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

    Summary
    EudraCT number
    2010-021825-11
    Trial protocol
    NL   HU   DE   ES   CZ   FR   IT   BG   Outside EU/EEA  
    Global end of trial date
    26 Aug 2013

    Results information
    Results version number
    v3(current)
    This version publication date
    14 Jun 2017
    First version publication date
    06 Aug 2015
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    correction of the unit for hemoglobin

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-052-373
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01223352
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000425-PIP02-10
    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
    25 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the pharmacokinetics (PK) of the dispersible tablet formulation of bosentan at doses of 2 mg/kg b.i.d. and 2 mg/kg t.i.d. in children with pulmonary arterial hypertension (PAH) from ≥ 3 months to < 12 years of age.
    Protection of trial subjects
    This clinical study was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCPs, with the ethical principles laid down in the ‘Declaration of Helsinki’ and with the laws and regulations of the countries in which the research was conducted. Child’s parents or legal representatives were asked if they agreed that their child took part in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study.
    Background therapy
    The following medications were allowed to be taken along with the study drug: anticoagulants, diuretics, digoxin, calcium channel blockers, prostanoids and phosphodiesterase-5 inhibitors. All background PAH therapies were required to be maintained at a stable dose during the study. Intiation or dose increase of ongoing PAH-specific therapy (prostanoids and / or phosphodiesterase-5 inhibitors) was required to be associated with PAH progression, and this led to study discontinuation. Patients receiving the commercial formulation of bosentan (adult tablet formulation) before entering the FUTURE 3 study had to stop it and instead take the study drug (dispersible tablet formulation).
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Mar 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    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
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Ukraine: 1
    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 45 expert pediatric centers in 20 countries worldwide.

    Pre-assignment
    Screening details
    The screening period took place within 4 weeks prior to enrollment into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Bosentan 2 mg/kg t.i.d.
    Arm description
    2 mg/kg bosentan was administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks
    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
    32 mg quadrisected dispersible tablet. The dosage of bosentan was adjusted according to the patient’s body weight at initiation of the study treatment and adminsitered after dispersion in a teaspoon of water. Dosage readjustment, by steps of 8 mg, was permitted after 12 weeks of treatment.

    Arm title
    Bosentan 2 mg/kg b.i.d.
    Arm description
    2 mg/kg bosentan was administered twice daily (morning and evening) for a planned duration of 24 weeks
    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
    32 mg quadrisected dispersible tablet. The dosage of bosentan was adjusted according to the patient’s body weight at initiation of the study treatment and adminsitered after dispersion in a teaspoon of water. Dosage readjustment, by steps of 8 mg, was permitted after 12 weeks of treatment.

    Number of subjects in period 1
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d.
    Started
    31
    33
    Completed
    31
    33

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bosentan 2 mg/kg t.i.d.
    Reporting group description
    2 mg/kg bosentan was administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks

    Reporting group title
    Bosentan 2 mg/kg b.i.d.
    Reporting group description
    2 mg/kg bosentan was administered twice daily (morning and evening) for a planned duration of 24 weeks

    Reporting group values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d. Total
    Number of subjects
    31 33 64
    Age categorical
    Units: Subjects
        Children (2-11 years)
    20 23 43
        Infants and toddlers (28 days-23 months)
    11 10 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    5.2 ± 3.81 4.5 ± 3.35 -
    Gender categorical
    Units:
        Female
    10 18 28
        Male
    21 15 36
    PAH etiology
    Units: Subjects
        Idiopathic
    15 14 29
        Heritable
    0 2 2
        Congenital heart disease associated w/ open shunts
    2 6 8
        Associated PAH
    13 11 24
        Missing data
    1 0 1
    WHO functional class (FC)
    Units: Subjects
        FC I
    10 9 19
        FC II
    15 12 27
        FC III
    6 12 18
    PAH-specifc therapy at baseline
    Units: Subjects
        Bosentan (adult tablet formulation)
    4 3 7
        Prostanoid
    1 0 1
        PDE-5 inhibitor
    13 10 23
        Bosentan / PDE-5 inhibitor combination
    2 2 4
        Bosentan / PDE-5 inhibitor/ prostanoid combination
    2 5 7
        None
    9 13 22
    Subject analysis sets

    Subject analysis set title
    All-treated set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set includes all randomized patients who received at least one dose of study drug. Because all randomized patients received study drug at least once, the all-randomized set and the all-treated set are identical. Baseline characteristics,safety data and exploratory endpoints were analyzed using this analysis set.

