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    Clinical Trial Results:
    An open-label, long term extension study for treatment of pulmonary arterial hypertension in paediatric patients aged 8 years up to 18 years who have participated in AMB112529 and in whom continued treatment with ambrisentan is desired

    Summary
    EudraCT number
    		 2010-021572-29
    Trial protocol
    		 GR   DE   NL   ES   HU   IT   FR  
    Global end of trial date
    09 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2022
    First version publication date
    21 Dec 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    114588
    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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Aug 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is the safety and tolerability of ambrisentan in the paediatric PAH population
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jun 2011
    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
    Argentina: 5
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 2
    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: 7
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    38
    EEA total number of subjects
    14
    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)
    24
    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 was an open label, long term extension of study AMB112529 (NCT01342952) which evaluated safety and tolerability of ambrisentan in the pediatric (aged 8 years up to 18 years) Pulmonary Arterial Hypertension (PAH) population.

    Pre-assignment
    Screening details
    		 A total of 38 participants were enrolled in this study.

    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
    		 Ambrisentan 2.5 mg (ITT)
    Arm description
    		 Participants received 2.5 milligrams (mg) dose of ambrisentan orally in tablet/s form once daily. The Intent-to-Treat (ITT) Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.
    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
    Ambrisentan was administered as oral tablet

    Arm title
    		 Ambrisentan 5 mg (ITT)
    Arm description
    		 Participants received 5 mg dose of ambrisenten orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.
    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
    Ambrisentan was administered as oral tablet

    Arm title
    		 Ambrisentan 7.5 mg (ITT)
    Arm description
    		 Participants received 7.5 mg dose of ambrisentan orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.
    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
    Ambrisentan was administered as oral tablet

    Arm title
    		 Ambrisentan 10 mg (ITT)
    Arm description
    		 Participants received 10 mg dose of ambrisentan orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.
    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
    Ambrisentan was administered as oral tablet

    Number of subjects in period 1
    		Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Started
    9
    19
    5
    5
    Intent-to-Treat Population
    9
    19
    5
    5
    Completed
    5
    8
    3
    5
    Not completed
    4
    11
    2
    0
         Adverse event, serious fatal
    -
    5
    1
    -
         Consent withdrawn by subject
    1
    1
    -
    -
         Physician decision
    3
    3
    1
    -
         Lost to follow-up
    -
    2
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Ambrisentan 2.5 mg (ITT)
    Reporting group description
    		 Participants received 2.5 milligrams (mg) dose of ambrisentan orally in tablet/s form once daily. The Intent-to-Treat (ITT) Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Reporting group title
    Ambrisentan 5 mg (ITT)
    Reporting group description
    		 Participants received 5 mg dose of ambrisenten orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Reporting group title
    Ambrisentan 7.5 mg (ITT)
    Reporting group description
    		 Participants received 7.5 mg dose of ambrisentan orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Reporting group title
    Ambrisentan 10 mg (ITT)
    Reporting group description
    		 Participants received 10 mg dose of ambrisentan orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Reporting group values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT) Total
    Number of subjects
    		 9 19 5 5 38
    Age categorical
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 6 7 1 0 14
        Adolescents (12-17 years)
    		 3 12 4 5 24
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: years
        arithmetic mean (standard deviation)
    		 9.7 ( 2.29 ) 11.9 ( 2.57 ) 12.6 ( 2.61 ) 15.2 ( 0.84 ) -
    Sex: Female, Male
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: Participants
        Female
    		 7 9 4 5 25
        Male
    		 2 10 1 0 13
    Race/Ethnicity, Customized
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: Subjects
        African American/African Heritage
    		 1 1 0 0 2
        American Indian or Alaskan Native
    		 1 0 0 0 1
        Asian - Central/South Asian Heritage
    		 0 1 0 0 1
        Asian - East Asian Heritage
    		 0 1 0 0 1
        Asian - Japanese Heritage
    		 3 2 0 0 5
        Asian - South East Asian Heritage
    		 0 0 1 0 1
        White - White/Caucasian/European Heritage
    		 4 14 4 5 27
    Subject analysis sets

