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    Clinical Trial Results:
    Open-label, individual dose titration study to evaluate safety, tolerability and pharmacokinetics of riociguat in children from 6 to less than 18 years of age with pulmonary arterial hypertension (PAH)

    Summary
    EudraCT number
    2014-003952-29
    Trial protocol
    HU   IT   GB   DE   FR   ES   PL   Outside EU/EEA   BE   RO  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Sep 2020
    First version publication date
    19 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15681
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02562235
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000718-PIP01-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    07 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Mar 2020
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate safety, tolerability and pharmacokinetics of oral riociguat treatment
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects or their legally authorized representative. Subjects or legal representatives 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
    Subjects must be on standard of care PAH medications, allowing Endothelin Receptor Antagonists (ERA) and/or Prostacyclin Analogues (PCA), for at least 12 weeks prior to baseline visit.
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    11 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    24
    EEA total number of subjects
    12
    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)
    6
    Adolescents (12-17 years)
    18
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted at multiple centers in 9 countries or regions between 29-Oct-2015 (first subject first visit) and 07-Mar-2020 (last subject last visit of main study part).

    Pre-assignment
    Screening details
    A total of 26 subjects were screened. Of them, 2 subjects were screening failures and 24 subjects received study treatment.

    Period 1
    Period 1 title
    Baseline and main treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Riociguat >=6 to <18 years
    Arm description
    Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration of the dose for safety reasons was allowed at any time.
    Arm type
    Experimental

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    BAY63-2521
    Other name
    Pharmaceutical forms
    Granules for oral suspension, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For children with body-weight <50 kg at screening: body-weight adjusted dose equivalent to the exposure of (0.5 mg) 1.0 - 2.5 mg three times a day, IDT in adults treated for PAH; oral suspension. For children ≥50 kg at screening, 1.0 to 2.5 mg three times a day; oral tablet.

    Number of subjects in period 1
    Riociguat >=6 to <18 years
    Started
    24
    Completed
    21
    Not completed
    3
         Adverse event
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Riociguat >=6 to <18 years
    Reporting group description
    Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration of the dose for safety reasons was allowed at any time.

