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    Clinical Trial Results:
    A prospective, multicenter, open-label extension of FUTURE 3 to assess the safety, tolerability and efficacy of the pediatric formulation of bosentan two versus three times a day in children with pulmonary arterial hypertension

    Summary
    EudraCT number
    2010-021793-12
    Trial protocol
    DE   HU   CZ   FR   NL   ES   IT   PL   Outside EU/EEA  
    Global end of trial date
    13 Aug 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    27 Jul 2016
    First version publication date
    12 Apr 2015
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-052-374
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01338415
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd.
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    clinical trial disclosure desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@actelion.com
    Scientific contact
    clinical trial disclosure desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@actelion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety, tolerability and efficacy of the pediatric formulation of bosentan two versus three times a day in children with pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    This clinical study was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, the US CFR Title 21, and with the ethical principles laid down in the Declaration of Helsinki. Only patients who performed the end of study assessments of the FUTURE 3 core study, who tolerated bosentan 32 mg dispersible tablets (pediatric formulation) during the core study and for whom continuation of bosentan treatment was considered beneficial by the investigator, were offered the oppurtunity to participate in the FUTURE 3 Extension trial.
    Background therapy
    Patients receiving the commercial formulation of bosentan before entering the FUTURE 3 core study had to stop it and instead take the study drug (pediatric formulation of bosentan). Previous therapies for PAH were allowed at a stable regimen
    Evidence for comparator
    not applicable
    Actual start date of recruitment
    08 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Ukraine: 1
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belarus: 3
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Serbia: 5
    Worldwide total number of subjects
    64
    EEA total number of subjects
    23
    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)
    21
    Children (2-11 years)
    43
    Adolescents (12-17 years)
    0
    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
    58 out of 64 patients randomized in the FUTURE 3 core study were enrolled in the FUTURE 3 extension study.

    Pre-assignment
    Screening details
    Treatment groups assigned at randomization of FUTURE 3 core study (AC-052-373) were continued in the extension study (AC-052-374).

    Period 1
    Period 1 title
    overall period (core+extension)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    bosentan 2mg/kg b.i.d.
    Arm description
    Patients received 2 mg/kg bosentan twice daily (morning and evening) during the FUTURE 3 core period and continued with the same dose regimen during the extension period
    Arm type
    Experimental

    Investigational medicinal product name
    bosentan
    Investigational medicinal product code
    ACT-050088
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The body weight-adjusted dose of the dispersible tablet was dispersed in a teaspoon of water (not mixed with food) before being administered orally twice a day (morning and evening)

    Arm title
    bosentan 2mg/kg t.i.d.
    Arm description
    Patients received 2 mg/kg bosentan 3 times a day (morning, afternoon, evening) during the FUTURE 3 core period and continued with the same dose regimen during the extension period
    Arm type
    Experimental

    Investigational medicinal product name
    bosentan
    Investigational medicinal product code
    ACT-050088
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The body weight-adjusted dose of the dispersible tablet was dispersed in a teaspoon of water (not mixed with food) before being administered orally three times a day (morning, afternoon and evening)

    Number of subjects in period 1
    bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d.
    Started
    33
    31
    Completed
    23
    22
    Not completed
    10
    9
         PAH not the main etiology of PH
    -
    2
         Administrative reason
    1
    -
         Adverse event, serious fatal
    2
    1
         Adverse event, non-fatal
    6
    5
         Consent withdrawn by subject
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    bosentan 2mg/kg b.i.d.
    Reporting group description
    Patients received 2 mg/kg bosentan twice daily (morning and evening) during the FUTURE 3 core period and continued with the same dose regimen during the extension period

    Reporting group title
    bosentan 2mg/kg t.i.d.
    Reporting group description
    Patients received 2 mg/kg bosentan 3 times a day (morning, afternoon, evening) during the FUTURE 3 core period and continued with the same dose regimen during the extension period