    Subject analysis set title
    Pharmacokinetic (PK) set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    This analysis set includes patients in the all-treated set without any major protocol violation and for whom at least 5 of the 6 blood samples requested for PK assessments were available. This set was used for the analysis of the pharmacokinetic data.

    Subject analysis sets values
    All-treated set Pharmacokinetic (PK) set
    Number of subjects
    64
    58
    Age categorical
    Units: Subjects
        Children (2-11 years)
    43
    41
        Infants and toddlers (28 days-23 months)
    21
    17
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    4.8 ± 3.57
    4.9 ± 3.47
    Gender categorical
    Units:
        Female
    28
    24
        Male
    36
    34
    PAH etiology
    Units: Subjects
        Idiopathic
    29
        Heritable
    2
        Congenital heart disease associated w/ open shunts
    8
        Associated PAH
    24
        Missing data
    1
    WHO functional class (FC)
    Units: Subjects
        FC I
    19
        FC II
    27
        FC III
    18
    PAH-specifc therapy at baseline
    Units: Subjects
        Bosentan (adult tablet formulation)
    7
        Prostanoid
    1
        PDE-5 inhibitor
    23
        Bosentan / PDE-5 inhibitor combination
    4
        Bosentan / PDE-5 inhibitor/ prostanoid combination
    7
        None
    22

    End points

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    End points reporting groups
    Reporting group title
    Bosentan 2 mg/kg t.i.d.
    Reporting group description
    2 mg/kg bosentan was administered three times a day (morning, afternoon, evening) for a planned duration of 24 weeks

    Reporting group title
    Bosentan 2 mg/kg b.i.d.
    Reporting group description
    2 mg/kg bosentan was administered twice daily (morning and evening) for a planned duration of 24 weeks

    Subject analysis set title
    All-treated set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    This analysis set includes all randomized patients who received at least one dose of study drug. Because all randomized patients received study drug at least once, the all-randomized set and the all-treated set are identical. Baseline characteristics,safety data and exploratory endpoints were analyzed using this analysis set.

    Subject analysis set title
    Pharmacokinetic (PK) set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    This analysis set includes patients in the all-treated set without any major protocol violation and for whom at least 5 of the 6 blood samples requested for PK assessments were available. This set was used for the analysis of the pharmacokinetic data.

    Primary: Daily exposure to bosentan [AUC(0-24c)]

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    End point title
    Daily exposure to bosentan [AUC(0-24c)]
    End point description
    Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. The area under the concentration-time curve over a period of 24 hours [AUC(0-24)] was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) [AUC(0-24c)].
    End point type
    Primary
    End point timeframe
    At Week 4, after at least 2 weeks of stable study drug treatment.
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d. Pharmacokinetic (PK) set
    Number of subjects analysed
    27
    31
    58
    Units: h*ng/mL
        geometric mean (confidence interval 95%)
    7275.1 (5468.2 to 9679)
    8535.4 (6936 to 10503.7)
    7923.6 (6692.4 to 9381.3)
    Statistical analysis title
    Treatment comparison of daily exposure
    Statistical analysis description
    Ratio of geometric means between the t.i.d. and b.i.d. dosing regimen (b.i.d. bosentan regimen taken as reference)
    Comparison groups
    Bosentan 2 mg/kg t.i.d. v Bosentan 2 mg/kg b.i.d.
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Ratio of geometric means
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.2
    Notes
    [1] - No statistical hypothesis tests were set for this study. The analysis of PK data was carried out descriptively.

