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    Clinical Trial Results:
    A randomized, open label study comparing safety and efficacy parameters for a high and a low dose of ambrisentan (adjusted for body weight) for the treatment of pulmonary arterial hypertension in paediatric patients aged 8 years up to 18 years

    Summary
    EudraCT number
    		 2010-019547-19
    Trial protocol
    		 GR   NL   HU   DE   ES   FR   IT   Outside EU/EEA  
    Global end of trial date
    12 Nov 2013

    Results information
    Results version number
    		 v1
    This version publication date
    24 Aug 2019
    First version publication date
    24 Aug 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    AMB112529
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000434-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    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
    12 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability, pharmacokinetics and efficacy of ambrisentan in the paediatric PAH population
    Protection of trial subjects
    The independent data monitoring committee (IDMC) were involved in this study to ensure objectives such as medical and/or statistical review of safety and/or efficacy concerns in order to protect the ethical and safety interests of participants and to protect scientific validity of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jan 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Argentina: 6
    Worldwide total number of subjects
    41
    EEA total number of subjects
    15
    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)
    14
    Adolescents (12-17 years)
    27
    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
    		 This study investigated the safety and efficacy of a high and low dose ambrisentan (adjusted as per participants body weight) administered orally in participants aged 8 to 18 years with pulmonary arterial hypertension (PAH).

    Pre-assignment
    Screening details
    		 A total of 41 participants were enrolled and randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Low dose ambrisentan
    Arm description
    		 Participants received ambrisentan low dose tablet either 2.5 milligram (mg) or 5 mg orally once daily for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ambrisentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ambrisentan low dose tablet either 2.5 mg or 5 mg orally once daily for 24 weeks.

    Arm title
    		 High dose ambrisentan
    Arm description
    		 Participants received ambrisentan high dose tablet either 5 mg, 7.5 mg or 10 mg orally once daily for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ambrisentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received ambrisentan high dose tablet either 5 mg, 7.5 mg or 10 mg orally once daily for 24 weeks.

    Number of subjects in period 1
    		Low dose ambrisentan High dose ambrisentan
    Started
    21
    20
    Completed
    19
    18
    Not completed
    2
    2
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Low dose ambrisentan
    Reporting group description
    		 Participants received ambrisentan low dose tablet either 2.5 milligram (mg) or 5 mg orally once daily for 24 weeks.

    Reporting group title
    High dose ambrisentan
    Reporting group description
    		 Participants received ambrisentan high dose tablet either 5 mg, 7.5 mg or 10 mg orally once daily for 24 weeks.

    Reporting group values
    		 Low dose ambrisentan High dose ambrisentan Total
    Number of subjects
    		 21 20 41
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 7 7 14
        Adolescents (12-17 years)
    		 14 13 27
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 11.8 ( 2.70 ) 12.3 ( 2.85 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 12 15 27
        Male
    		 9 5 14
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 2 0 2
        American Indian or Alaskan Native
    		 1 0 1
        Asian - Central/South Asian Heritage
    		 1 0 1
        Asian - East Asian Heritage
    		 1 0 1
        Asian - Japanese Heritage
    		 5 0 5
        Asian - South East Asian Heritage
    		 0 1 1
        White - White/Caucasian/European Heritage
    		 11 19 30

    End points

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    End points reporting groups
    Reporting group title
    Low dose ambrisentan
    Reporting group description
    		 Participants received ambrisentan low dose tablet either 2.5 milligram (mg) or 5 mg orally once daily for 24 weeks.

    Reporting group title
    High dose ambrisentan
    Reporting group description
    		 Participants received ambrisentan high dose tablet either 5 mg, 7.5 mg or 10 mg orally once daily for 24 weeks.

    Primary: Number of participants with treatment-emergent adverse events (AEs) and serious treatment-emergent adverse events (SAEs)

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    End point title
    		 Number of participants with treatment-emergent adverse events (AEs) and serious treatment-emergent adverse events (SAEs) [1]
    End point description
    AEs defined as any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAEs defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect, medical events that may not immediately life threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention as per medical or scientific judgement and events of drug-induced liver injury with hyperbilirubinaemia. Safety population comprised of all randomized participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [2]
    20 [3]
    Units: Participants
        Any AEs
    16
    16
        Any SAEs
    6
    2
    Notes
    [2] - Safety Population
    [3] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with post Baseline Potential Clinical importance (PCI) value for clinical chemistry parameters: alanine amino transferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), total bilirubin and creatinine

