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    Clinical Trial Results:
    An open-label, long-term, safety, and tolerability extension study using the pediatric formulation of bosentan in the treatment of children with idiopathic or familial pulmonary arterial hypertension who completed FUTURE 1

    Summary
    EudraCT number
    2005-001967-70
    Trial protocol
    GB   DE   IT  
    Global end of trial date
    28 Oct 2011

    Results information
    Results version number
    v2(current)
    This version publication date
    17 Jun 2016
    First version publication date
    06 Aug 2015
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-052-367
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00319020
    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?
    Yes
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Oct 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the long-term safety and tolerability of the pediatric formulation of bosentan in children with idiopathic or familial pulmonary arterial hypertension (iPAH or fPAH)
    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 of the countries where the study was conducted, and with the ethical principles laid down in the Declaration of Helsinki. Only patients who completed the FUTURE 1 study, who tolerated bosentan 32 mg dispersible tablets (pediatric formulation) during FUTURE 1 and for whom continuation of bosentan treatment was considered beneficial by the investigator, were offered the oppurtunity to participate in the FUTURE 1 Extension trial.
    Background therapy
    The following concomitant medications were allowed at inclusion and during the study: calcium channel blockers, intravenous epoprostenol, intravenous or inhaled iloprost, anticoagulants, diuretics, digoxin
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Aug 2005
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    36
    EEA total number of subjects
    28
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    36
    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
    36 Children (≥ 2 years and < 12 years) with idiopathic or familial pulmonary arterial hypertension were recruited from 11 centers across Europe and USA and enrolled in the FUTURE 1 trial (baseline). Only patients who completed FUTURE 1 (n=34) could be enrolled in FUTURE 2. Enrollment in FUTURE 2 started August 23, 2005.

    Pre-assignment
    Screening details
    The actual number of patients enrolled in FUTURE 2 was 33 because 2 patients did not complete FUTURE 1 and one patient completed FUTURE 1 but was not enrolled in FUTURE 2.

    Period 1
    Period 1 title
    Overall trial (FUTURE 1 + FUTURE 2) (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    In this open-label extension trial, all subjects received the pediatric formulation of bosentan according to the core (FUTURE 1) study drug regimen, with the aim to determine its long term safety.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Patients with previous bosentan
    Arm description
    This group included patients who already received bosentan (film-coated tablets) before enrollment in FUTURE 1, and then received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen.
    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 pediatric formulation of bosentan was initiated at a dose of 2 mg/kg b.i.d. for 4 weeks, then uptitrated to the maintenance dose of 4 mg/kg b.i.d. for the next 8 weeks of the FUTURE 1 trial (AC-052- 365) and to be continued in FUTURE 2. The dose could be down-titrated to 2 mg/kg b.i.d. if not tolerated. The body weight-adjusted dose of the dispersible tablet was dispersed in a teaspoon of water (not mixed with food) before being administered orally.

    Arm title
    Bosentan-naive Patients
    Arm description
    This group included patients who were not treated with bosentan before enrollment in FUTURE 1, and received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen.
    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 pediatric formulation of bosentan was initiated at a dose of 2 mg/kg b.i.d. for 4 weeks, then uptitrated to the maintenance dose of 4 mg/kg b.i.d. for the next 8 weeks of the FUTURE 1 trial (AC-052- 365) and to be continued in FUTURE 2. The dose could be down-titrated to 2 mg/kg b.i.d. if not tolerated. The body weight-adjusted dose of the dispersible tablet was dispersed in a teaspoon of water (not mixed with food) before being administered orally.

    Number of subjects in period 1
    Patients with previous bosentan Bosentan-naive Patients
    Started
    15
    21
    Enrollment in FUTURE 2
    13
    20
    Completed
    8
    8
    Not completed
    7
    13
         Death
    2
    2
         Administrative reason
    -
    5
         FUTURE 1 completed but not enrolled in FUTURE 2
    1
    -
         Transplant
    -
    1
         Treatment failure
    -
    1
         Adverse event, non-fatal
    -
    1
         Consent withdrawn by subject
    4
    1
         Disease progression
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Patients with previous bosentan
    Reporting group description
    This group included patients who already received bosentan (film-coated tablets) before enrollment in FUTURE 1, and then received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen.

    Reporting group title
    Bosentan-naive Patients
    Reporting group description
    This group included patients who were not treated with bosentan before enrollment in FUTURE 1, and received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen.