    Reporting group values
    Riociguat >=6 to <18 years Total
    Number of subjects
    24 24
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    12.8 ± 2.8 -
    Gender Categorical
    Units: Subjects
        Female
    11 11
        Male
    13 13
    Bone age compared to chronological age
    X-ray of left hand was performed for each subject and bone age was determined centrally by a specialist. For each subject, bone age was compared to chronological age and assessed as as "delayed, in accordance or advanced".
    Units: Subjects
        Delayed
    1 1
        In accordance
    12 12
        Advanced
    10 10
        Missing
    1 1
    WHO functional class
    The World Health Organization (WHO) functional class describes how severe a patient’s pulmonary hypertension (PH) symptoms are. There are four different classes – I is the mildest and IV the most severe form of PH.
    Units: Subjects
        Class I
    1 1
        Class II
    18 18
        Class III
    5 5
        Class IV
    0 0
    Heart rate
    Units: Beats per minute (BPM)
        arithmetic mean (standard deviation)
    84.5 ± 19.0 -
    Diastolic blood pressure
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    63.8 ± 7.9 -
    Systolic blood pressure
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    112.9 ± 10.9 -
    Respiratory Rate
    Number of subjects with respiration rate data at baseline: n=21
    Units: Breath per minute
        arithmetic mean (standard deviation)
    19.6 ± 4.4 -
    6-minute walking distance
    6-minute walking distance (6MWD) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. An increase in the distance walked indicates improvement in basic mobility. Number of subjects with 6MWD data at baseline: n=23
    Units: Meter
        arithmetic mean (standard deviation)
    442.12 ± 109.67 -
    N-terminal prohormone brain-type natriuretic peptide
    Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the subjects. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit. Number of subjects with NT-proBNP data at baseline: n=15
    Units: Picograms per milliliter (pg/mL)
        arithmetic mean (standard deviation)
    982.68 ± 1595.77 -
    Brain-type natriuretic peptide
    Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the subjects. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit. Number of subjects with BNP data at baseline: n=7
    Units: Picograms per milliliter (pg/mL)
        arithmetic mean (standard deviation)
    10.46 ± 9.10 -
    Quality of life evaluated by SF-10 questionnaire physical summary score
    SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored to produce physical and psychosocial health summary measures. Each of the 10 questions responses is scored with a point value from 1 to 6 (1 is the worst possible condition and 6 is the best possible condition). The SF-10 physical and psychosocial measures are scored such that higher scores indicate more favorable functioning.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    30.964 ± 13.335 -
    Quality of life evaluated by SF-10 questionnaire psychosocial summary score
    SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored to produce physical and psychosocial health summary measures. Each of the 10 questions responses is scored with a point value from 1 to 6 (1 is the worst possible condition and 6 is the best possible condition). The SF-10 physical and psychosocial measures are scored such that higher scores indicate more favorable functioning.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    48.765 ± 8.263 -
    Quality of life evaluated by PedsQL total scale score
    PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score, physical health summary score (physical functioning) and psychosocial health summary score (emotional, social and school functioning). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life. Number of subjects with data at baseline: n=21
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    69.77 ± 16.29 -
    Quality of life evaluated by PedsQL physical health summary score
    PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score, physical health summary score (physical functioning) and psychosocial health summary score (emotional, social and school functioning). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life. Number of subjects with data at baseline: n=21
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    64.43 ± 15.80 -
    Quality of life evaluated by PedsQL psychosocial health summary score
    PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score, physical health summary score (physical functioning) and psychosocial health summary score (emotional, social and school functioning). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life. Number of subjects with data at baseline: n=21
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    72.62 ± 19.20 -
    Estimate right atrial pressure
    Estimate right atrial pressure was measured by echocardiography. Number of subjects with estimate right atrial pressure data at baseline: n=18
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    9.2 ± 2.9 -
    Left ventricular eccentricity index
    Left ventricular eccentricity index was measured by echocardiography. Number of subjects with left ventricular eccentricity index data at baseline: n=17
    Units: Index
        arithmetic mean (standard deviation)
    2.099 ± 1.275 -
    Pulmonary artery acceleration time
    Pulmonary artery acceleration time was measured by echocardiography. Number of subjects with pulmonary artery acceleration time data at baseline: n=17
    Units: Millisecond (msec)
        arithmetic mean (standard deviation)
    91.568 ± 36.853 -
    Right ventricular cardiac index
    Right ventricular cardiac index was measured by echocardiography. Number of subjects with right ventricular cardiac index data at baseline: n=16
    Units: Liter/minute/square meter (L/min/m2)
        arithmetic mean (standard deviation)
    4.343 ± 1.599 -
    Right ventricular cardiac output
    Right ventricular cardiac output was measured by echocardiography. Number of subjects with right ventricular cardiac output data at baseline: n=16
    Units: Liter per minute (L/min)
        arithmetic mean (standard deviation)
    5.511 ± 2.093 -
    Right atrial diastolic area
    Right atrial diastolic area was measured by echocardiography. Number of subjects with right atrial diastolic area data at baseline: n=18
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    16.944 ± 11.071 -
    Right atrial diastolic area index
    Right atrial diastolic area index was measured by echocardiography. Number of subjects with right atrial diastolic area index data at baseline: n=18
    Units: Index
        arithmetic mean (standard deviation)
    12.788 ± 6.977 -
    Right atrial systolic area
    Right atrial systolic area was measured by echocardiography. Number of subjects with right atrial systolic area data at baseline: n=18
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    12.017 ± 9.391 -
    Right atrial systolic area index
    Right atrial systolic area index was measured by echocardiography. Number of subjects with right atrial systolic area index data at baseline: n=18
    Units: Index
        arithmetic mean (standard deviation)
    8.996 ± 6.021 -
    Right ventricular fractional area change
    Right ventricular fractional area change was measured by echocardiography. Number of subjects with right ventricular fractional area change data at baseline: n=17
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    25.7 ± 8.5 -
    Right ventricular diastolic area
    Right ventricular diastolic area was measured by echocardiography. Number of subjects with right ventricular diastolic area data at baseline: n=17
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    27.155 ± 11.993 -
    Right ventricular diastolic area index
    Right ventricular diastolic area index was measured by echocardiography. Number of subjects with right ventricular diastolic area index data at baseline: n=17
    Units: Index
        arithmetic mean (standard deviation)
    20.722 ± 6.564 -
    Right ventricular systolic area
    Right ventricular systolic area was measured by echocardiography. Number of subjects with right ventricular systolic area data at baseline: n=17
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    20.235 ± 9.343 -
    Right ventricular systolic area index
    Right ventricular systolic area index was measured by echocardiography. Number of subjects with right ventricular systolic area index data at baseline: n=17
    Units: Index
        arithmetic mean (standard deviation)
    15.613 ± 5.745 -
    Systolic pulmonary artery pressure
    Systolic pulmonary artery pressure was measured by echocardiography. Number of subjects with systolic pulmonary artery pressure data at baseline: n=6
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    117.2 ± 51.6 -
    Tricuspid annular plane systolic excursion
    Tricuspid annular plane systolic excursion was measured by echocardiography. Number of subjects with tricuspid annular plane systolic excursion data at baseline: n=17
    Units: Millimeter (mm)
        arithmetic mean (standard deviation)
    18.82 ± 4.21 -
    Tricuspid regurgitation peak velocity
    Tricuspid regurgitation peak velocity was measured by echocardiography. Number of subjects with tricuspid regurgitation peak velocity data at baseline: n=11
    Units: Meter/second (m/s)
        arithmetic mean (standard deviation)
    4.915 ± 1.100 -
    Pericardial effusion
    Pericardial effusion was measured by echocardiography. Number of subjects with pericardial effusion data at baseline: n=2
    Units: Millimeter (mm)
        arithmetic mean (standard deviation)
    1.280 ± 0.212 -
    Platelets
    Hematology parameters were collected and analyzed.
    Units: Giga per liter (Giga/L)
        arithmetic mean (standard deviation)
    218.8 ± 50.6 -
    Lymphocytes/leucocytes ratio
    Hematology parameters were collected and analyzed.
    Units: Percentage of leucocytes in blood
        arithmetic mean (standard deviation)
    48.98 ± 8.15 -
    Neutrophils/leucocytes ratio
    Hematology parameters were collected and analyzed.
    Units: Percentage of leucocytes in blood
        arithmetic mean (standard deviation)
    18.71 ± 10.37 -
    Alanine aminotransferase
    Clinical chemistry parameters were collected and analyzed.
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    18.71 ± 10.37 -
    Aspartate aminotransferase
    Clinical chemistry parameters were collected and analyzed.
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    23.76 ± 8.38 -
    Urea
    Clinical chemistry parameters were collected and analyzed. Number of subjects with urea data at baseline: n=11
    Units: microgram per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    25.17 ± 7.23 -
    Gamma glutamyl transferase
    Clinical chemistry parameters were collected and analyzed. Number of subjects with gamma glutamyl transferase data at baseline: n=20
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    16.9 ± 14.5 -
    Blood urea nitrogen
    Clinical chemistry parameters were collected and analyzed. Number of subjects with blood urea nitrogen data at baseline: n=17
    Units: microgram per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    11.8 ± 4.7 -
    Estimated Glomerular Filtration Rate (eGFR)
    Clinical chemistry parameters were collected and analyzed.
    Units: milliliter/minute/1.73 square meter
        arithmetic mean (standard deviation)
    117.877 ± 30.649 -
    Sodium
    Clinical chemistry parameters were collected and analyzed. Number of subjects with blood urea nitrogen data at baseline: n=22
    Units: millimole per Liter (mmol/L)
        arithmetic mean (standard deviation)
    140.5 ± 2.0 -