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    End point title
    		 Number of participants with post Baseline Potential Clinical importance (PCI) value for clinical chemistry parameters: alanine amino transferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), total bilirubin and creatinine [4]
    End point description
    Blood samples were collected from participants for analysis of following clinical chemistry parameters: ALT, AST, GGT, total bilirubin and creatinine. PCI ranges were <3 times the upper limit of normal (ULN), <34.2 Micromoles per liter (UMOL/L) for total bilirubin and <176.8 (UMOL/L) for creatinine. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [5]
    20 [6]
    Units: Participants
        ALT
    0
    0
        AST
    0
    0
        GGT
    0
    0
        Total bilirubin
    1
    0
        Creatinine
    0
    0
    Notes
    [5] - Safety Population
    [6] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with post Baseline PCI value for hematology parameter: hemoglobin

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    End point title
    		 Number of participants with post Baseline PCI value for hematology parameter: hemoglobin [7]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameters: hemoglobin. PCI ranges were Males: 98 to180 grams per liter (G/L), Females: 91 to 161 (G/L) for hemoglobin. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [8]
    20 [9]
    Units: Participants
        Reference high range
    0
    2
        Reference low range
    1
    0
    Notes
    [8] - Safety Population
    [9] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with post Baseline PCI value for hematology parameter: hematocrit

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    End point title
    		 Number of participants with post Baseline PCI value for hematology parameter: hematocrit [10]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameter: hematocrit. PCI ranges were males: <0.32 to >0.54, females: <0.29 to >0.506 proportion of red blood cells in blood for hematocrit. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    Notes
    [10] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [11]
    20 [12]
    Units: Participants
        Reference high range
    0
    2
        Reference low range
    1
    2
    Notes
    [11] - Safety Population
    [12] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with post Baseline PCI value for hematology parameter: platelet count

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    End point title
    		 Number of participants with post Baseline PCI value for hematology parameter: platelet count [13]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameter: platelet count. PCI ranges were 100 to 400 for Giga cells per liter platelet count. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [14]
    20 [15]
    Units: Participants
        Reference high range
    0
    0
        Reference low range
    0
    1
    Notes
    [14] - Safety Population
    [15] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal value for physical examination parameter: liver size

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    End point title
    		 Number of participants with abnormal value for physical examination parameter: liver size [16]
    End point description
    Physical examination included measurement of liver size. Any abnormal enlargement or reduction in the size of the liver is reported.
    End point type
    Primary
    End point timeframe
    Week 12 and 24
    Notes
    [16] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [17]
    20 [18]
    Units: Participants
        Week 12, Abnormal: Improved, n=20, 19
    1
    1
        Week 12, Abnormal: Worsened, n=20, 19
    1
    1
        Week 12, Abnormal: Unchanged, n=20, 19
    1
    0
        Week 24, Abnormal: Improved, n=19, 18
    2
    1
        Week 24, Abnormal: Worsened, n=19, 18
    0
    0
        Week 24, Abnormal: Unchanged, n=19, 18
    0
    0
    Notes
    [17] - Safety population. Participants with available data at the specified time points were analyzed.
    [18] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Number of participants with abnormal value for physical examination parameter: jugular venous pressure

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    End point title
    		 Number of participants with abnormal value for physical examination parameter: jugular venous pressure [19]
    End point description
    Physical examination of participants jugular venous pressure is measured.
    End point type
    Primary
    End point timeframe
    Week 12 and 24
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [20]
    20 [21]
    Units: Participants
        Week 12, Abnormal: Improved, n=20, 19
    0
    1
        Week 12, Abnormal: Worsened, n=20, 19
    0
    1
        Week 12, Abnormal: Unchanged, n=20, 19
    0
    3
        Week 24, Abnormal: Improved, n=19, 18
    0
    1
        Week 24, Abnormal: Worsened, n=19, 18
    1
    0
        Week 24, Abnormal: Unchanged, n=19, 18
    0
    4
    Notes
    [20] - Safety population. Participants with available data at the specified time points were analyzed.
    [21] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Number of participants with abnormal value for physical examination parameter: peripheral edema