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis sets values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects
    4
    16
    6
    12
    10
    5
    9
    3
    9
    10
    6
    3
    7
    1
    3
    1
    3
    2
    5
    4
    2
    2
    2
    5
    4
    1
    1
    Age categorical
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    0.0 ( 11.31 )
    14.0 ( 67.48 )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Sex: Female, Male
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: Participants
        Female
        Male
    Race/Ethnicity, Customized
    Baseline characteristics were presented for ITT Population, consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT population at the start of study AMB114588
    Units: Subjects
        African American/African Heritage
        American Indian or Alaskan Native
        Asian - Central/South Asian Heritage
        Asian - East Asian Heritage
        Asian - Japanese Heritage
        Asian - South East Asian Heritage
        White - White/Caucasian/European Heritage

    End points

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    End points reporting groups
    Reporting group title
    Ambrisentan 2.5 mg (ITT)
    Reporting group description
    		 Participants received 2.5 milligrams (mg) dose of ambrisentan orally in tablet/s form once daily. The Intent-to-Treat (ITT) Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Reporting group title
    Ambrisentan 5 mg (ITT)
    Reporting group description
    		 Participants received 5 mg dose of ambrisenten orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Reporting group title
    Ambrisentan 7.5 mg (ITT)
    Reporting group description
    		 Participants received 7.5 mg dose of ambrisentan orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Reporting group title
    Ambrisentan 10 mg (ITT)
    Reporting group description
    		 Participants received 10 mg dose of ambrisentan orally in tablet/s form once daily. The ITT Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to ITT treatment group at the start of study AMB114588.

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 2.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 2.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 7.5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 7.5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 5 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 5 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Subject analysis set title
    Ambrisentan 10 mg (Safety)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received ambrisentan 10 mg tablet/s orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Primary: Number of Participants With Non-serious Treatment-emergent Adverse Events (Non-STEAEs) and Serious Treatment-emergent Adverse Events (STEAEs)

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    End point title
    		 Number of Participants With Non-serious Treatment-emergent Adverse Events (Non-STEAEs) and Serious Treatment-emergent Adverse Events (STEAEs) [1]
    End point description
    AE was defined as any untoward medical occurrence in participant/clinical investigation participant,temporally associated with use of medicinal product,whether/not considered related to medicinal product.SAE was defined as any untoward medical occurrence that,at any dose:results in death,is life threatening,requires hospitalization/prolongation of existing hospitalization,results in disability or incapacity, or is congenital anomaly or birth defect,important medical events that may not immediately life threatening or result in death or hospitalization but may jeopardize participant or may require medical or surgical intervention as per medical or scientific judgement or associated with drug-induced liver injury.TEAE is any event that was not present prior to initiation of study treatment/any event already present that worsens in either intensity/frequency following exposure to study treatment.Safety Population consisted of all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 10 years and 11 months
    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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [2]
    16 [3]
    6 [4]
    12 [5]
    Units: Participants
        Non-STEAEs
    3
    13
    5
    10
        STEAEs
    2
    7
    4
    8
    Notes
    [2] - Safety Population
    [3] - Safety Population
    [4] - Safety Population
    [5] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Liver function parameters: Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Gamma Glutamyl Transferase (GGT), Total Bilirubin

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    End point title
    		 Change from Baseline in Liver function parameters: Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Gamma Glutamyl Transferase (GGT), Total Bilirubin [6]
    End point description
    Blood samples were collected from participants for analysis of following clinical chemistry parameters: ALT, AST, GGT, total bilirubin. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [7]
    10 [8]
    5 [9]
    9 [10]
    Units: Millimoles per liter
    arithmetic mean (standard deviation)
        ALT
    -7.5 ( 12.56 )
    -1.0 ( 8.64 )
    0.8 ( 4.09 )
    4.0 ( 7.42 )
        AST
    -11.8 ( 6.29 )
    -5.6 ( 7.23 )
    -1.0 ( 2.55 )
    -2.1 ( 8.13 )
        GGT
    -0.5 ( 15.00 )
    -7.0 ( 10.45 )
    -0.8 ( 8.44 )
    -4.6 ( 28.30 )
        Total bilirubin
    -5.3 ( 12.47 )
    -4.0 ( 3.30 )
    -2.8 ( 6.06 )
    3.1 ( 8.45 )
    Notes
    [7] - Safety Population
    [8] - Safety Population
    [9] - Safety Population
    [10] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Chemistry parameters: Calcium, Chloride, Carbon dioxide (CO2) content, Glucose, Potassium, Magnesium, Sodium, Phosphorus inorganic, Blood Urea Nitrogen (BUN)

