and without ERAs therapy at baseline evaluation were reported.
    Units: Subjects
        With ERAs therapy
    50 50
        Without ERAs therapy
    11 11
    Six-Minute Walking Distance (6MWD) Test
    6MWD test was used to measure the subjects functional exercise capacity. Subjects were instructed to walk alone, not run, from one end to the other end of the walking course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. No “warm-up” period was performed before the test. Investigators have not walked with the subjects. This was an encouraged test (the person conducting the test encouraged subjects to walk farther or faster by using only standardized phrases). 61 subjects performed the 6MWD test at baseline.
    Units: meter
        arithmetic mean (standard deviation)
    356.93 ± 80.58 -
    Cardiac Index
    The cardiac output was measured by using the thermodilution methodology and a respective electronic device. 50 subjects performed the cardiac index test at baseline. The cardiac index was assessed by dividing the cardiac output by the person’s body surface area (BSA).
    Units: liters per minute per square meter
        arithmetic mean (standard deviation)
    2.32 ± 0.42 -
    Pulmonary vascular resistance (PVR)
    Baseline value of PVR was calculated in 51 subjects.
    Units: dyne*second*centimeter^-5
        arithmetic mean (standard deviation)
    835.36 ± 272.33 -
    N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP)
    Baseline value of NT-proBNP was calculated in 61 subjects.
    Units: picogram per milliliter (pg/mL)
        arithmetic mean (standard deviation)
    1189.62 ± 1827.76 -
    EuroQol questionnaire (EQ-5D)
    EQ-5D was a standardized instrument which was used to measure the health outcome. The EQ-5D was a selfreport questionnaire and need to be completed by the subject. After the subject has filled in the questionnaire, the questionnaire was transferred into the electronic case report form (eCRF). EQ-5D was calculated by two types of questionnaires Part A (descriptive health profile) and Part B (visual analogue scale).
    Units: score on a scale
        arithmetic mean (standard deviation)
    62 ± 17.7 -

    End points

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    End points reporting groups
    Reporting group title
    Riociguat up to 2.5 mg tid (Main Phase)
    Reporting group description
    Subjects received riociguat film coated immediate-release (IR) tablet 3 times a day (tid) with or without food at a starting dose of 1.0 milligram (mg) and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase). An optimal dose was determined based on systolic blood pressure (SBP) and well-being. Thereafter, riociguat continued at the optimal individual dose until Week 24 (Main phase). Dose reductions or stop of study medication for safety reasons were allowed at any time. Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) were possible at the investigator’s discretion weighing the benefit with potential risks implied.
    Reporting group title
    Riociguat up to 2.5 mg tid EDSP
    Reporting group description
    Subjects were offered participation in EDSP and received riociguat 2.5 mg film coated IR tablet 3 tid with or without food for 18 months or until reimbursement.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    FAS (N=61) included all subjects who were included in the study, were assigned to study treatment, and received at least one dose of study drug.

    Primary: Change From Baseline in 6 Minute Walking Distance (6MWD)

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    End point title
    Change From Baseline in 6 Minute Walking Distance (6MWD) [1]
    End point description
    6MWD test was used to measure the subjects functional exercise capacity. Subjects were instructed to walk alone, not run, from one end to the other end of the walking course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. No “warm-up” period was performed before the test. Investigators have not walked with the subjects. This was an encouraged test (the person conducting the test encouraged subjects to walk farther or faster by using only standardized phrases). In the below table 'n' signifies number of evaluable subjects for the respective category.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12 and Week 24
    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: No formal statistical testing was planned.
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    52 [2]
    Units: meter
    arithmetic mean (standard deviation)
        Change at Week 12 (n=52)
    26.95 ± 58.23
        Change at Week 24 (n=51)
    34.28 ± 61.49
    Notes
    [2] - FAS with evaluable subjects for this end point.
    No statistical analyses for this end point

    Other pre-specified: Change From Pre-treatment in 6 Minute Walking Distance (6MWD)