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    End point title
    		 Number of participants with abnormal value for physical examination parameter: peripheral edema [22]
    End point description
    Physical examination of paricipants peripheral edema is measured. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Week 12 and 24
    Notes
    [22] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [23]
    20 [24]
    Units: Participants
        Week 12, Abnormal: Improved, n=20, 19
    0
    0
        Week 12, Abnormal: Worsened, n=20, 19
    1
    1
        Week 12, Abnormal: Unchanged, n=20, 19
    0
    1
        Week 24, Abnormal: Improved, n=19, 18
    1
    0
        Week 24, Abnormal: Worsened, n=19, 18
    1
    0
        Week 24, Abnormal: Unchanged, n=19, 18
    0
    0
    Notes
    [23] - Safety population. Participants with available data at the specified time points were analyzed.
    [24] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Number of participants with abnormal value for physical examination parameter: ascites

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    End point title
    		 Number of participants with abnormal value for physical examination parameter: ascites [25]
    End point description
    Physcial examination of paricipants ascites was measured. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Week 12 and 24
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [26]
    20 [27]
    Units: Participants
        Week 12, Abnormal: Improved, n=20, 19
    0
    0
        Week 12, Abnormal: Worsened, n=20, 19
    0
    0
        Week 12, Abnormal: Unchanged, n=20, 19
    0
    0
        Week 24, Abnormal: Improved, n=19, 18
    0
    0
        Week 24, Abnormal: Worsened, n=19, 18
    0
    0
        Week 24, Abnormal: Unchanged, n=19, 18
    0
    0
    Notes
    [26] - Safety population. Participants with available data at the specified time points were analyzed.
    [27] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Percentage of physical examination parameter: saturated oxygen level

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    End point title
    		 Percentage of physical examination parameter: saturated oxygen level [28]
    End point description
    Physical examination of participants saturated oxygen level was measured. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Week 12 and 24
    Notes
    [28] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [29]
    20 [30]
    Units: Percentage of oxygen saturation
    arithmetic mean (standard deviation)
        Week 12, n=20, 18
    96.9 ( 2.59 )
    96.9 ( 6.93 )
        Week 24, n=19, 18
    97.3 ( 1.85 )
    97.4 ( 1.92 )
    Notes
    [29] - Safety population. Participants with available data at the specified time points were analyzed.
    [30] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Number of participants with post Baseline PCI value for vital signs parameter: systolic blood pressure (SBP) and diastolic blood pressure (DBP)

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    End point title
    		 Number of participants with post Baseline PCI value for vital signs parameter: systolic blood pressure (SBP) and diastolic blood pressure (DBP) [31]
    End point description
    SBP and DBP were measured in semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges were <80 to >160 millimeters of mercury (mmHg) for SDP and <40 to >110 mmHg for DBP. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    Notes
    [31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [32]
    20 [33]
    Units: Participants
        SBP, Reference range high
    0
    0
        SBP, Reference range low
    1
    2
        DBP, Reference range high
    0
    0
        DBP, Reference range low
    0
    0
    Notes
    [32] - Safety population
    [33] - Safety population
    No statistical analyses for this end point

    Primary: Number of participants with post Baseline PCI value for vital signs parameter: heart rate

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    End point title
    		 Number of participants with post Baseline PCI value for vital signs parameter: heart rate [34]
    End point description
    Heart rate was measured in semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges were <50 to >120 beats per minute (beats/min). Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    Notes
    [34] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [35]
    20 [36]
    Units: Participants
        Reference range high
    2
    2
        Reference range low
    1
    0
    Notes
    [35] - Safety population
    [36] - Safety population
    No statistical analyses for this end point

    Primary: Number of participants with post Baseline PCI value for vital signs parameter: weight

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    End point title
    		 Number of participants with post Baseline PCI value for vital signs parameter: weight [37]
    End point description
    Weight of the participants was measured. PCI ranges were <20 kilograms (kg) for weight. Only those parameters having any time post-Baseline PCI values were presented. Day 1 was considered as Baseline.
    End point type
    Primary
    End point timeframe
    Up to 24 Weeks
    Notes
    [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [38]
    20 [39]
    Units: Participants
        Reference range high
    0
    0
        Reference range low
    0
    0
    Notes
    [38] - Safety population
    [39] - Safety population
    No statistical analyses for this end point

    Primary: Change from Baseline of pubertal development: Men- testicular volume (TV) at Weeks 12 and 24