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    End point title
    		 Change from Baseline in Chemistry parameters: Calcium, Chloride, Carbon dioxide (CO2) content, Glucose, Potassium, Magnesium, Sodium, Phosphorus inorganic, Blood Urea Nitrogen (BUN) [11]
    End point description
    Blood samples were collected from participants for analysis of following clinical chemistry parameters: Calcium, chloride, CO2 content, glucose, potassium, magnesium, sodium, phosphorus inorganic, and BUN. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [11] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety)
    Number of subjects analysed
    10 [12]
    5 [13]
    9 [14]
    3 [15]
    Units: Millimoles per liter
    arithmetic mean (standard deviation)
        Calcium
    -0.054 ( 0.0779 )
    0.028 ( 0.0630 )
    -0.060 ( 0.1075 )
    -0.150 ( 0.1769 )
        Chloride
    2.6 ( 1.65 )
    0.4 ( 3.44 )
    -0.6 ( 2.96 )
    1.7 ( 5.13 )
        CO2 content
    2.2 ( 1.87 )
    0.2 ( 3.70 )
    0.0 ( 1.80 )
    -0.3 ( 2.89 )
        Glucose
    -0.150 ( 1.1414 )
    0.120 ( 0.5541 )
    0.478 ( 0.9107 )
    0.167 ( 0.4163 )
        Potassium
    -0.07 ( 0.337 )
    -0.02 ( 0.148 )
    -0.12 ( 0.327 )
    -0.30 ( 0.529 )
        Magnesium
    -0.062 ( 0.0898 )
    0.028 ( 0.0683 )
    0.012 ( 0.0716 )
    -0.100 ( 0.0872 )
        Sodium
    1.0 ( 1.63 )
    -0.2 ( 0.84 )
    0.7 ( 1.87 )
    2.7 ( 1.15 )
        Phosphorus inorganic
    -0.159 ( 0.3055 )
    -0.212 ( 0.3440 )
    -0.108 ( 0.2408 )
    -0.340 ( 0.1311 )
        BUN
    -0.51 ( 1.649 )
    -0.14 ( 1.274 )
    0.33 ( 1.507 )
    -0.10 ( 1.808 )
    Notes
    [12] - Safety Population
    [13] - Safety Population
    [14] - Safety Population
    [15] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Chemistry parameters: Alkaline Phosphatase (ALP), Creatine kinase (CK), Lactate Dehydrogenase (LDH)

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    End point title
    		 Change from Baseline in Chemistry parameters: Alkaline Phosphatase (ALP), Creatine kinase (CK), Lactate Dehydrogenase (LDH) [16]
    End point description
    Blood samples were collected from participants for analysis of following clinical chemistry parameters: ALP, CK, LDH. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety)
    Number of subjects analysed
    10 [17]
    5 [18]
    9 [19]
    3 [20]
    Units: International units per Liter
    arithmetic mean (standard deviation)
        ALP
    -109.5 ( 71.51 )
    -148.8 ( 151.78 )
    -135.6 ( 97.33 )
    -77.7 ( 57.01 )
        CK
    4.0 ( 100.83 )
    46.6 ( 89.55 )
    -9.7 ( 13.96 )
    -18.7 ( 23.07 )
        LDH
    -48.9 ( 71.64 )
    -12.8 ( 22.58 )
    -28.3 ( 37.23 )
    -40.3 ( 45.54 )
    Notes
    [17] - Safety Population
    [18] - Safety Population
    [19] - Safety Population
    [20] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Chemistry parameters: Creatinine, Uric acid

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    End point title
    		 Change from Baseline in Chemistry parameters: Creatinine, Uric acid [21]
    End point description
    Blood samples were collected from participants for analysis of following clinical chemistry parameters: Creatinine, uric acid. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [21] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety)
    Number of subjects analysed
    10 [22]
    5 [23]
    9 [24]
    3 [25]
    Units: Micromoles per liter
    arithmetic mean (standard deviation)
        Creatinine
    8.16 ( 9.602 )
    10.26 ( 8.008 )
    19.31 ( 14.698 )
    6.27 ( 19.775 )
        Uric acid
    -83.60 ( 90.103 )
    -45.40 ( 77.584 )
    21.22 ( 79.330 )
    -64.67 ( 119.169 )
    Notes
    [22] - Safety Population
    [23] - Safety Population
    [24] - Safety Population
    [25] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Chemistry parameters: Albumin, Total protein