    End points

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    End points reporting groups
    Reporting group title
    Riociguat >=6 to <18 years
    Reporting group description
    Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration of the dose for safety reasons was allowed at any time.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subject who was assigned to receive study medication and had received at least one dose of the study medication.

    Subject analysis set title
    Riociguat 0.5 mg or equivalent - PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received riociguat at 0.5 mg or body weight-adjusted dose equivalent to the exposure of 0.5 mg dose in adults at the day of PK measurement

    Subject analysis set title
    Riociguat 1.0 mg or equivalent - PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received riociguat at 1.0 mg or body weight-adjusted dose equivalent to the exposure of 1.0 mg dose in adults at the day of PK measurement

    Subject analysis set title
    Riociguat 2.0 mg or equivalent - PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received riociguat at 2.0 mg or body weight-adjusted dose equivalent to the exposure of 2.0 mg dose in adults at the day of PK measurement

    Subject analysis set title
    Riociguat 2.5 mg or equivalent - PK
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects who received riociguat at 2.5 mg or body weight-adjusted dose equivalent to the exposure of 2.5 mg dose in adults at the day of PK measurement

    Primary: Number of subjects with any treatment-emergent adverse events

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    End point title
    Number of subjects with any treatment-emergent adverse events [1]
    End point description
    An adverse event (AE), including AE in relation to a medical device (i.e. Raumedic dosing pipette), is any untoward medical occurrence in a subject administered with a pharmaceutical product and does not necessarily have to have a causal relationship with this treatment. A serious AE (SAE) is any untoward medical occurrence that at any dose is resulting in death, is lifethreatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity. AEs occurring between start of study drug and up to 2 days after the last dose were defined as treatment-emergent AEs (TEAEs).
    End point type
    Primary
    End point timeframe
    From start of study drug up to 2 days after the last dose of study drug in the main study part, up to 24 weeks plus/minus 5 days.
    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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    24 [2]
    Units: Subjects
        Any TEAE
    20
        Any serious TEAE
    4
    Notes
    [2] - SAF
    No statistical analyses for this end point

    Primary: Change in heart rate from baseline

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    End point title
    Change in heart rate from baseline [3]
    End point description
    Mean change in heart rate from baseline is reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [4]
    Units: Beats per minute (BPM)
        arithmetic mean (standard deviation)
    4.1 ± 10.1
    Notes
    [4] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in blood pressure from baseline

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    End point title
    Change in blood pressure from baseline [5]
    End point description
    Mean changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline are reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [6]
    Units: millimetre of mercury (mmHg)
    arithmetic mean (standard deviation)
        SBP
    -3.1 ± 10.5
        DBP
    -2.4 ± 10.0
    Notes
    [6] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in respiratory rate from baseline

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    End point title
    Change in respiratory rate from baseline [7]
    End point description
    Mean change in respiratory rate from baseline by age subgroups (≥6 to <12 years and ≥12 to <18 years) were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    18 [8]
    Units: Breath per minute
        arithmetic mean (standard deviation)
    0.3 ± 3.3
    Notes
    [8] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Number of subjects with transitions from baseline in bone age compared to chronological age

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    End point title
    Number of subjects with transitions from baseline in bone age compared to chronological age [9]
    End point description
    X-ray of left hand was performed for each subject and bone age was determined centrally by a specialist. For each subject, the bone age was compared to the chronological age and assigned to one of the categories - "delayed", "in accordance" or "advanced", indicating the advancement or delay in the growth of the bone. Number of subjects who transitioned to another category different from baseline was calculated and reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [9] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [10]
    Units: Subjects
        Transitioned from Delayed to In Accordance
    0
        Transitioned from Delayed to Advanced
    0
        Transitioned from In Accordance to Delayed
    1
        Transitioned from In Accordance to Advanced
    3
        Transitioned from In Accordance to Missing
    1
        Transitioned from Advanced to Delayed
    1
        Transitioned from Advanced to In Accordance
    0
    Notes
    [10] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in hematology parameters (platelets) from baseline

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    End point title
    Change in hematology parameters (platelets) from baseline [11]
    End point description
    Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [11] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    20 [12]
    Units: Giga per Liter (Giga/L)
        arithmetic mean (standard deviation)
    -4.4 ± 51.1
    Notes
    [12] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in hematology parameters (lymphocytes/leucocytes ratio) from baseline

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    End point title
    Change in hematology parameters (lymphocytes/leucocytes ratio) from baseline [13]
    End point description
    Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [13] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    20 [14]
    Units: Percentage of leucocytes in blood
        arithmetic mean (standard deviation)
    -4.77 ± 11.08
    Notes
    [14] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in hematology parameters (neutrophils/leucocytes ratio) from baseline