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    End point title
    		 Change from Baseline of pubertal development: Men- testicular volume (TV) at Weeks 12 and 24 [40]
    End point description
    Testicular volume was assessed by Prader's orchiodometer and the assessment was performed by a pediatric endocrinologist using the Tanner's criteria. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12 and 24
    Notes
    [40] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [41]
    20 [42]
    Units: Milliliter
    arithmetic mean (standard deviation)
        Week 12, Right TV, n=7, 4
    0.4 ( 1.27 )
    0.3 ( 0.50 )
        Week 12, Left TV, n=8, 5
    0.0 ( 0.53 )
    0.2 ( 0.45 )
        Week 24, Right TV, n=6, 4
    0.5 ( 1.38 )
    0.1 ( 0.25 )
        Week 24, Left TV, n=7, 5
    1.4 ( 2.76 )
    0.5 ( 1.50 )
    Notes
    [41] - Safety population. Participants with available data at the specified time points were analyzed.
    [42] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Change from Baseline in plasma endocrine parameter - Female : Follicle stimulating hormone (FSH) and Luteinizing hormone (LH) at Weeks 12 and 24

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    End point title
    		 Change from Baseline in plasma endocrine parameter - Female : Follicle stimulating hormone (FSH) and Luteinizing hormone (LH) at Weeks 12 and 24 [43]
    End point description
    FSH and LH level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12 and 24
    Notes
    [43] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [44]
    20 [45]
    Units: International unit per Liter
    arithmetic mean (standard deviation)
        Week 12, FSH, n=11, 13
    0.586 ( 1.412 )
    -0.023 ( 2.104 )
        Week 24, FSH, n=10, 12
    0.010 ( 1.390 )
    1.542 ( 2.518 )
        Week 12, LH, n=11, 13
    0.39 ( 3.117 )
    -0.28 ( 6.881 )
        Week 24, LH, n=11, 13
    -0.56 ( 1.192 )
    1.15 ( 6.806 )
    Notes
    [44] - Safety population. Participants with available data at the specified time points were analyzed.
    [45] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Change from Baseline in plasma endocrine parameter - Female : Inhibin B at Weeks 12 and 24

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    End point title
    		 Change from Baseline in plasma endocrine parameter - Female : Inhibin B at Weeks 12 and 24 [46]
    End point description
    Inhibin B level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12 and 24
    Notes
    [46] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [47]
    20 [48]
    Units: Nanogram per liter
    arithmetic mean (standard deviation)
        Week 12, Right TV, n=9, 7
    4.9 ( 10.03 )
    1.7 ( 33.70 )
        Week 24, Left TV, n=9, 7
    -5.2 ( 36.44 )
    16.0 ( 37.96 )
    Notes
    [47] - Safety population. Participants with available data at the specified time points were analyzed.
    [48] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Primary: Change from Baseline in plasma endocrine parameter - Female : Sex hormone binding globulin at Weeks 12 and 24

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    End point title
    		 Change from Baseline in plasma endocrine parameter - Female : Sex hormone binding globulin at Weeks 12 and 24 [49]
    End point description
    Sex hormone binding globulin level of participants were measured. Only those parameters having status - overall were presented. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12 and 24
    Notes
    [49] - 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: No statistical analyses have been performed for this outcome measure.
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [50]
    20 [51]
    Units: Milliliter
    arithmetic mean (standard deviation)
        Week 12, Right TV, n=10, 9
    1.3 ( 9.55 )
    7.4 ( 18.91 )
        Week 24, Left TV, n=10, 8
    -9.2 ( 13.62 )
    3.1 ( 14.21 )
    Notes
    [50] - Safety population. Participants with available data at the specified time points were analyzed.
    [51] - Safety population. Participants with available data at the specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Change from Baseline in the 6 minutes walking distance (6MWD) test