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    End point title
    		 Change from Baseline in Chemistry parameters: Albumin, Total protein [26]
    End point description
    Blood samples were collected from participants for analysis of following clinical chemistry parameters: Albumin, total protein. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [26] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety)
    Number of subjects analysed
    10 [27]
    5 [28]
    9 [29]
    3 [30]
    Units: Grams per liter
    arithmetic mean (standard deviation)
        Albumin
    -1.2 ( 3.16 )
    1.6 ( 1.14 )
    -2.0 ( 4.42 )
    -3.3 ( 4.04 )
        Total protein
    -3.4 ( 4.93 )
    3.0 ( 5.24 )
    -3.0 ( 7.33 )
    -3.7 ( 4.51 )
    Notes
    [27] - Safety Population
    [28] - Safety Population
    [29] - Safety Population
    [30] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Hematology parameters: Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC)

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    End point title
    		 Change from Baseline in Hematology parameters: Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) [31]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameters: Hemoglobin and MCHC. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    5 [32]
    9 [33]
    3 [34]
    9 [35]
    Units: Grams per Liter
    arithmetic mean (standard deviation)
        Hemoglobin
    0.8 ( 9.71 )
    1.3 ( 20.12 )
    -23.0 ( 38.63 )
    -4.7 ( 16.15 )
        MCHC
    -6.0 ( 12.98 )
    -1.1 ( 11.72 )
    -9.3 ( 16.01 )
    -12.4 ( 17.31 )
    Notes
    [32] - Safety Population
    [33] - Safety Population
    [34] - Safety Population
    [35] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Hematology parameters: Hematocrit

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    End point title
    		 Change from Baseline in Hematology parameters: Hematocrit [36]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameters: Hematocrit. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [36] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    5 [37]
    9 [38]
    3 [39]
    9 [40]
    Units: Proportion of red blood cells in blood
        arithmetic mean (standard deviation)
    0.0100 ( 0.02884 )
    0.0040 ( 0.06572 )
    -0.0610 ( 0.10235 )
    -0.0004 ( 0.04543 )
    Notes
    [37] - Safety Population
    [38] - Safety Population
    [39] - Safety Population
    [40] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total neutrophils, White Blood Cells (WBC), Platelet count

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    End point title
    		 Change from Baseline in Hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Total neutrophils, White Blood Cells (WBC), Platelet count [41]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameters: Basophils, eosinophils, lymphocytes, monocytes, total neutrophils, WBC, platelet count. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed (represented by n=X in category titles).
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [41] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    5 [42]
    9 [43]
    3 [44]
    9 [45]
    Units: Giga cells per Liter
    arithmetic mean (standard deviation)
        Basophils, n=3, 9, 5, 9
    -0.006 ( 0.0152 )
    -0.002 ( 0.0148 )
    -0.007 ( 0.0153 )
    0.019 ( 0.0417 )
        Eosinophils, n=3, 9, 5, 9
    -0.026 ( 0.0602 )
    0.009 ( 0.0746 )
    -0.210 ( 0.4139 )
    0.034 ( 0.1096 )
        Lymphocytes, n=3, 9, 5, 9
    -0.152 ( 0.6937 )
    -0.394 ( 1.1063 )
    -1.107 ( 0.7310 )
    -0.329 ( 1.1373 )
        Monocytes, n=3, 9, 5, 9
    -0.006 ( 0.1635 )
    0.037 ( 0.1986 )
    -0.013 ( 0.1550 )
    0.040 ( 0.1273 )
        Total neutrophils, n= 3, 9, 5, 9
    0.412 ( 0.6278 )
    0.524 ( 2.0030 )
    0.677 ( 1.9014 )
    -0.974 ( 1.2239 )
        WBC, n=3, 9, 5, 9
    0.22 ( 0.421 )
    0.18 ( 2.787 )
    -0.67 ( 2.616 )
    -1.22 ( 2.072 )
        Platelet count, n=3, 9, 5, 7
    -9.2 ( 30.87 )
    -0.4 ( 64.78 )
    -34.0 ( 27.18 )
    -29.3 ( 50.03 )
    Notes
    [42] - Safety Population
    [43] - Safety Population
    [44] - Safety Population
    [45] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Hematology parameter: Mean Corpuscle Hemoglobin