    Reporting group values
    bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d. Total
    Number of subjects
    33 31 64
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    10 11 21
        Children (2-11 years)
    23 20 43
    Age continuous
    Age at randomization in the FUTURE 3 core study (AC-052-373)
    Units: years
        arithmetic mean (standard deviation)
    4.5 ± 3.35 5.2 ± 3.81 -
    Gender categorical
    Number of males and females randomized in the FUTURE 3 core study (AC-052-373)
    Units: Subjects
        Female
    18 10 28
        Male
    15 21 36
    Pulmonary Arterial Hypertension (PAH) etiology
    Number of subjects in each PAH category at randomization (before treatment initiation) in the FUTURE 3 core study (AC-052-373)
    Units: Subjects
        idiopathic
    14 15 29
        heritable
    2 0 2
        congenital heart disease
    6 2 8
        associated PAH (i.e.,PAH after surgery for CHD)
    11 13 24
        missing data
    0 1 1
    WHO functional class (FC)
    Number of subjects in each WHO FC at randomization (before treatment initiation) in the FUTURE 3 core study (AC-052-373)
    Units: Subjects
        FC I
    9 10 19
        FC II
    12 15 27
        FC III
    12 6 18
    Subject analysis sets

    Subject analysis set title
    all treated set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    "All Randomized" analysis set includes all patients assigned to a study treatment in FUTURE 3. The "All Treated" analysis set comprised all patients in the FUTURE 3 core study who received at least one dose of the study drug. Because the same patients were included in the "All randomized " and the "All Treated" analysis sets, only the "All Treated analysis set was used.

    Subject analysis sets values
    all treated set
    Number of subjects
    64
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
    Age continuous
    Age at randomization in the FUTURE 3 core study (AC-052-373)
    Units: years
        arithmetic mean (standard deviation)
    4.8 ± 3.57
    Gender categorical
    Number of males and females randomized in the FUTURE 3 core study (AC-052-373)
    Units: Subjects
        Female
    28
        Male
    36
    Pulmonary Arterial Hypertension (PAH) etiology
    Number of subjects in each PAH category at randomization (before treatment initiation) in the FUTURE 3 core study (AC-052-373)
    Units: Subjects
        idiopathic
    29
        heritable
    2
        congenital heart disease
    8
        associated PAH (i.e.,PAH after surgery for CHD)
    24
        missing data
    1
    WHO functional class (FC)
    Number of subjects in each WHO FC at randomization (before treatment initiation) in the FUTURE 3 core study (AC-052-373)
    Units: Subjects
        FC I
    19
        FC II
    27
        FC III
    18

    End points

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    End points reporting groups
    Reporting group title
    bosentan 2mg/kg b.i.d.
    Reporting group description
    Patients received 2 mg/kg bosentan twice daily (morning and evening) during the FUTURE 3 core period and continued with the same dose regimen during the extension period

    Reporting group title
    bosentan 2mg/kg t.i.d.
    Reporting group description
    Patients received 2 mg/kg bosentan 3 times a day (morning, afternoon, evening) during the FUTURE 3 core period and continued with the same dose regimen during the extension period

    Subject analysis set title
    all treated set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    "All Randomized" analysis set includes all patients assigned to a study treatment in FUTURE 3. The "All Treated" analysis set comprised all patients in the FUTURE 3 core study who received at least one dose of the study drug. Because the same patients were included in the "All randomized " and the "All Treated" analysis sets, only the "All Treated analysis set was used.

    Primary: Not applicable

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    End point title
    Not applicable [1]
    End point description
    no primary endpoint was defined. As it is an exploratory study, all efficacy endpoints were considered as exploratory endpoints
    End point type
    Primary
    End point timeframe
    not applicable
    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: Not applicable because no primary efficacy endpoint was defined
    End point values
    all treated set
    Number of subjects analysed
    0 [2]
    Units: not applicable
    Notes
    [2] - not applicable (no primary endpoint defined)
    No statistical analyses for this end point

    Other pre-specified: Change from baseline up to 18 months of treatment in Their World Health Organization (WHO) Functional Classification (FC)

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    End point title
    Change from baseline up to 18 months of treatment in Their World Health Organization (WHO) Functional Classification (FC)
    End point description
    This is the change from baseline up to 18 months of treatment with bosentan over FUTURE 3 core and extension studies in WHO FC. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study. The WHO FC indicates the severity of Pulmonary Arterial Hypertension: class I (none) to class IV (most severe).
    End point type
    Other pre-specified
    End point timeframe
    Up to 18 months
    End point values
    bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d. all treated set
    Number of subjects analysed
    33
    31
    64
    Units: Percentage of patients
        Stable, Month 12
    67
    80
    73
        Improved, Month 12
    21
    10
    16
        Worsened, Month 12
    12
    10
    11
        Stable, Month 18
    76
    80
    78
        Improved, Month 18
    9
    10
    9
        Worsened, Month 18
    15
    10
    13
    No statistical analyses for this end point