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    End point title
    Change From Pre-treatment in 6 Minute Walking Distance (6MWD)
    End point description
    6MWD test was used to measure the subjects functional exercise capacity. Subjects were instructed to walk alone, not run, from one end to the other end of the walking course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. No “warm-up” period was performed before the test. Investigators have not walked with the subjects. This was an encouraged test (the person conducting the test encouraged subjects to walk farther or faster by using only standardized phrases). In the below table 'n' signifies number of evaluable subjects for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Pre-treatment, Week 12 and Week 24
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    52 [3]
    Units: meter
    arithmetic mean (standard deviation)
        Change at Week 12 (n=52)
    24.42 ± 57.28
        Change at Week 24 (n=51)
    31 ± 63.32
    Notes
    [3] - FAS with evaluable subjects for this end point.
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Cardiac Index

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    End point title
    Change From Baseline in Cardiac Index
    End point description
    The cardiac output was measured by using the thermodilution methodology and a respective electronic device. The cardiac index was assessed by dividing the cardiac output by the person’s BSA.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 24
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    48 [4]
    Units: liter per minute per square meter
    arithmetic mean (standard deviation)
        Change at Week 24
    0.32 ± 0.53
    Notes
    [4] - FAS with evaluable subjects for this end point.
    No statistical analyses for this end point

    Other pre-specified: Change From Pre-treatment in N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP)

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    End point title
    Change From Pre-treatment in N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP)
    End point description
    NT-proBNP cardiac biomarker was used to detect, diagnose, and evaluate the severity of heart failure. A higher level of the marker was indicative of heart failure. In the below table 'n' signifies number of evaluable subjects for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    54 [5]
    Units: picogram per milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Change at Week 12 (n=54)
    -77.17 ± 1251.99
        Change at Week 24 (n=52)
    -347.12 ± 1235.21
    Notes
    [5] - FAS with evaluable subjects for this end point.
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in World Health Organization Functional Class (WHO FC)

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    End point title
    Change From Baseline in World Health Organization Functional Class (WHO FC)
    End point description
    WHO FC assessment of PAH ranged from functional class I (subjects with PH but without resulting limitation of physical activity); class II (subjects with PH resulting in slight limitation of physical activity); class III (subjects with PH resulting in marked limitation of physical activity); class IV (subjects with PH with inability to carry out any physical activity without symptoms); and class V death. Changes to a lower WHO FC resemble improvement; changes to a higher functional class resemble deterioration of PAH. In the below table 'n' signifies number of evaluable subjects for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    54 [6]
    Units: subjects
        Change at Week 12 (n=54): WHO FC -2
    1
        Change at Week 12 (n=54): WHO FC -1
    26
        Change at Week 12 (n=54): WHO FC 0
    27
        Change at Week 12 (n=54): WHO FC 1
    0
        Change at Week 12 (n=54): WHO FC 2
    0
        Change at Week 24 (n=52): WHO FC -2
    1
        Change at Week 24 (n=52): WHO FC -1
    27
        Change at Week 24 (n=52): WHO FC 0
    24
        Change at Week 24 (n=52): WHO FC 1
    0
        Change at Week 24 (n=52): WHO FC 2
    0
    Notes
    [6] - FAS with evaluable subjects for this end point.
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Clinical Worsening

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    End point title
    Percentage of Subjects With Clinical Worsening
    End point description
    Clinical worsening was defined as death (all-cause mortality); atrial septostomy; lung transplantation; non-planned PAH-related hospitalisation; start of new PAH treatment (ERA, inhaled or oral prostanoid) or modification of pre-existing treatment, initiation of intravenous or subcutaneous prostanoids; persistent decrease of greater than (>) 15% from baseline or >30% from last measurement in 6MWD; persistent worsening of WHO FC; or appearance or worsening of signs/symptoms of right heart failure not responding to optimised oral diuretic therapy. All identified and suspected clinical worsening events were confirmed by independent central adjudication.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 24
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    61 [7]
    Units: percentage of subjects
        number (not applicable)
    9.8
    Notes
    [7] - FAS
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in European Quality of life (Qol)-Group (EQ)-5D Questionnaire