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    End point title
    		 Change from Baseline in Hematology parameter: Mean Corpuscle Hemoglobin [46]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameter: Mean Corpuscle Hemoglobin. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    5 [47]
    9 [48]
    3 [49]
    9 [50]
    Units: Picograms
        arithmetic mean (standard deviation)
    -0.70 ( 1.512 )
    0.11 ( 1.981 )
    -1.70 ( 3.315 )
    -1.46 ( 2.823 )
    Notes
    [47] - Safety Population
    [48] - Safety Population
    [49] - Safety Population
    [50] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Hematology parameter: Mean Corpuscle Volume

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    End point title
    		 Change from Baseline in Hematology parameter: Mean Corpuscle Volume [51]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameter: Mean Corpuscle Volume. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [51] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    5 [52]
    9 [53]
    3 [54]
    9 [55]
    Units: Femtoliters
        arithmetic mean (standard deviation)
    -0.8 ( 2.68 )
    0.8 ( 5.61 )
    -2.3 ( 6.66 )
    -1.0 ( 5.52 )
    Notes
    [52] - Safety Population
    [53] - Safety Population
    [54] - Safety Population
    [55] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Hematology parameters: Red Blood Cell count, Reticulocytes

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    End point title
    		 Change from Baseline in Hematology parameters: Red Blood Cell count, Reticulocytes [56]
    End point description
    Blood samples were collected from participants for analysis of following hematology parameters: Red Blood Cell count, reticulocytes. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [56] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    5 [57]
    9 [58]
    3 [59]
    9 [60]
    Units: Trillion cells per liter
    arithmetic mean (standard deviation)
        Red Blood Cell count
    0.14 ( 0.251 )
    0.00 ( 0.497 )
    -0.57 ( 0.862 )
    0.07 ( 0.387 )
        Reticulocytes
    0.00906 ( 0.013265 )
    0.01843 ( 0.041832 )
    0.01427 ( 0.024625 )
    -0.00816 ( 0.043615 )
    Notes
    [57] - Safety Population
    [58] - Safety Population
    [59] - Safety Population
    [60] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal values for physical examination parameter: Liver size

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    End point title
    		 Number of participants with abnormal values for physical examination parameter: Liver size [61]
    End point description
    Physical examination included measurement of liver size. Any abnormal enlargement or reduction in the size of the liver is reported. Liver size was assessed as normal or abnormal. Data for abnormal (improved, worsened and unchanged) liver size is presented. End of study visit data is presented. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 10 years and 11 months
    Notes
    [61] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [62]
    10 [63]
    5 [64]
    10 [65]
    Units: Participants
        Liver Size: Abnormal: Improved
    0
    0
    0
    0
        Liver Size: Abnormal: Worsened
    0
    0
    0
    0
        Liver Size: Abnormal: Unchanged
    0
    0
    0
    2
    Notes
    [62] - Safety Population
    [63] - Safety Population
    [64] - Safety Population
    [65] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal values for physical examination parameter: Jugular Venous Pressure

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    End point title
    		 Number of participants with abnormal values for physical examination parameter: Jugular Venous Pressure [66]
    End point description
    Physical examination included measurement of Jugular venous pressure. Jugular venous pressure was assessed as normal or abnormal. Data for abnormal (improved, worsened and unchanged) jugular venous pressure is presented. End of study visit data is presented. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 10 years and 11 months
    Notes
    [66] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [67]
    10 [68]
    5 [69]
    10 [70]
    Units: Participants
        Jugular Venous Pressure: Abnormal: Improved
    0
    0
    0
    0
        Jugular Venous Pressure: Abnormal: Worsened
    0
    0
    0
    0
        Jugular Venous Pressure: Abnormal: Unchanged
    0
    0
    0
    2
    Notes
    [67] - Safety Population
    [68] - Safety Population
    [69] - Safety Population
    [70] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal values for physical examination parameters: Ascites