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    End point title
    Change in hematology parameters (neutrophils/leucocytes ratio) from baseline [15]
    End point description
    Hematology parameters were collected. Parameters with a decrease or increase in the mean value compared to baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [15] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    20 [16]
    Units: Percentage of leucocytes in blood
        arithmetic mean (standard deviation)
    5.71 ± 11.73
    Notes
    [16] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in clinical chemistry (alanine aminotransferase) from baseline

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    End point title
    Change in clinical chemistry (alanine aminotransferase) from baseline [17]
    End point description
    Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [17] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [18]
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    -1.01 ± 9.86
    Notes
    [18] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in clinical chemistry (aspartate aminotransferase) from baseline

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    End point title
    Change in clinical chemistry (aspartate aminotransferase) from baseline [19]
    End point description
    Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [19] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [20]
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    -1.94 ± 6.52
    Notes
    [20] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in clinical chemistry (eGFR) from baseline

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    End point title
    Change in clinical chemistry (eGFR) from baseline [21]
    End point description
    Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported. eGFR = estimated glomerular filtration rate
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [21] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [22]
    Units: milliliter/minute/1.73 square meter
        arithmetic mean (standard deviation)
    -4.459 ± 25.686
    Notes
    [22] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in clinical chemistry (sodium) from baseline

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    End point title
    Change in clinical chemistry (sodium) from baseline [23]
    End point description
    Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [23] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    19 [24]
    Units: millimole per Liter (mmol/L)
        arithmetic mean (standard deviation)
    -1.0 ± 1.9
    Notes
    [24] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in clinical chemistry (blood urea nitrogen) from baseline

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    End point title
    Change in clinical chemistry (blood urea nitrogen) from baseline [25]
    End point description
    Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [25] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    14 [26]
    Units: microgram per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    1.3 ± 4.3
    Notes
    [26] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in clinical chemistry (urea) from baseline

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    End point title
    Change in clinical chemistry (urea) from baseline [27]
    End point description
    Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [27] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    9 [28]
    Units: microgram per deciliter (mg/dL)
        arithmetic mean (standard deviation)
    4.06 ± 10.52
    Notes
    [28] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Change in clinical chemistry (gamma glutamyl transferase) from baseline

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    End point title
    Change in clinical chemistry (gamma glutamyl transferase) from baseline [29]
    End point description
    Clinical chemistry parameters were collected and analyzed. Parameters with a trend to lower or higher mean values from baseline were reported.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    Notes
    [29] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    18 [30]
    Units: Units per liter (U/L)
        arithmetic mean (standard deviation)
    1.7 ± 4.0
    Notes
    [30] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Plasma concentration of riociguat at Week 0

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    End point title
    Plasma concentration of riociguat at Week 0 [31]
    End point description
    Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics, Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) were reported. W = Week. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
    End point type
    Primary
    End point timeframe
    Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
    Notes
    [31] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat 1.0 mg or equivalent - PK
    Number of subjects analysed
    22 [32]
    Units: microgram per liter (mcg/L)
    geometric mean (geometric coefficient of variation)
        W0 (30-90 min post-dose)
    15.340 ± 90.536
        W0 (2.5-4 h post-dose)
    17.791 ± 55.690
    Notes
    [32] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Plasma concentration of riociguat at Week 4

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    End point title
    Plasma concentration of riociguat at Week 4 [33]
    End point description
    Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics, Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
    End point type
    Primary
    End point timeframe
    Week 4 (pre-dose)
    Notes
    [33] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat 0.5 mg or equivalent - PK Riociguat 1.0 mg or equivalent - PK Riociguat 2.0 mg or equivalent - PK
    Number of subjects analysed
    1 [34]
    2 [35]
    17 [36]
    Units: microgram per liter (mcg/L)
        geometric mean (geometric coefficient of variation)
    4.510 ± 99999
    65.585 ± 47.727
    31.126 ± 89.790
    Notes
    [34] - Subjects in SAF with evaluable data
    [35] - Subjects in SAF with evaluable data
    [36] - SAF
    No statistical analyses for this end point

    Primary: Plasma concentration of riociguat at Week 8

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    End point title
    Plasma concentration of riociguat at Week 8 [37]
    End point description
    Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics, Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
    End point type
    Primary
    End point timeframe
    Week 8 (pre-dose)
    Notes
    [37] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat 0.5 mg or equivalent - PK Riociguat 1.0 mg or equivalent - PK Riociguat 2.0 mg or equivalent - PK Riociguat 2.5 mg or equivalent - PK
    Number of subjects analysed
    2 [38]
    1 [39]
    1 [40]
    15 [41]
    Units: microgram per liter (mcg/L)
    geometric mean (geometric coefficient of variation)
        Riociguat
    11.650 ± 244.238
    27.100 ± 99999
    14.000 ± 99999
    32.381 ± 137.719
        BAY60-4552
    23.065 ± 91.296
    13.200 ± 99999
    49.600 ± 99999
    65.849 ± 26.864
    Notes
    [38] - Subjects in SAF with evaluable data
    [39] - Subjects in SAF with evaluable data
    [40] - Subjects in SAF with evaluable data
    [41] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Plasma concentration of BAY60-4552 at Week 0

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    End point title
    Plasma concentration of BAY60-4552 at Week 0 [42]
    End point description
    BAY60-4552 is riociguat's active metabolite. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics, Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) were reported. W = Week; n = number of subjects. "99999" denotes that value was not calculated due to very low number of subjects.
    End point type
    Primary
    End point timeframe
    Week 0 (30-90 minutes post-dose; 2.5-4 hours post-dose)
    Notes
    [42] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat 1.0 mg or equivalent - PK
    Number of subjects analysed
    22 [43]
    Units: microgram per liter (mcg/L)
    geometric mean (geometric coefficient of variation)
        W0 (30-90 min post-dose)
    99999 ± 99999
        W0 (2.5-4 h post-dose)
    3.922 ± 94.399
    Notes
    [43] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Plasma concentration of BAY60-4552 at Week 4