    Reporting group values
    Patients with previous bosentan Bosentan-naive Patients Total
    Number of subjects
    15 21 36
    Age categorical
    Age when starting FUTURE 1 trial (baseline)
    Units: Subjects
        Children (2-3 years)
    1 3 4
        Children (4-5 years)
    3 6 9
        Children (6-11 years)
    11 12 23
    Age continuous
    Age when starting FUTURE 1 trial (baseline)
    Units: years
        median (full range (min-max))
    7 (3 to 10) 7 (2 to 11) -
    Gender categorical
    Units:
        Female
    5 10 15
        Male
    10 11 21
    Etiology of PAH
    Units: Subjects
        Idiopathic PAH
    12 19 31
        Familial PAH
    3 2 5
    Duration of PAH
    Units: months
        median (full range (min-max))
    37.6 (1.2 to 82.6) 14 (0 to 133.5) -

    End points

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    End points reporting groups
    Reporting group title
    Patients with previous bosentan
    Reporting group description
    This group included patients who already received bosentan (film-coated tablets) before enrollment in FUTURE 1, and then received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen.

    Reporting group title
    Bosentan-naive Patients
    Reporting group description
    This group included patients who were not treated with bosentan before enrollment in FUTURE 1, and received the pediatric formulation of bosentan during FUTURE 1 and FUTURE 2 (see "Dosage and administration details" of the investigational medicinal compound). Note: In this single arm trial, data are presented according to whether patients received bosentan or not before enrollment in FUTURE 1 but all the subjects received the study drug according to the same regimen.

    Subject analysis set title
    All-treated set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All patients (bosentan-naive patients and patients treated with film-coated bosentan tablets before enrollment) who received at least one dose of study drug (dispersible bosentan tablets) in the combined FUTURE 1 / FUTURE 2 trial periods.

    Primary: Change from baseline to end of study (EOS) in systolic blood pressure (SBP)

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    End point title
    Change from baseline to end of study (EOS) in systolic blood pressure (SBP) [1]
    End point description
    The main study objective was to assess the long-term safety of bosentan in children with PAH, including changes from baseline in blood pressure. Only subjects with non missing data at both time points were considered.
    End point type
    Primary
    End point timeframe
    From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
    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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    10
    14
    24
    Units: mmHg
    median (full range (min-max))
        SBP at baseline
    101.5 (87 to 115)
    104 (79 to 121)
    102.5 (79 to 121)
        SBP change from baseline to EOS
    -10.5 (-20 to 25)
    4 (-21 to 28)
    -4.5 (-21 to 28)
    No statistical analyses for this end point

    Primary: Change from baseline to end of study (EOS) in diastolic blood pressure (DBP)

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    End point title
    Change from baseline to end of study (EOS) in diastolic blood pressure (DBP) [2]
    End point description
    The main study objective was to assess the long-term safety of bosentan in children with PAH, including changes from baseline in blood pressure. Only subjects with non missing data at both time points were considered.
    End point type
    Primary
    End point timeframe
    From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
    Notes
    [2] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    10
    13
    23
    Units: mmHg
    median (full range (min-max))
        DBP at baseline
    54.5 (47 to 94)
    60 (52 to 75)
    59 (47 to 94)
        DBP change from baseline to EOS
    -5 (-34 to 19)
    -2 (-13 to 20)
    -3 (-34 to 20)
    No statistical analyses for this end point

    Primary: Change from baseline to end of study (EOS) in pulse rate

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    End point title
    Change from baseline to end of study (EOS) in pulse rate [3]
    End point description
    The main study objective was to assess the long-term safety of bosentan in children with PAH, including changes from baseline in pulse rate. Only subjects with non missing data at both time points were considered.
    End point type
    Primary
    End point timeframe
    From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    11
    14
    25
    Units: beats per minutes
    median (full range (min-max))
        Pulse rate at baseline
    87 (55 to 118)
    94.5 (62 to 133)
    88 (55 to 133)
        Pulse rate: change from baseline to EOS
    -11 (-46 to 36)
    -10 (-30 to 11)
    -11 (-46 to 36)
    No statistical analyses for this end point

    Primary: Change from baseline to end of study (EOS) in body weight

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    End point title
    Change from baseline to end of study (EOS) in body weight [4]
    End point description
    The main study objective was to assess the long-term safety of bosentan in children with PAH, including growth as measured by changes from baseline in body weight and height.
    End point type
    Primary
    End point timeframe
    From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
    Notes
    [4] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    10
    14
    24
    Units: kg
    median (full range (min-max))
        Weight at baseline
    19.6 (12.5 to 30.2)
    21.6 (11 to 39)
    19.6 (11 to 39)
        Weight change from baseline to EOS
    8.2 (5 to 24.8)
    8.5 (1.8 to 18.5)
    8.3 (1.8 to 24.8)
    No statistical analyses for this end point