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    End point title
    		 Number of participants with abnormal values for physical examination parameters: Ascites [71]
    End point description
    Physical examination included measurement of ascites. Ascites were assessed as present or absent. Data for ascites present with improved, worsened and unchanged is presented. End of study visit data is presented. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 10 years and 11 months
    Notes
    [71] - 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: here are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [72]
    10 [73]
    5 [74]
    10 [75]
    Units: Participants
        Ascites: Present: Improved
    0
    0
    0
    0
        Ascites: Present: Worsened
    0
    0
    0
    0
        Ascites: Present: Unchanged
    0
    0
    0
    2
    Notes
    [72] - Safety Population
    [73] - Safety Population
    [74] - Safety Population
    [75] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal values for physical examination parameter: Peripheral edema

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    End point title
    		 Number of participants with abnormal values for physical examination parameter: Peripheral edema [76]
    End point description
    Physical examination included measurement of peripheral edema. Peripheral edema were assessed as present or absent. Data for peripheral edema present with improved, worsened and unchanged is presented. End of study visit data is presented. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 10 years and 11 months
    Notes
    [76] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [77]
    10 [78]
    5 [79]
    10 [80]
    Units: Participants
        Peripheral edema: Present: Improved
    0
    0
    0
    0
        Peripheral edema: Present: Worsened
    0
    0
    0
    0
        Peripheral edema: Present: Unchanged
    0
    0
    0
    0
    Notes
    [77] - Safety Population
    [78] - Safety Population
    [79] - Safety Population
    [80] - Safety Population
    No statistical analyses for this end point

    Primary: Percentage of Saturated Oxygen Level (Physical Examination Parameter)

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    End point title
    		 Percentage of Saturated Oxygen Level (Physical Examination Parameter) [81]
    End point description
    Physical examination included measurement of saturated oxygen. End of study visit data is presented. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 10 years and 11 months
    Notes
    [81] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [82]
    10 [83]
    5 [84]
    10 [85]
    Units: Percentage of oxygen saturation
        arithmetic mean (standard deviation)
    95.5 ( 4.20 )
    96.8 ( 2.04 )
    97.4 ( 1.34 )
    96.9 ( 1.97 )
    Notes
    [82] - Safety Population
    [83] - Safety Population
    [84] - Safety Population
    [85] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in vital signs parameter: Systolic blood pressure (SBP) and Diastolic blood pressure (DBP)

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    End point title
    		 Change from Baseline in vital signs parameter: Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) [86]
    End point description
    SBP and DBP was measured for the participants at indicated time points. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [86] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [87]
    10 [88]
    5 [89]
    10 [90]
    Units: Millimeters of mercury
    arithmetic mean (standard deviation)
        SBP
    16.3 ( 16.38 )
    8.4 ( 17.99 )
    1.2 ( 18.63 )
    8.5 ( 12.22 )
        DBP
    1.5 ( 5.80 )
    2.3 ( 12.70 )
    3.6 ( 16.96 )
    2.1 ( 9.67 )
    Notes
    [87] - Safety Population
    [88] - Safety Population
    [89] - Safety Population
    [90] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in vital signs parameter: Heart rate

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    End point title
    		 Change from Baseline in vital signs parameter: Heart rate [91]
    End point description
    Heart rate was measured for the participants at indicated time points. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [91] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [92]
    10 [93]
    5 [94]
    10 [95]
    Units: Beats per minute
        arithmetic mean (standard deviation)
    -9.0 ( 13.44 )
    -4.0 ( 8.08 )
    -3.8 ( 11.50 )
    -6.0 ( 15.06 )
    Notes
    [92] - Safety Population
    [93] - Safety Population
    [94] - Safety Population
    [95] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in vital signs parameter: Weight

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    End point title
    		 Change from Baseline in vital signs parameter: Weight [96]
    End point description
    Weight was measured for the participants at indicated time points. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [96] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [97]
    10 [98]
    5 [99]
    10 [100]
    Units: Kilograms
        arithmetic mean (standard deviation)
    17.43 ( 12.695 )
    10.73 ( 8.628 )
    7.12 ( 5.346 )
    12.17 ( 16.300 )
    Notes
    [97] - Safety Population
    [98] - Safety Population
    [99] - Safety Population
    [100] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Vital Sign Parameter: Height

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    End point title
    		 Change from Baseline in Vital Sign Parameter: Height [101]
    End point description
    Height was measured for the participants at indicated time points. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [101] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [102]
    10 [103]
    5 [104]
    10 [105]
    Units: Centimeters
        arithmetic mean (standard deviation)
    25.3 ( 19.99 )
    9.9 ( 9.92 )
    7.2 ( 9.47 )
    12.1 ( 17.55 )
    Notes
    [102] - Safety Population
    [103] - Safety Population
    [104] - Safety Population
    [105] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Vital Sign Parameter: Body mass index