    Other pre-specified: Change from baseline up to 18 months of treatment in the global clinical impression scale (GCIS)

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    End point title
    Change from baseline up to 18 months of treatment in the global clinical impression scale (GCIS)
    End point description
    This is the change from baseline up to 18 months of treatment with bosentan over FUTURE 3 core and extension studies in GCIS as assessed by both the physician and parents or legal representatives independently. Baseline was defined as the last valid assessment performed prior to first study drug intake in the FUTURE 3 core study. The GCIS is a scale used to rate the patient’s current overall clinical condition (“Very Good”, “Good”, “Neither Good or Bad”, “Bad”, and “Very Bad”).
    End point type
    Other pre-specified
    End point timeframe
    Up to 18 months
    End point values
    bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d. all treated set
    Number of subjects analysed
    33 [3]
    31 [4]
    64 [5]
    Units: Percentage of patients
        Stable, Month 12 (Physician)
    57
    70
    63
        Stable, Month 12 (Parents)
    57
    52
    55
        Improved, Month 12 (Physician)
    36
    26
    31
        Improved, Month 12 (Parents)
    32
    48
    39
        Worsened, Month 12 (Physician)
    7
    4
    6
        Worsened, Month 12(Parents)
    11
    0
    6
        Stable, Month 18 (Physician)
    47
    67
    57
        Stable, Month 18 (Parents)
    42
    39
    41
        Improved, Month 18 (Physician)
    32
    28
    30
        Improved, Month 18 (Parents)
    32
    55
    43
        Worsened, Month 18 (Physician)
    21
    5
    13
        Worsened, Month 18 (Parents)
    26
    6
    16
    Notes
    [3] - No imputation performed; number of subjects analyzed = 28 at Month 12, 19 at Month 18
    [4] - No imputation performed; number of subjects analyzed = 23 at Month 12, 18 at Month 18
    [5] - No imputation performed; number of subjects analyzed = 41 at Month 12, 37 at Month 18
    No statistical analyses for this end point

    Other pre-specified: Percentage of patients with Pulmonary Arterial Hypertension (PAH) worsening components

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    End point title
    Percentage of patients with Pulmonary Arterial Hypertension (PAH) worsening components
    End point description
    Percentage of patients with PAH progression events (death, lung transplant or hospitalization due to PAH progression, initiation of new therapy for PAH or new/worsening right heart failure) up to the last day of treatment + 7 days in the two treatment groups.
    End point type
    Other pre-specified
    End point timeframe
    Up to end of treatment + 7 days
    End point values
    bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d. all treated set
    Number of subjects analysed
    33
    31
    64
    Units: Percentage of patients
        New or worsening RHF
    24
    10
    17
        Death
    18
    13
    16
        Hospitalization
    12
    10
    11
        Initiation of new PAH therapy
    6
    7
    6
    No statistical analyses for this end point

    Other pre-specified: Pulmonary Arterial Hypertension (PAH) progression time

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    End point title
    Pulmonary Arterial Hypertension (PAH) progression time
    End point description
    Kaplan-Meier estimates for PAH worsening defined by time to any components of PAH progression (death, lung transplant, hospitalization due to PAH progression, initiation of new therapy for PAH or new / worsening right heart failure) in the 2 treatment groups
    End point type
    Other pre-specified
    End point timeframe
    Up to end of treatment + 7 days
    End point values
    bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d. all treated set
    Number of subjects analysed
    29 [6]
    28 [7]
    57 [8]
    Units: kaplan-Meier estimates
    number (confidence interval 95%)
        Month 12
    74.9 (56 to 86.6)
    88.9 (69.4 to 96.3)
    81.4 (69 to 89.3)
        Month 18
    68.2 (48.9 to 81.5)
    81 (60.1 to 91.7)
    74.1 (60.8 to 83.6)
    Notes
    [6] - patients at risk: n=23 at Month 12, n=5 at Month 18
    [7] - patients at risk: n=23 at Month 12, n=5 at Month 18
    [8] - patients at risk n=46 at Month 12, n=10 at Month 18
    No statistical analyses for this end point