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    End point title
    Change From Baseline in European Quality of life (Qol)-Group (EQ)-5D Questionnaire
    End point description
    EQ-5D was a standardized instrument which was used to measure the health outcome. The EQ-5D was a selfreport questionnaire and needed to be completed by the subject. After the subject filled in the questionnaire, the questionnaire was transferred into the electronic case report form (eCRF). EQ-5D was calculated by two types of questionnaires Part A (descriptive health profile) and Part B (visual analogue scale). Part A, EQ-5D comprised 5-item questionnaires to measure own health profile status (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each measure has three levels (1. no problems, 2. some problems, 3. extreme problems). In Part B, visual analogue rating scale to measure how good or bad a health state was. Scale was drawn by using thermometer-like scale, on which the best state imagine was marked as 100 and worst state imagine was marked as 0. In the below table 'n' signifies number of evaluable subjects for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    52 [8]
    Units: score on a scale
    arithmetic mean (standard deviation)
        EQ-5D-Visual Analog Scale:Change at Week 12 (n=52)
    6.1 ± 15.4
        EQ-5D-Visual Analog Scale:Change at Week 24 (n=52)
    6.5 ± 19.4
        EQ-5D-Utility score: Change at Week 12 (n=51)
    0.07 ± 0.29
        EQ-5D-Utility score: Change at Week 24 (n=52)
    0.07 ± 0.28
    Notes
    [8] - FAS with evaluable subjects for this end point.
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects Without Clinical Worsening who Achieve at Least WHO FC II and an Improvement in 6 MWD of Greater Than or Equal to (>=) 30 meters

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    End point title
    Percentage of Subjects Without Clinical Worsening who Achieve at Least WHO FC II and an Improvement in 6 MWD of Greater Than or Equal to (>=) 30 meters
    End point description
    Percentage of subjects without clinical worsening who achieve at least who FC II and an improvement in 6 MWD of >= 30 meters were reported. In the below table 'n' signifies number of evaluable subjects for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Riociguat up to 2.5 mg tid (Main Phase)
    Number of subjects analysed
    54 [9]
    Units: percentage of subjects
    number (not applicable)
        WHO FC II, Week 12: No (n=27)
    50
        WHO FC II, Week 12: Yes (n=27)
    50
        WHO FC II, Week 24: No (n=24)
    46.2
        WHO FC II, Week 24: Yes (n=28)
    53.8
        6 MWD >=30 m, Week 12: No (n=24)
    46.2
        6 MWD >=30 m, Week 12: Yes (n=28)
    53.8
        6 MWD >=30 m, Week 24: No (n=25)
    49
        6 MWD >=30 m, Week 24: Yes (n=26)
    51
    Notes
    [9] - FAS with evaluable subjects for this end point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to 30 days after last study drug intake for main phase and from start of study treatment in EDSP up to the end of study in EDSP subjects
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Riociguat up to 2.5 mg tid Main phase
    Reporting group description
    Subjects received riociguat (BAY63-2521) film coated IR tablet tid with or without food at a starting dose of 1.0 mg and increased by 0.5 mg increments at 2-weekly intervals to a maximum of 2.5 mg tid, until Week 8 (titration phase). An optimal dose was determined based on SBP and well-being. Thereafter, riociguat continued at the optimal individual dose until Week 24 (Main phase). Dose reductions or stop of study medication for safety reasons were allowed at any time. Increases or re-increases in 0.5 mg steps (maximum dose 2.5 mg) were possible at the investigator’s discretion weighing the benefit with potential risks implied.

    Reporting group title
    Riociguat up to 2.5 mg tid EDSP
    Reporting group description
    Subjects were offered participation in EDSP and received riociguat 2.5 mg film coated IR tablet 3 tid with or without food for 18 months or until reimbursement. Treatment-emergent adverse events (TEAEs) during EDSP included either ongoing from main phase at the time of entry into EDSP or newly reported in EDSP.