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    End point title
    Plasma concentration of BAY60-4552 at Week 4 [44]
    End point description
    BAY60-4552 is riociguat's active metabolite. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics, Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
    End point type
    Primary
    End point timeframe
    Week 4 (pre-dose)
    Notes
    [44] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat 0.5 mg or equivalent - PK Riociguat 1.0 mg or equivalent - PK Riociguat 2.0 mg or equivalent - PK
    Number of subjects analysed
    1 [45]
    2 [46]
    17 [47]
    Units: microgram per liter (mcg/L)
        geometric mean (geometric coefficient of variation)
    12.700 ± 99999
    48.822 ± 193.584
    38.579 ± 27.242
    Notes
    [45] - Subjects in SAF with evaluable data
    [46] - Subjects in SAF with evaluable data
    [47] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Primary: Plasma concentration of BAY60-4552 at Week 8

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    End point title
    Plasma concentration of BAY60-4552 at Week 8 [48]
    End point description
    BAY60-4552 is riociguat's active metabolite. Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation in statistics, Means at any time were only calculated if at least 2/3 of the individual data were measured and were above the limit of quantification (LOQ). Geometric mean and percentage geometric coefficient of variation (%CV) were reported. "99999" denotes that value was not calculated due to very low number of subjects. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
    End point type
    Primary
    End point timeframe
    Week 8 (pre-dose)
    Notes
    [48] - 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: Due to the nature of this trial, only descriptive statistics were performed. This trial was planned as fully exploratory, based on a small number of subjects, and without any inferential statistics.
    End point values
    Riociguat 0.5 mg or equivalent - PK Riociguat 1.0 mg or equivalent - PK Riociguat 2.0 mg or equivalent - PK Riociguat 2.5 mg or equivalent - PK
    Number of subjects analysed
    2 [49]
    1 [50]
    1 [51]
    15 [52]
    Units: microgram per liter (mcg/L)
        geometric mean (geometric coefficient of variation)
    23.065 ± 91.296
    13.200 ± 99999
    49.600 ± 99999
    65.849 ± 26.864
    Notes
    [49] - Subjects in SAF with evaluable data
    [50] - Subjects in SAF with evaluable data
    [51] - Subjects in SAF with evaluable data
    [52] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in 6-minute walking distance from baseline

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    End point title
    Change in 6-minute walking distance from baseline
    End point description
    6-minute walking distance (6MWD) is a exercise test used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity. An increase in the distance walked indicates improvement in basic mobility.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    19 [53]
    Units: Meter
        arithmetic mean (standard deviation)
    23.01 ± 68.80
    Notes
    [53] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Number of subjects with change in WHO functional class from baseline

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    End point title
    Number of subjects with change in WHO functional class from baseline
    End point description
    The World Health Organization (WHO) functional class describes how severe a patient’s pulmonary hypertension (PH) symptoms are. There are four different classes – I is the mildest and IV the most severe form of PH. Number of subjects per change in number of classes was reported.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [54]
    Units: Subjects
        -3 classes
    0
        -2 classes
    0
        -1 classes
    0
        0 classes
    21
        1 classes
    0
        2 classes
    0
        3 classes
    0
    Notes
    [54] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in NT-proBNP from baseline

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    End point title
    Change in NT-proBNP from baseline
    End point description
    Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the subjects. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    14 [55]
    Units: picograms per milliliter (pg/mL)
        arithmetic mean (standard deviation)
    -65.77 ± 585.41
    Notes
    [55] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in BNP from baseline

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    End point title
    Change in BNP from baseline
    End point description
    Laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were tested for the subjects. When both tests were available, NT-proBNP was chosen over BNP and the same test was performed at every required visit.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    6 [56]
    Units: Picograms per milliliter (pg/mL)
        arithmetic mean (standard deviation)
    7.45 ± 10.65
    Notes
    [56] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in quality of life evaluated by SF-10 questionnaire from baseline

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    End point title
    Change in quality of life evaluated by SF-10 questionnaire from baseline
    End point description
    SF-10 is a parent-completed health survey for children that contains 10 questions adapted from the Child Health Questionnaire. It is scored to produce physical and psychosocial health summary measures. Each of the 10 questions responses is scored with a point value from 1 to 6 (1 is the worst possible condition and 6 is the best possible condition). The SF-10 physical and psychosocial measures are scored such that higher scores indicate more favorable functioning.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    21 [57]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Physical summary score
    5.79 ± 12.46
        Psychosocial summary score
    1.10 ± 6.85
    Notes
    [57] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in quality of life evaluated by PedsQL scale

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    End point title
    Change in quality of life evaluated by PedsQL scale
    End point description
    The PedsQL Generic Core Scales were designed to measure health-related quality of life in children and adolescents. It has 4 dimensions: physical functioning, emotional functioning, social functioning and school functioning. 3 Summary Scores of PedsQL were calculated from the scales including total scale score (23 questions), physical health summary score (physical functioning, 8 questions) and psychosocial health summary score (emotional, social and school functioning, 15 questions). Responses of the questions are transformed to a 0-100 scale. Higher scores indicate better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    19 [58]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Total scale score
    3.49 ± 10.81
        Physical health summary score
    4.28 ± 13.51
        Psychosocial health summary score
    3.07 ± 11.21
    Notes
    [58] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Number of subjects with clinical worsening