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    End point title
    		 Change from Baseline in the 6 minutes walking distance (6MWD) test
    End point description
    Participant's 6MWD data has been presented into three categories as overall, with oxygen use and without oxygen use. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. 99999 indicates that standard deviation could not be calculated for single participant. Intent-to-Treat (ITT) population consist of all randomized participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 16, 20 and 24
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [52]
    20 [53]
    Units: Meters
    arithmetic mean (standard deviation)
        Week 4, Overall, n=21, 18
    33.10 ( 66.979 )
    24.96 ( 71.254 )
        Week 4, With oxygen use, n=2, 1
    -16.00 ( 11.314 )
    85.20 ( 99999 )
        Week 4, Without oxygen use, n=19, 17
    38.27 ( 68.421 )
    21.41 ( 71.793 )
        Week 8, Overall, n=20, 18
    23.84 ( 65.154 )
    37.70 ( 74.339 )
        Week 8, With oxygen use, n=2, 1
    -16.00 ( 22.627 )
    81.10 ( 99999 )
        Week 8, Without oxygen use, n=18, 17
    28.26 ( 67.133 )
    35.15 ( 75.809 )
        Week 12, Overall, n=19, 18
    29.51 ( 79.657 )
    40.29 ( 69.137 )
        Week 12, With oxygen use, n=2, 1
    -1.00 ( 65.054 )
    75.40 ( 99999 )
        Week 12, Without oxygen use, n=17, 17
    33.09 ( 82.121 )
    38.22 ( 70.690 )
        Week 16, Overall, n=19, 18
    22.31 ( 88.832 )
    36.43 ( 78.220 )
        Week 16, With oxygen use, n=2, 1
    -21.00 ( 57.983 )
    65.40 ( 99999 )
        Week 16, Without oxygen use, n=17, 17
    27.41 ( 91.681 )
    34.73 ( 80.282 )
        Week 20, Overall, n=19, 18
    48.49 ( 90.645 )
    31.19 ( 71.209 )
        Week 20, With oxygen use, n=3, 1
    -0.33 ( 43.753 )
    73.20 ( 99999 )
        Week 20, Without oxygen use, n=16, 17
    57.64 ( 95.070 )
    28.72 ( 72.600 )
        Week 24, Overall, n=18, 18
    55.14 ( 102.182 )
    26.25 ( 62.011 )
        Week 24, With oxygen use, n=3, 1
    43.00 ( 53.395 )
    65.90 ( 99999 )
        Week 24, Without oxygen use, n=15, 17
    57.57 ( 110.605 )
    23.92 ( 63.100 )
    Notes
    [52] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    [53] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Time to the first clinical worsening of pulmonary arterial hypertension (PAH)

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    End point title
    		 Time to the first clinical worsening of pulmonary arterial hypertension (PAH)
    End point description
    Time to clinical worsening of PAH is defined as the time from randomization to the first occurrence of death or placed for lung transplant, hospitalization due to PAH deterioration, addition or increased dose of other targeted PAH therapeutic agents like prostanoids and PDE-5 inhibitors) and/or atrial septostomy, other PAH related deterioration identified by increase in WHO functional class, deterioration in exercise testing and clinical signs or symptoms of right sided heart failure.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    3 [54]
    3 [55]
    Units: Days
        arithmetic mean (standard deviation)
    77.3 ( 62.56 )
    71.7 ( 29.26 )
    Notes
    [54] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    [55] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Subject Global Assessment to Week 24 using the SF-10 health survey for children

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    End point title
    		 Change from Baseline in Subject Global Assessment to Week 24 using the SF-10 health survey for children
    End point description
    Short-form 10 (SF-10) Health Survey for Children is a 10-item parent-completed health assessment that measures physical (Items 1, 2a, 2b, 3, and 5) and psychosocial (Items 4, 6, 7, 8, and 9) functioning for children ages five and over. Each item has either 4, 5 or 6 response choices with associated point systems. An aggregated point score was generated across the 5 items within each summary score (range of 5 to 30 points for each 5-item score). This aggregated point score was then standardised and transformed to a norm-based scoring metric in accordance with the developer’s guidelines. A higher value on each summary score indicates better functioning. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [56]
    20 [57]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Physical health summary, n=16, 15
    0.194 ( 11.7733 )
    2.811 ( 13.1172 )
        Psychosocial summary, n=16, 15
    0.725 ( 8.6431 )
    0.412 ( 10.1331 )
    Notes
    [56] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    [57] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Change from baseline in world health organization (WHO) functional class to Week 24

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    End point title
    		 Change from baseline in world health organization (WHO) functional class to Week 24
    End point description
    PAH was classified by WHO functional class (FC) at specific time points. There were four WHO FC grades based on severity of PAH symptoms (Class I=none, Class IV=most severe). Grades were then mapped to numeric scale, for which scores ranged from 1 to 4 (Class I=1 and Class IV=4). Score at Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 12, 16, 20 and 24
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [58]
    20 [59]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 4, n=21, 19
    -0.1 ( 0.36 )
    -0.1 ( 0.23 )
        Week 8, n=20, 19
    -0.1 ( 0.45 )
    -0.1 ( 0.40 )
        Week 12, n=20, 19
    -0.1 ( 0.45 )
    0.0 ( 0.58 )
        Week 16, n=20, 18
    -0.2 ( 0.49 )
    -0.2 ( 0.38 )
        Week 20, n=19, 18
    -0.2 ( 0.50 )
    -0.2 ( 0.38 )
        Week 24, n=19, 18
    -0.3 ( 0.56 )
    -0.2 ( 0.43 )
    Notes
    [58] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    [59] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    No statistical analyses for this end point