    Primary: Change from baseline to end of study (EOS) in height for age

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    End point title
    Change from baseline to end of study (EOS) in height for age [5]
    End point description
    The main study objective was to assess the long-term safety of bosentan in children with PAH, including growth as measured by changes from baseline in body weight and height. For each patient, height was put in the perspective of the height of healthy children of the same age according to the WHO growth standards.
    End point type
    Primary
    End point timeframe
    From baseline (FUTURE 1) up to end of study or premature study treatment discontinuation (FUTURE 1 or FUTURE 2)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    10
    14
    24
    Units: Z-score
    median (full range (min-max))
        Z-score at baseline
    -0.8 (-3.32 to 3.72)
    0.32 (-2.62 to 1.99)
    -0.64 (-3.32 to 3.72)
        Z-score at EOS
    -0.74 (-3.52 to 2.78)
    -0.08 (-2.44 to 1.84)
    -0.36 (-3.52 to 2.78)
        Z-score change from baseline to EOS
    -0.05 (-0.94 to 0.91)
    -0.01 (-0.77 to 1.08)
    -0.01 (-0.94 to 1.08)
    No statistical analyses for this end point

    Primary: Proportion of patients with treatment-emergent liver function abnormalities

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    End point title
    Proportion of patients with treatment-emergent liver function abnormalities [6]
    End point description
    The main study objective was to assess the long-term safety of bosentan in children with PAH, including laboratory abnormalities related to liver enzymes. Proportion of patients with increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above 3 x ULN (upper limit of normal) is reported here.
    End point type
    Primary
    End point timeframe
    After baseline, up to 1 calendar day after study drug discontinuation in FUTURE 1 or FUTURE 2
    Notes
    [6] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    15
    21
    36
    Units: Percentage
    number (not applicable)
        ALT > 3x ULN
    0
    4.8
    2.8
        AST > 3 x ULN
    0
    4.8
    2.8
    No statistical analyses for this end point

    Primary: Proportion of patients with treatment-emergent hemoglobin abnormalities

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    End point title
    Proportion of patients with treatment-emergent hemoglobin abnormalities [7]
    End point description
    The main study objective was to assess the long-term safety of bosentan in children with PAH, including hemoglobin abnormalities. Proportion of patients with marked hemoglobin decreases (i.e., decrease of or above 15% of the lower normal limit (LL)) is reported here.
    End point type
    Primary
    End point timeframe
    After baseline, up to 1 calendar day after study drug discontinuation in FUTURE 1 or FUTURE 2
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    15
    21
    36
    Units: percentage
        number (not applicable)
    13.3
    9.5
    11.1
    No statistical analyses for this end point

    Primary: Number of subjects with adverse events leading to premature discontinuation of study treatment

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    End point title
    Number of subjects with adverse events leading to premature discontinuation of study treatment [8]
    End point description
    End point type
    Primary
    End point timeframe
    From the first study drug administration in FUTURE 1
    Notes
    [8] - 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: This was an exploratory study; no statistical hypothesis was set and only descriptive analyses were performed
    End point values
    Patients with previous bosentan Bosentan-naive Patients All-treated set
    Number of subjects analysed
    15
    21
    36
    Units: Number of subjects
    1
    5
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study drug initiation up to 1 day after study drug discontinuation (up to 28 days after study drug discontinuation for serious adverse events)
    Adverse event reporting additional description
    Four deaths occurred during this time frame and two other deaths (1 due to PAH and cardiac complications and 1 during cardiac catheterization; not listed below) occurred later (38 days and 11 months after study drug discontinuation, respectively).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    All treated set
    Reporting group description
    The 36 patients included in this analysis set were exposed to the study drug (pediatric formulation of bosentan), for at least 8.4 weeks up to a maximum of 258 weeks (median: 119.9 weeks).

    Serious adverse events
    All treated set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 36 (50.00%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Arterial catheterisation
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheterisation cardiac
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary arterial pressure
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Systemic pulmonary artery shunt
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Adenoidectomy
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Balloon atrial septostomy
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Right ventricular failure
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pericardial effusion
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary arterial hypertension
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary vein stenosis
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dystonia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injection site nodule
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral rhinitis
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All treated set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 36 (72.22%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Vascular disorders
    Flushing
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    5
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Palpitations
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Pulmonary arterial hypertension
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    4
    Nasal congestion
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    4
    Pulmonary hypertension
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Cough
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    4
    Epistaxis
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    7
    Dizziness
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    4
    Syncope
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    6
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    4
    Chest pain
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    10
    Pyrexia
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Adverse drug reaction
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    3
    Fatigue
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    3
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 36 (16.67%)
         occurrences all number
    7
    Abdominal pain upper
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    4
    Vomiting
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Renal and urinary disorders
    Enurisis
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 36 (19.44%)
         occurrences all number
    11
    Bronchitis
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    6
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 36 (13.89%)
         occurrences all number
    7
    Pneumonia
         subjects affected / exposed
    3 / 36 (8.33%)
         occurrences all number
    7
    Influenza
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    H1N1 influenza
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Otitis media
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2
    Tonsilitis
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    2 / 36 (5.56%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Aug 2008
    The purpose of this amendment is to adjust the monitoring schedule during this open label extension study.

    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.
    In 3 patients new therapy was initiated in spite of absence of clinical worsening, reflecting a changing treatment paradigm towards combination therapy. The patients were kept in the time to PAH worsening analyses.
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