    Serious adverse events
    Riociguat up to 2.5 mg tid Main phase Riociguat up to 2.5 mg tid EDSP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 61 (16.39%)
    7 / 28 (25.00%)
         number of deaths (all causes)
    5
    4
         number of deaths resulting from adverse events
    2
    3
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    Medical device change
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interventional procedure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Riociguat up to 2.5 mg tid Main phase Riociguat up to 2.5 mg tid EDSP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 61 (93.44%)
    23 / 28 (82.14%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Hypotension
         subjects affected / exposed
    9 / 61 (14.75%)
    2 / 28 (7.14%)
         occurrences all number
    10
    2
    Hypertension
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Colon adenoma
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Monoclonal gammopathy
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Chest discomfort
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Cyst
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    6 / 61 (9.84%)
    0 / 28 (0.00%)
         occurrences all number
    8
    0
    Feeling cold
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Injection site inflammation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Oedema
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Oedema peripheral
         subjects affected / exposed
    8 / 61 (13.11%)
    1 / 28 (3.57%)
         occurrences all number
    9
    1
    Pyrexia
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Puncture site haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Sensation of foreign body
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Haematospermia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Menorrhagia
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Haemorrhagic ovarian cyst
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Arthropod bite
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Overdose
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Subcutaneous haematoma
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Contusion
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Thermal burn
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Blood potassium decreased
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    International normalised ratio increased
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Respiratory rate increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Weight increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Occult blood positive
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Right ventricular failure
         subjects affected / exposed
    4 / 61 (6.56%)
    1 / 28 (3.57%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 28 (7.14%)
         occurrences all number
    6
    2
    Dyspnoea
         subjects affected / exposed
    6 / 61 (9.84%)
    4 / 28 (14.29%)
         occurrences all number
    6
    4
    Dyspnoea exertional
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 28 (7.14%)
         occurrences all number
    6
    4
    Haemoptysis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    3
    Hyperventilation
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Hypoxia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Pulmonary artery aneurysm
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Oropharyngeal discomfort
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 28 (3.57%)
         occurrences all number
    3
    2
    Increased tendency to bruise
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 61 (16.39%)
    0 / 28 (0.00%)
         occurrences all number
    11
    0
    Cervicobrachial syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Headache
         subjects affected / exposed
    12 / 61 (19.67%)
    3 / 28 (10.71%)
         occurrences all number
    18
    3
    Multiple sclerosis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    Sciatica
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2
    Balance disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Cataract
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Ear pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Abdominal pain lower
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 28 (7.14%)
         occurrences all number
    7
    2
    Constipation
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    11 / 61 (18.03%)
    4 / 28 (14.29%)
         occurrences all number
    14
    5
    Dyspepsia
         subjects affected / exposed
    13 / 61 (21.31%)
    4 / 28 (14.29%)
         occurrences all number
    13
    4
    Dysphagia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Haematochezia
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    5 / 61 (8.20%)
    3 / 28 (10.71%)
         occurrences all number
    6
    3
    Rectal haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    9 / 61 (14.75%)
    5 / 28 (17.86%)
         occurrences all number
    11
    6
    Colon dysplasia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Bladder disorder
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 28 (0.00%)
         occurrences all number
    4
    0
    Pruritus
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Psoriasis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Rash macular
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Skin lesion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    3
    Skin reaction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Telangiectasia
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Ingrown hair
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 28 (3.57%)
         occurrences all number
    3