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    End point title
    Number of subjects with clinical worsening
    End point description
    Clinical worsening was defined as: hospitalization for right heart failure, death, lung transplantation, Pott’s anastomosis and atrioseptostomy, worsening of PAH symptoms, which must include either an increase in WHO functional class or appearance/worsening symptoms of right heart failure and need for additional PAH therapy.
    End point type
    Secondary
    End point timeframe
    Up to Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    24 [59]
    Units: Subjects
    2
    Notes
    [59] - SAF
    No statistical analyses for this end point

    Secondary: Change in estimated right atrial pressure from baseline

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    End point title
    Change in estimated right atrial pressure from baseline
    End point description
    Estimated right atrial pressure was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    16 [60]
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    -0.6 ± 3.6
    Notes
    [60] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in left ventricular eccentricity index from baseline

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    End point title
    Change in left ventricular eccentricity index from baseline
    End point description
    Left ventricular eccentricity index was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [61]
    Units: Index
        arithmetic mean (standard deviation)
    0.002 ± 0.907
    Notes
    [61] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in pericardial effusion from baseline

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    End point title
    Change in pericardial effusion from baseline
    End point description
    Pericardial effusion was measured by echocardiography. "99999" denotes that value was not calculated due to very low number of subjects.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    1 [62]
    Units: Millimeter (mm)
        arithmetic mean (standard deviation)
    1.040 ± 99999
    Notes
    [62] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in pulmonary artery acceleration time from baseline

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    End point title
    Change in pulmonary artery acceleration time from baseline
    End point description
    Pulmonary artery acceleration time was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [63]
    Units: Millisecond (msec)
        arithmetic mean (standard deviation)
    -7.777 ± 35.898
    Notes
    [63] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right ventricular cardiac index from baseline

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    End point title
    Change in right ventricular cardiac index from baseline
    End point description
    Rright ventricular cardiac index was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    13 [64]
    Units: Liter/minute/square meter (L/min/m2)
        arithmetic mean (standard deviation)
    0.188 ± 2.094
    Notes
    [64] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right ventricular cardiac output from baseline

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    End point title
    Change in right ventricular cardiac output from baseline
    End point description
    Right ventricular cardiac output was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    13 [65]
    Units: Liter per minute (L/min)
        arithmetic mean (standard deviation)
    0.457 ± 3.066
    Notes
    [65] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right atrial diastolic area from baseline

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    End point title
    Change in right atrial diastolic area from baseline
    End point description
    Right atrial diastolic area was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    16 [66]
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    1.078 ± 3.330
    Notes
    [66] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right atrial diastolic area index from baseline

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    End point title
    Change in right atrial diastolic area index from baseline
    End point description
    Right atrial diastolic area index was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    16 [67]
    Units: Index
        arithmetic mean (standard deviation)
    0.643 ± 2.314
    Notes
    [67] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right atrial systolic area from baseline

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    End point title
    Change in right atrial systolic area from baseline
    End point description
    Right atrial systolic area was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    16 [68]
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    0.424 ± 3.758
    Notes
    [68] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right atrial systolic area index from baseline

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    End point title
    Change in right atrial systolic area index from baseline
    End point description
    Right atrial systolic area index was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    16 [69]
    Units: Index
        arithmetic mean (standard deviation)
    0.329 ± 2.417
    Notes
    [69] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right ventricular fractional area change from baseline

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    End point title
    Change in right ventricular fractional area change from baseline
    End point description
    Right ventricular fractional area change was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [70]
    Units: Percentage (%)
        arithmetic mean (standard deviation)
    -4.3 ± 7.3
    Notes
    [70] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right ventricular diastolic area from baseline

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    End point title
    Change in right ventricular diastolic area from baseline
    End point description
    Right ventricular diastolic area was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [71]
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    0.618 ± 4.519
    Notes
    [71] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right ventricular diastolic area index from baseline

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    End point title
    Change in right ventricular diastolic area index from baseline
    End point description
    Right ventricular diastolic area index was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [72]
    Units: Index
        arithmetic mean (standard deviation)
    0.451 ± 3.562
    Notes
    [72] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right ventricular systolic area from baseline

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    End point title
    Change in right ventricular systolic area from baseline
    End point description
    Right ventricular systolic area was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [73]
    Units: Square centimeter (cm^2)
        arithmetic mean (standard deviation)
    1.725 ± 3.847
    Notes
    [73] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in right ventricular systolic area index from baseline

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    End point title
    Change in right ventricular systolic area index from baseline
    End point description
    Right ventricular systolic area index was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [74]
    Units: Index
        arithmetic mean (standard deviation)
    1.244 ± 3.277
    Notes
    [74] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in systolic pulmonary artery pressure from baseline

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    End point title
    Change in systolic pulmonary artery pressure from baseline
    End point description
    Systolic pulmonary artery pressure was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    3 [75]
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    5.7 ± 49.0
    Notes
    [75] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in tricuspid annular plane systolic excursion from baseline

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    End point title
    Change in tricuspid annular plane systolic excursion from baseline
    End point description
    Tricuspid annular plane systolic excursion (TAPSE) was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    15 [76]
    Units: Millimeter (mm)
        arithmetic mean (standard deviation)
    -1.27 ± 3.87
    Notes
    [76] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Secondary: Change in tricuspid regurgitation peak velocity from baseline

