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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
    		 v1
    This version publication date
    18 Jul 2016
    First version publication date
    12 Apr 2015
    Other versions
    		 v2 , v3

    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?
    Yes
    Primary completion date
    13 Aug 2014
    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
    Poland: 5
    Country: Number of subjects enrolled
    Spain: 3
    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
    Italy: 1
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Ukraine: 1
    Country: Number of subjects enrolled
    Belarus: 3
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    India: 3
    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
    		 Patients were recruited from 30 centers worldwide

    Pre-assignment
    Screening details
    		 Treatment groups assigned at randomization of FUTURE 3 core study were continued in the extension study.

    Period 1
    Period 1 title
    core future 3 period (baseline)
    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
    		 2 mg/kg bosentan was administered twice daily (morning and evening)
    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
    		 2 mg/kg bosentan was administered 3 times a day (morning, afternoon, evening)
    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
    33
    31
    Period 2
    Period 2 title
    treatment extension period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 bosentan 2mg/kg b.i.d.
    Arm description
    		 patients on 2 mg/kg bosentan b.i.d. during the FUTURE 3 core period continued with the same dose regimen (2 mg/kg, morning and evening)
    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 on 2 mg/kg bosentan t.i.d. during the FUTURE 3 core period continued with the same dose regimen (2 mg/kg, morning, afternoon and evening)
    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 2
    		bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d.
    Started
    33
    31
    Completed
    23
    22
    Not completed
    10
    9
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    6
    5
         administrative reason
    1
    -
         PAH not the main etiology of PH
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    bosentan 2mg/kg b.i.d.
    Reporting group description
    		 2 mg/kg bosentan was administered twice daily (morning and evening)

    Reporting group title
    bosentan 2mg/kg t.i.d.
    Reporting group description
    		 2 mg/kg bosentan was administered 3 times a day (morning, afternoon, evening)

    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
    Units: years
        arithmetic mean (standard deviation)
    		 4.5 ( 0.58 ) 5.2 ( 0.68 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 10 28
        Male
    		 15 21 36
    PAH etiology
    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
    Units: Subjects
        FC I
    		 9 10 19
        FC II
    		 12 15 27
        FC III
    		 12 6 18

    End points

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    End points reporting groups
    Reporting group title
    bosentan 2mg/kg b.i.d.
    Reporting group description
    		 2 mg/kg bosentan was administered twice daily (morning and evening)

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

    Reporting group title
    bosentan 2mg/kg t.i.d.
    Reporting group description
    		 patients on 2 mg/kg bosentan t.i.d. during the FUTURE 3 core period continued with the same dose regimen (2 mg/kg, morning, afternoon and evening)

    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: Statistical analysis not applicable as no primary endpoint was defined for this exploratory study
    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: WHO functional class

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    End point title
    		 WHO functional class
    End point description
    Change from baseline up to 18 months of treatment over FUTURE 3 core and extension studies in WHO FC
    End point type
    Other pre-specified
    End point timeframe
    Baseline to month 18
    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: global clinical impression scale

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    End point title
    		 global clinical impression scale
    End point description
    Change from baseline up to 18 months of treatment over FUTURE 3 core and extension studies in GCIS assessed by the physician
    End point type
    Other pre-specified
    End point timeframe
    Baseline to month 18
    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
    57
    70
    63
        Improved, Month 12
    36
    26
    31
        Worsened, Month 12
    7
    4
    6
        Stable, Month 18
    47
    67
    57
        Improved, Month 18
    32
    28
    30
        Worsened, Month 18
    21
    5
    13
    No statistical analyses for this end point

    Other pre-specified: PAH worsening components

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    End point title
    		 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: PAH progression time

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    End point title
    		 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) at month 18 in the 2 treatment groups
    End point type
    Other pre-specified
    End point timeframe
    From baseline 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: kaplan-Meier estimates
        number (confidence interval 95%)
    68.2 (48.9 to 81.5)
    81 (60.1 to 91.7)
    74.1 (60.8 to 83.6)
    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
    From baseline 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
    31
    64
    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)
    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)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    bosentan 2mg/kg b.i.d.
    Reporting group description
    		 2 mg/kg bosentan was administered twice daily (morning and evening)

    Reporting group title
    bosentan 2mg/kg t.i.d.
    Reporting group description
    		 2 mg/kg bosentan was administered 3 times a day (morning, afternoon, evening)

    Serious adverse events
    		 bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 33 (45.45%)
    13 / 31 (41.94%)
         number of deaths (all causes)
    8
    4
         number of deaths resulting from adverse events
    Investigations
    Body temperature increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Mucopolysaccharidosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 31 (3.23%)
         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
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Atrial septal defect repair
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac operation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (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
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         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
    4 / 33 (12.12%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Adenoidal hypertrophyhy
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertensive crisis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 31 (9.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bronchopneumonia
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 31 (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
    1 / 33 (3.03%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 bosentan 2mg/kg b.i.d. bosentan 2mg/kg t.i.d.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 33 (75.76%)
    24 / 31 (77.42%)
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    Liver function test abnormal
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 33 (15.15%)
    7 / 31 (22.58%)
         occurrences all number
    15
    15
    Oedema peripheral
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 31 (19.35%)
         occurrences all number
    5
    10
    Diarrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    6 / 31 (19.35%)
         occurrences all number
    2
    9
    Constipation
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 31 (9.68%)
         occurrences all number
    1
    4
    Abdominal pain
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Pulmonary arterial hypertension
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Cough
         subjects affected / exposed
    4 / 33 (12.12%)
    3 / 31 (9.68%)
         occurrences all number
    4
    3
    Epistaxis
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    0
    4
    Rhinorrhoea
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    Nasal congestion
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Urticaria
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 33 (27.27%)
    13 / 31 (41.94%)
         occurrences all number
    22
    26
    Nasopharyngitis
         subjects affected / exposed
    6 / 33 (18.18%)
    5 / 31 (16.13%)
         occurrences all number
    16
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 33 (12.12%)
    3 / 31 (9.68%)
         occurrences all number
    6
    3
    Gastroentiritis
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 31 (9.68%)
         occurrences all number
    3
    3
    Bronchitis
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 31 (6.45%)
         occurrences all number
    4
    2
    Viral infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 31 (3.23%)
         occurrences all number
    2
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    Otitis media
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 31 (3.23%)
         occurrences all number
    5
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 31 (3.23%)
         occurrences all number
    2
    2
    Ear infection
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Influenza
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    Laryngitis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    Otitis media chronic
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    Rhinitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    3
    Tonsilitis
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2

    More information

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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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