    2
    Back pain
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Bone pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Muscle spasms
         subjects affected / exposed
    2 / 61 (3.28%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Musculoskeletal pain
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    3 / 61 (4.92%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Pain in jaw
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Fluid overload
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 28 (7.14%)
         occurrences all number
    4
    2
    Decreased appetite
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 28 (10.71%)
         occurrences all number
    2
    3
    Cellulitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Eye infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Laryngitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Mastitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    9 / 61 (14.75%)
    1 / 28 (3.57%)
         occurrences all number
    11
    1
    Sinusitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Catheter site infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    3
    Post viral fatigue syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Puncture site infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2014
    Following modifications were done in this amendment: 1: Changed sildenafil dose from 20 mg tid to 80 mg tid. 2: Reduced washout period for sildenafil from 3 to 1 day. It stayed 3 days for tadalafil. 3: Revised inclusion criteria: A. Subjects with associated PAH due to congenital heart disease were allowed to be enrolled. B. The upper limit for cardiac index as one of the criteria for insufficient response/not at treatment target was increased from <2.5 to <3.0 liter per minute per square meter (L/min/m2). Lower limit for pulmonary vascular resistance as an additional inclusion criterion was proportionally decreased from >480 to 400 dyne*second*centimeter^-5. C. Age range widened to include subjects up to 75 years old. 4: Following exclusion criteria revised: A -Moderate to severe bronchial asthma or chronic obstructive pulmonary disease and -Moderate to severe restrictive lung disease total lung capacity <70% predicted replaced with: -Evidence of clinically significant restrictive or obstructive parenchymal lung diseases in the judgment of the investigator (based on a clean computed tomography [CT] lung scan). B. The lower limit for diffusing capacity of lung for carbon monoxide as an exclusion criterion was decreased from 40 to 30% predicted. C. Previous treatment with riociguat was added as an exclusion criterion. 5: Revised withdrawal criteria: Subject diagnosed with pulmonary veno-occlusive disease while on treatment with study drug the administration of riociguat had to be stopped immediately. 6: Dose increase time during titration phase was increased to also allow increase at Visit 5 (Week 8). 7: LPH questionnaire was removed from the study procedures. 8: Corrected time periods definitions: Time periods of 3 months and 12 weeks were replaced by 90 days. 9: Syncope as special interest AE was replaced by symptomatic hypotension and hemoptysis. 10: Left atrial volume index was added as an additional echocardiogram parameter.
    27 Feb 2015
    Following modifications were done in this amendment: Modification 1: Added interim analysis: An interim analysis was added to evaluate clinical monitoring signals on efficacy and/or safety, which would be presented to the advisory board to support continued enrollment in the study, because experience of switching from PDE-5i in this patient population is very limited. Modification 2: Added time window for prior PDE-5i therapy: Time window of 7 days was added to the period of 90 days for prior PDE-5i therapy, to better adapt to routine clinical practice and to allow for more flexibility. Modification 3: Change of the sponsor’s medically responsible person: Sponsor’s medically responsible person was changed; therefore the name was updated on the signature page. Modification 4: Other text/inconsistencies corrections: In addition to the changes specified above the protocol text was corrected for better clarity and consistency.
    24 Feb 2016
    Following modifications were done in this amendment: Modification 1. The definition of end of study and the time point for reporting was clarified. The time point for the clinical study report is the last visit of the last subject in the main phase (maintenance phase up to Visit 7 at Week 24 including the safety follow-up visit, if applicable). The extended drug supply phase is considered an extension of the study and will be reported as an addendum to the study report. Modification 2. Addition of transition to long-term extension study: The option was implemented for subjects to transition to a separate long-term extension study at the end of the maintenance phase or during the extended drug supply phase. Modification 3: Change of the sponsor’s medically responsible person: Sponsor’s medically responsible person was changed; therefore the name was updated on the signature page. Modification 4. Clarification of applicability of the safety follow-up visit: It was clarified that the safety follow-up visit is applicable only for subjects who terminate the treatment prematurely or formally complete treatment according to protocol at Visit 7. Subjects continuing treatment after Visit 7 without treatment interruption in the extended drug supply phase of the study or in a Bayer/ Merck Sharp & Dohme (MSD-sponsored) riociguat long-term extension study or any other extended access program for riociguat are not required to come in for the safety follow-up visit.

    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.
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