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    End point title
    Change in tricuspid regurgitation peak velocity from baseline
    End point description
    Ttricuspid regurgitation peak velocity was measured by echocardiography.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    10 [77]
    Units: Meter/second (m/s)
        arithmetic mean (standard deviation)
    -0.085 ± 0.726
    Notes
    [77] - Subjects in SAF with evaluable data
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Questions 1 to 4) of the oral suspension of Riociguat at Week 0

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    End point title
    Taste and texture (Questions 1 to 4) of the oral suspension of Riociguat at Week 0
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Questions 1 to 4 were reported in this endpoint. Questions 1 and 2 were asked before the subjects received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Subjects were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
    End point type
    Other pre-specified
    End point timeframe
    At the beginning of the treatment (Week 0)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    16 [78]
    Units: Subjects
        Like the look of the drink - Yes
    4
        Like the look of the drink - No
    2
        Like the look of the drink - Unsure
    9
        Like the look of the drink - Missing
    1
        Like the smell of the drink - Yes
    4
        Like the smell of the drink - No
    2
        Like the smell of the drink - Unsure
    9
        Like the smell of the drink - Missing
    1
        Like the drink - Yes
    9
        Like the drink - No
    1
        Like the drink - Unsure
    5
        Like the drink - Missing
    1
        Like to drink again - Yes
    12
        Like to drink again - No
    0
        Like to drink again - Unsure
    3
        Like to drink again - Missing
    1
    Notes
    [78] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Questions 1 to 4) the oral suspension of Riociguat at Week 24

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    End point title
    Taste and texture (Questions 1 to 4) the oral suspension of Riociguat at Week 24
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Responses to Qusestions 1 to 4 were reported in this endpoint. Questions 1 and 2 were asked before the subjects received the suspension; whereas questions 3 and 4 were asked right after administration of the suspension. Subjects were asked to respond to the 4 questions as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
    End point type
    Other pre-specified
    End point timeframe
    Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    14 [79]
    Units: Subjects
        Like the look of the drink - Yes
    6
        Like the look of the drink - No
    1
        Like the look of the drink - Unsure
    6
        Like the look of the drink - Missing
    1
        Like the smell of the drink - Yes
    7
        Like the smell of the drink - No
    2
        Like the smell of the drink - Unsure
    4
        Like the smell of the drink - Missing
    1
        Like the drink - Yes
    6
        Like the drink - No
    4
        Like the drink - Unsure
    3
        Like the drink - Missing
    1
        Like to drink again - Yes
    6
        Like to drink again - No
    3
        Like to drink again - Unsure
    4
        Like to drink again - Missing
    1
    Notes
    [79] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Question 5) of the oral suspension of Riociguat at Week 0

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    End point title
    Taste and texture (Question 5) of the oral suspension of Riociguat at Week 0
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 5 "Taste of the drink" was reported in this endpoint. Question 5 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".
    End point type
    Other pre-specified
    End point timeframe
    At the beginning of the treatment (Week 0)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    1 [80]
    Units: Subjects
        Sweet - Yes
    1
        Sour - No
    1
        Bitter - No
    1
        Salty - No
    1
        Disgusting - No
    1
        Fruity - Yes
    1
    Notes
    [80] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Question 5) of the oral suspension of Riociguat at Week 24

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    End point title
    Taste and texture (Question 5) of the oral suspension of Riociguat at Week 24
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 5 "Taste of the drink" was reported in this endpoint. Question 5 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each taste including "sweet, sour, bitter, salty, disgusting and fruity".
    End point type
    Other pre-specified
    End point timeframe
    Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    4 [81]
    Units: Subjects
        Sweet - Yes
    2
        Sweet - No
    1
        Sweet - Unsure
    1
        Sour - Yes
    1
        Sour - No
    3
        Bitter - No
    3
        Bitter - Unsure
    1
        Salty - No
    4
        Disgusting - Yes
    4
        Fruity - No
    2
        Fruity - Unsure
    2
    Notes
    [81] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Question 6) of the oral suspension of Riociguat at Week 0

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    End point title
    Taste and texture (Question 6) of the oral suspension of Riociguat at Week 0
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 6 "Drink feels in mouth" was reported in this endpoint. Question 6 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".
    End point type
    Other pre-specified
    End point timeframe
    At the beginning of the treatment (Week 0)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    1 [82]
    Units: Subjects
        Like Sand - No
    1
        Sticky - No
    1
        Gooey - No
    1
        Slimy - No
    1
        Creamy - No
    1
    Notes
    [82] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Question 6) of the oral suspension of Riociguat in mouth at Week 24

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    End point title
    Taste and texture (Question 6) of the oral suspension of Riociguat in mouth at Week 24
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 6 "Drink feels in mouth" was reported in this endpoint. Question 6 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to answer "yes", "I do not know/unsure" or "No" to each feeling including "like sand, sticky, gooey, slimy, creamy".
    End point type
    Other pre-specified
    End point timeframe
    Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    4 [83]
    Units: Subjects
        Like sand - No
    3
        Like sand - Unsure
    1
        Sticky - Yes
    1
        Sticky - No
    3
        Gooey - No
    3
        Gooey - Unsure
    1
        Slimy - Yes
    2
        Slimy - No
    1
        Slimy - Unsure
    1
        Creamy - No
    2
        Creamy - Unsure
    2
    Notes
    [83] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Question 7) of the oral suspension of Riociguat in mouth at Week 0