    Secondary: Ratio to Baseline in plasma N-terminal pro-B type natriuretic peptide (NT-Pro BNP) concentration at Week 24

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    End point title
    		 Ratio to Baseline in plasma N-terminal pro-B type natriuretic peptide (NT-Pro BNP) concentration at Week 24
    End point description
    NT-Pro BNP plasma concentrations were determined at specific time points. Geometric mean and SD logs has been presented. Day 1 was considered as Baseline. Ratio to Baseline is expressed as percentage change from Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and 24
    End point values
    		 Low dose ambrisentan High dose ambrisentan
    Number of subjects analysed
    21 [60]
    20 [61]
    Units: Percentage Change
    geometric mean (standard deviation)
        Week 12, n=19, 17
    -15.93 ( 0.895 )
    -12.43 ( 0.862 )
        Week 24, n=18, 17
    -30.91 ( 0.851 )
    -28.25 ( 1.179 )
    Notes
    [60] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    [61] - Intent-to-treat population. Participants with available data at specified time points were analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non serious AEs were collected from the start of study treatment up to 24 weeks
    Adverse event reporting additional description
    Safety Population was used. Safety Population comprised of all randomized participants who received at least one dose of a study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    High dose ambrisentan
    Reporting group description
    		 Participants received ambrisentan high dose tablet either 5 mg, 7.5 mg or 10 mg orally once daily for 24 weeks.

    Reporting group title
    Low dose ambrisentan
    Reporting group description
    		 Participants received ambrisentan low dose tablet either 2.5 mg or 5 mg orally once daily for 24 weeks.

    Serious adverse events
    		 High dose ambrisentan Low dose ambrisentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
    6 / 21 (28.57%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         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
    General physical health deterioration
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 High dose ambrisentan Low dose ambrisentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 20 (80.00%)
    16 / 21 (76.19%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Face oedema
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Nasal congestion
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    2
    Oropharyngeal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Toxicity to various agents
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Headache
         subjects affected / exposed
    6 / 20 (30.00%)
    4 / 21 (19.05%)
         occurrences all number
    9
    5
    Blood and lymphatic system disorders
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Lymphopenia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    4 / 21 (19.05%)
         occurrences all number
    2
    4
    Abdominal pain upper
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    4
    3
    Diarrhoea
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    Dry mouth
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Gastritis
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    3 / 20 (15.00%)
    4 / 21 (19.05%)
         occurrences all number
    3
    5
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Erythema
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Myalgia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    Neck pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    Laryngitis
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 21 (14.29%)
         occurrences all number
    2
    4
    Pneumonia
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    Pharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    Respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jun 2010
    Amendment No. 1 • Clarify the inclusion criteria that existing drug treatment for pulmonary arterial hypertension (PAH) would continue unchanged throughout the study. • Clarify that two forms of contraception is required only for female participants of child bearing potential who are sexually active. • Expand the eligibility for the continuation study to all participants who participate in this study and in whom continued treatment with ambrisentan is desired. • Specify that participants will be given a diary card to collect information about dosing and days missed from school. • Remove references to “brain natriuretic peptide” and clarify that it is N-terminal pro-B-type Natriuretic Peptide that is being assessed. • Add more specific references for the Tanner development criteria. • Change the wording of the questions regarding days missed from school to make it clear that the total number of days missed includes the days missed because of PAH and that the days missed because of PAH are due to symptoms of PAH and do not include clinic visits. • Remove the requirement for an unblinded person to enter compliance data into InForm. • Allow the investigator to be unblinded to treatment for an individual patient once that participant has completed the study.
    26 Oct 2010
    Amendment No. 2 • To clarify that it is hepatitis B surface antigen, and not hepatitis B surface antibody, that is being assessed as part of the exclusion criteria. • Add the United States (US) Investigational New Drug (IND) number to the Sponsor Information Page and clarify that the medical monitor and Serious Adverse Events contact are the same person.
    02 Feb 2011
    Amendment No. 3 • Add oestrogen to the laboratory tests being performed on female participants at all times that pubertal development assessments are performed. • Remove testosterone from the laboratory tests being performed on female participants at all times that the pubertal development assessments are performed. • Change the storage requirements for the study medication to store below 30°C.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 Jul 2013
    Global Enrolment Hold due to preclinical findings.
    -

    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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