    Other pre-specified: Maximum plasma concentration of bosentan (Cmaxc)

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    End point title
    Maximum plasma concentration of bosentan (Cmaxc)
    End point description
    Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. The peak plasma concentration (Cmax) of bosentan was directly obtained from the measured plasma concentrations and was dose-corrected to the target dose of 2 mg/kg (Cmaxc).
    End point type
    Other pre-specified
    End point timeframe
    At Week 4, after at least 2 weeks of stable study drug treatment.
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d. Pharmacokinetic (PK) set
    Number of subjects analysed
    27
    31
    58
    Units: ng/mL
        geometric mean (confidence interval 95%)
    527.9 (386 to 721.9)
    742.8 (572.8 to 963.2)
    633.6 (518.7 to 774)
    Statistical analysis title
    Ratio of geometric means for Cmax
    Statistical analysis description
    Ratio of geometric means between the t.i.d. and b.i.d. dosing regimen (b.i.d. bosentan regimen taken as reference), unadjusted
    Comparison groups
    Bosentan 2 mg/kg t.i.d. v Bosentan 2 mg/kg b.i.d.
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    ratio of geometric means
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    1.05
    Notes
    [2] - No statistical hypothesis tests were set for this study. The analysis of PK data was carried out descriptively.

    Other pre-specified: Time to reach Cmax of bosentan (tmax)

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    End point title
    Time to reach Cmax of bosentan (tmax)
    End point description
    Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. tmax was obtained directly from the measured plasma concentrations.
    End point type
    Other pre-specified
    End point timeframe
    At Week 4, after at least 2 weeks of stable study drug treatment
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d. Pharmacokinetic (PK) set
    Number of subjects analysed
    27
    31
    58
    Units: hours
        median (full range (min-max))
    3 (1 to 8)
    3 (0 to 7.5)
    3 (0 to 8)
    No statistical analyses for this end point

    Other pre-specified: Daily exposure to bosentan metabolites (Ro 47-8634, Ro 48-5033, Ro 64-1056)

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    End point title
    Daily exposure to bosentan metabolites (Ro 47-8634, Ro 48-5033, Ro 64-1056)
    End point description
    Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 12 hours or up to 8 hours post-dose for the b.i.d and t.i.d. dosing regimen, respectively. Daily exposure to the metabolites corresponds to the area under the concentration-time curve [AUC(0-24)c] of the corresponding metabolite over a period of 24 hours, and was calculated in the same manner as the primary endpoint.
    End point type
    Other pre-specified
    End point timeframe
    At Week 4, after at least 2 weeks of stable study drug treatment.
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d. Pharmacokinetic (PK) set
    Number of subjects analysed
    27
    31
    58
    Units: h*ng/mL
    geometric mean (confidence interval 95%)
        Ro 47-8634
    173.2 (126.2 to 237.6)
    200.4 (152.2 to 263.9)
    187.2 (152.9 to 229.3)
        Ro 48-5033
    968.8 (723.3 to 1297.7)
    1352.5 (1073.4 to 1704)
    1157.9 (964 to 1390.9)
        Ro 64-1056
    716.2 (543.5 to 943.8)
    1014.1 (801.2 to 1283.6)
    862.5 (720.3 to 1032.9)
    No statistical analyses for this end point

    Other pre-specified: Change from baseline in WHO functional class at end of study

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    End point title
    Change from baseline in WHO functional class at end of study
    End point description
    Number of patients with improvement, worsening or no change in WHO functional class at end of study compared to baseline.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and end of study
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d.
    Number of subjects analysed
    31
    33
    Units: Number of subjects
    number (not applicable)
        Worsened
    1
    1
        Unchanged
    27
    25
        Improved
    3
    7
    No statistical analyses for this end point

    Other pre-specified: Change from baseline in Global clincial impression scale (GCIS) at end of study