    Other pre-specified: Overall Survival

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    End point title
    Overall Survival
    End point description
    Kaplan-Meier estimates for overall survival defined by the time to death due to any cause up to end of study (Month 18 survival follow-up) in the 2 treatment groups. Patients still alive at the time of the analysis were censored using their last contact date.
    End point type
    Other pre-specified
    End point timeframe
    Up to the Month 18 survival follow-up
    End point values
    bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d. all treated set
    Number of subjects analysed
    33 [9]
    31 [10]
    64 [11]
    Units: Kaplan-Meier estimates
        number (confidence interval 95%)
    75.8 (57.3 to 87.1)
    86.5 (68 to 94.7)
    80.9 (68.7 to 88.6)
    Notes
    [9] - patients at risk = 17
    [10] - patients at risk = 13
    [11] - patients at risk = 30
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to end of treatment (and up to additional 60 days for serious adverse events)
    Adverse event reporting additional description
    Adverse events (AEs) and deaths are reported cumulatively for both AC-052-373 and AC-052-374 (FUTURE 3 core & extension). Serious AEs with fatal outcome are not mutually exclusive (One death can be linked to more than one Serious AE). 5% threshold applied to total and individual frequent AEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    bosentan 2mg/kg t.i.d.
    Reporting group description
    2 mg/kg bosentan was administered 3 times a day for a cumulative mean (± SD) duration of 60.4 ± 4.20 weeks (FUTURE 3 core + extension studies)

    Reporting group title
    bosentan 2mg/kg b.i.d.
    Reporting group description
    2 mg/kg bosentan was administered twice daily for a cumulative mean (± SD) duration of 64.1 ± 3.38 weeks (FUTURE 3 core + extension studies)

    Serious adverse events
    bosentan 2mg/kg t.i.d. bosentan 2mg/kg b.i.d.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 31 (41.94%)
    15 / 33 (45.45%)
         number of deaths (all causes)
    4
    8
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Atrial septal defect repair
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac operation
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cyanosis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Mucopolysaccharidosis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary arterial hypertension
         subjects affected / exposed
    2 / 31 (6.45%)
    4 / 33 (12.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 4
    Adenoidal hypertrophyhy
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary hypertensive crisis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multi-organ failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic disorder
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchopneumonia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    bosentan 2mg/kg t.i.d. bosentan 2mg/kg b.i.d.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 31 (74.19%)
    24 / 33 (72.73%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Cough
         subjects affected / exposed
    3 / 31 (9.68%)
    4 / 33 (12.12%)
         occurrences all number
    3
    4
    Epistaxis
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 33 (0.00%)
         occurrences all number
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Nasal congestion
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 31 (22.58%)
    5 / 33 (15.15%)
         occurrences all number
    15
    15
    Oedema peripheral
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 33 (12.12%)
         occurrences all number
    10
    5
    Diarrhoea
         subjects affected / exposed
    6 / 31 (19.35%)
    2 / 33 (6.06%)
         occurrences all number
    9
    2
    Constipation
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 33 (3.03%)
         occurrences all number
    4
    1
    Abdominal pain
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Urticaria
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Rash
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 31 (41.94%)
    9 / 33 (27.27%)
         occurrences all number
    26
    22
    Nasopharyngitis
         subjects affected / exposed
    5 / 31 (16.13%)
    6 / 33 (18.18%)
         occurrences all number
    8
    16
    Gastroentiritis
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 33 (9.09%)
         occurrences all number
    3
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 31 (9.68%)
    4 / 33 (12.12%)
         occurrences all number
    3
    6
    Bronchitis
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 33 (9.09%)
         occurrences all number
    2
    4
    Viral infection
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Otitis media
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         occurrences all number
    1
    5
    Respiratory tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         occurrences all number
    2
    3
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Influenza
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Ear infection
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Laryngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    4
    Otitis media chronic
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Pharyngitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Rhinitis
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Tonsilitis
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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