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    End point title
    Taste and texture (Question 7) of the oral suspension of Riociguat in mouth at Week 0
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 7 "Did you like the taste after swallowing" was reported in this endpoint. Question 7 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
    End point type
    Other pre-specified
    End point timeframe
    At the beginning of the treatment (Week 0)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    1 [84]
    Units: Subjects
        Like the taste after swallowing - Yes
    1
        Like the taste after swallowing - No
    0
        Like the taste after swallowing - Unsure
    0
    Notes
    [84] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Taste and texture (Question 7) of the oral suspension of Riociguat in mouth at Week 24

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    End point title
    Taste and texture (Question 7) of the oral suspension of Riociguat in mouth at Week 24
    End point description
    To assess the taste and texture of oral suspension of Riociguat, a questionnaire including 7 questions was used. Number of subjects per responses to Questions 7 "Did you like the taste after swallowing" was reported in this endpoint. Question 7 was only asked to subjects who answered "No" to Question 3 "Did you like the drink" or Question 4 "Would you like to drink this again". Subjects were asked to respond as "yes" (= positive answer), "I do not know/unsure"(= indifferent answer) or "No" (= negative answer).
    End point type
    Other pre-specified
    End point timeframe
    Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    4 [85]
    Units: Subjects
        Like the taste after swallowing - Yes
    0
        Like the taste after swallowing - No
    3
        Like the taste after swallowing - Unsure
    1
    Notes
    [85] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Expression assessment on the taste and texture of oral suspension of Riociguat - Week 0

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    End point title
    Expression assessment on the taste and texture of oral suspension of Riociguat - Week 0
    End point description
    The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased".
    End point type
    Other pre-specified
    End point timeframe
    At the beginning of the treatment (Week 0)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    16 [86]
    Units: Subjects
        Comfortable
    7
        Indifferent
    8
        Displeased
    0
        Missing
    1
    Notes
    [86] - Subjects in SAF with assessment
    No statistical analyses for this end point

    Other pre-specified: Expression assessment on the taste and texture of oral suspension of Riociguat - Week 24

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    End point title
    Expression assessment on the taste and texture of oral suspension of Riociguat - Week 24
    End point description
    The facial expression of the subjects concerning appearance, smell and taste of the suspension of Riociguat was captured by the investigators as "comfortable", "indifferent" and "displeased".
    End point type
    Other pre-specified
    End point timeframe
    Week 24 (plus/minus 5 days)
    End point values
    Riociguat >=6 to <18 years
    Number of subjects analysed
    14 [87]
    Units: Subjects
        Comfortable
    6
        Indifferent
    5
        Displeased
    2
        Missing
    1
    Notes
    [87] - Subjects in SAF with assessment
    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 drug up to 2 days after the last dose of study drug in the main study part, up to 24 weeks plus/minus 5 days.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Riociguat >=6 to <18 years
    Reporting group description
    Subjects with age >=6 to <18 years received riociguat up to 2.5 mg three times a day (titration between 0.5 mg and 2.5 mg) for up to 8 weeks during the individual dose titration (IDT) phase, and followed with the last dose administered in the IDT phase for up to 16 weeks during the maintenance phase. Down-titration of the dose for safety reasons was allowed at any time.

    Serious adverse events
    Riociguat >=6 to <18 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 24 (16.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Right ventricular failure
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Pain of skin
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin swelling
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Vascular device infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 24 (4.17%)
         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 >=6 to <18 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 24 (62.50%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    11
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    7
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2015
    Amendment 3 introduced the following changes: The wording describing the LTE part of the study was changed (“study” was replaced with “phase” and “optional” was added) to clarify that the subjects can volunteer to participate in the LTE, which is a part of this study. Clarification of primary completion and end of study. Pharmacodynamics was deleted from primary objective. Addition of a safety follow up visit for subjects participating in the LTE phase.
    31 May 2016
    Amendment 5 introduced the following changes: The collection of the following parameters: GGT, UA, T-Bil, Alb, Na, K, Ca, and P at visit 0, 5 and 9 were added for safety reasons. Addition of the statement that all laboratory parameters are recorded to the eCRF when obtained as medically required according to a local package insert of bosentan or medical practice at any time. The collection of RHC parameters in the eCRF was included. The echocardiography parameter of right heart dimensions was introduced in the study and all Echo parameters were listed as main secondary variables. Central reading of the echocardiographic parameters were added. Taste and texture was downgraded from secondary efficacy endpoint to other endpoint.
    09 Jan 2017
    Amendment 6 introduced the following changes: A new exclusion criterion “patients with pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP)” was added. The study population was broadened to include patients treated with PAH medications including ERA (besides bosentan), PCAs or combination of these. Parents and patients questionnaires were added. Exclusion criteria were changed regarding the pretreatment with PDE5 inhibitors. Clarification that pretreatment with PDE5i was allowed but up to 3 three days prior to start of riociguat treatment (Visit 1) was added. BNP was added as an alternative for NT-proBNP.
    13 Mar 2018
    Amendment 9 introduced the following changes: The inclusion of patients with ostium secundum atrial septal defect ≤1 cm without hemodynamic alterations was allowed. The inclusion of patients with patent foramen ovale ≤1 cm was allowed. The definition of “effective” methods was added in inclusion criterion 7.
    23 Aug 2019
    Amendment 12 introduced the following changes: Description of the pregnancy testing (to be performed in 4-weekly intervals starting at Visit 1 until 4 weeks after the patient stopped intake of study drug) in the optional LTE phase was added. The conditions for transitioning into the optional LTE phase was clarified. The dosing recommendation for patients with body weight ≥12 to <14 kg was added.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The results should be interpreted with caution due to the limited number of subjects. The number of subjects with clinical worsening events was too low to produce valid Kaplan-Meier estimates for the time to clinical worsening.
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