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    End point title
    Change from baseline in Global clincial impression scale (GCIS) at end of study
    End point description
    The GCIS is an assessment tool to rate the patient’s current overall clinical condition (“Very Good”, “Good”, “Neither Good or Bad”, “Bad” and “Very Bad”). The assessment was performed both by the physician and the parents / legal representatives independently. Number of patients with clinical condition (as measured by the GCIS) considered as worsened, improved or unchanged are reported here.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and end of study
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d.
    Number of subjects analysed
    31
    33
    Units: Number of subjects
    number (not applicable)
        Worsened- Physician
    2
    2
        Unchanged- Physician
    24
    24
        Improved- Physician
    5
    7
        Worsened- Parents
    4
    3
        Unchanged- Parents
    19
    19
        Improved- Parents
    8
    11
    No statistical analyses for this end point

    Other pre-specified: Number of patients with treatment-emergent liver function abnormalities

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    End point title
    Number of patients with treatment-emergent liver function abnormalities
    End point description
    Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 x ULN (upper limit of normal) The worst post-baseline value was considered.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to 7 days after end of treatment
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d.
    Number of subjects analysed
    30
    33
    Units: percentage
    number (not applicable)
        ALT > 3 x ULN
    1
    0
        AST > 3 x ULN
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Number of patients with treatment-emergent hemoglobin abnormalities

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    End point title
    Number of patients with treatment-emergent hemoglobin abnormalities
    End point description
    Number of patientsof patients with marked hemoglobin decreases. The worst post-baseline value was considered.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to 7 days after end of treatment
    End point values
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d.
    Number of subjects analysed
    30
    33
    Units: Percentage
    number (not applicable)
        Hemoglobin decrease with values < 10 g/dL
    1
    3
        Hemoglobin decrease with values < 8 g/dL
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to 7 days after end of treatment
    Adverse event reporting additional description
    1-SAEs with fatal outcome are not mutually exclusive (One death related to concomitant bronchopneumonia and PAH) 2-One patient (group 2 mg/kg t.i.d). experienced a SAE (adenoviral gastroenteritis) that was reported to the investigator by the parents about 2 months after database closure. This SAE is not displayed below but in the extension study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Bosentan 2 mg/kg t.i.d.
    Reporting group description
    Subjects received 2 mg/kg bosentan 3 times a day for at least 0.4 week to a maximum duration of 28.7 weeks.

    Reporting group title
    Bosentan 2 mg/kg b.i.d.
    Reporting group description
    Subjects received 2 mg/kg bosentan twice daily for a at least 6 weeks to a maximum duration of 26.4 weeks.

    Serious adverse events
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d.
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 33 (12.12%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    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
    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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary arterial hypertension
         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 / 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
    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
    Nervous system disorders
    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
    General disorders and administration site conditions
    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 / 0
    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
    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 / 0
    Infections and infestations
    Bronchopneumonia
         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
    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
    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
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Bosentan 2 mg/kg t.i.d. Bosentan 2 mg/kg b.i.d.
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 31 (58.06%)
    18 / 33 (54.55%)
    Vascular disorders
    Flushing
         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
    Cough
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Epistaxis
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 33 (0.00%)
         occurrences all number
    3
    0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 33 (12.12%)
         occurrences all number
    7
    7
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Diarrhea
         subjects affected / exposed
    4 / 31 (12.90%)
    2 / 33 (6.06%)
         occurrences all number
    5
    2
    Vomiting
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 33 (3.03%)
         occurrences all number
    7
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Otitis media
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 31 (9.68%)
    5 / 33 (15.15%)
         occurrences all number
    4
    8
    Respiratory tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         occurrences all number
    2
    3
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 31 (35.48%)
    6 / 33 (18.18%)
         occurrences all number
    13
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2012
    Due to the difficulties in recruitment, inclusion criteria was modified as follows : Reduction of the proportion of patients < 2 years of age and possibility to include patients with pulmonary arterial hypertension associated with unrepaired congenital heart defect

    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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