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    End point title
    		 Change from Baseline in Vital Sign Parameter: Body mass index [106]
    End point description
    Body mass index was measured for the participants at indicated time points. Body mass index was calculated as weight in kilograms (kg) divided by the square of their height in meters (m^2). Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [106] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [107]
    10 [108]
    5 [109]
    10 [110]
    Units: Kilogram per meter square
        arithmetic mean (standard deviation)
    2.65 ( 2.195 )
    2.45 ( 1.828 )
    1.52 ( 1.633 )
    1.99 ( 2.642 )
    Notes
    [107] - Safety Population
    [108] - Safety Population
    [109] - Safety Population
    [110] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Vital Sign Parameter: Body surface area

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    End point title
    		 Change from Baseline in Vital Sign Parameter: Body surface area [111]
    End point description
    Body surface area was measured for the participants at indicated time points. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [111] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [112]
    10 [113]
    5 [114]
    10 [115]
    Units: Meter square
        arithmetic mean (standard deviation)
    0.398 ( 0.3024 )
    0.207 ( 0.1744 )
    0.144 ( 0.1254 )
    0.236 ( 0.3163 )
    Notes
    [112] - Safety Population
    [113] - Safety Population
    [114] - Safety Population
    [115] - Safety Population
    No statistical analyses for this end point

    Primary: Number of participants with abnormal electrocardiogram (ECG) findings

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    End point title
    		 Number of participants with abnormal electrocardiogram (ECG) findings [116]
    End point description
    12-lead ECG was measured in a semi-supine position using an automated ECG machine. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Data for any time till end of study were presented. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 10 years and 11 months
    Notes
    [116] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [117]
    16 [118]
    6 [119]
    12 [120]
    Units: Participants
        Abnormal, not clinically significant
    4
    14
    3
    9
        Abnormal, clinically significant
    0
    2
    1
    3
    Notes
    [117] - Safety Population
    [118] - Safety Population
    [119] - Safety Population
    [120] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at End of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at End of study [121]
    End point description
    FSH and LH level of participants were measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [121] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    3 [122]
    6 [123]
    3 [124]
    7 [125]
    Units: International units per Liter
    arithmetic mean (standard deviation)
        FSH
    0.200 ( 1.2490 )
    3.217 ( 4.0455 )
    0.100 ( 3.6042 )
    -0.336 ( 3.7053 )
        LH
    0.03 ( 0.058 )
    5.17 ( 9.665 )
    4.17 ( 9.563 )
    0.61 ( 9.778 )
    Notes
    [122] - Safety Population
    [123] - Safety Population
    [124] - Safety Population
    [125] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) at 20 years of age of participants [126]
    End point description
    FSH and LH level of participants were measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed.99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [126] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    1 [127]
    3 [128]
    1 [129]
    3 [130]
    Units: International units per Liter
    arithmetic mean (standard deviation)
        FSH
    35.800 ( 99999 )
    0.800 ( 1.2530 )
    -2.500 ( 99999 )
    0.967 ( 0.3055 )
        LH
    8.60 ( 99999 )
    6.17 ( 16.717 )
    -6.30 ( 99999 )
    5.10 ( 4.597 )
    Notes
    [127] - Safety Population
    [128] - Safety Population
    [129] - Safety Population
    [130] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Inhibin B at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Inhibin B at end of study [131]
    End point description
    Inhibin B level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [131] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    2 [132]
    5 [133]
    4 [134]
    Units: Nanogram per liter
        arithmetic mean (standard deviation)
    0.0 ( 11.31 )
    14.0 ( 67.48 )
    -29.0 ( 27.60 )
    Notes
    [132] - Safety Population
    [133] - Safety Population
    [134] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Inhibin B at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Inhibin B at 20 years of age of participants [135]
    End point description
    Inhibin B level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [135] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    1 [136]
    1 [137]
    2 [138]
    2 [139]
    Units: Nanogram per liter
        arithmetic mean (standard deviation)
    0.0 ( 99999 )
    37.0 ( 99999 )
    49.0 ( 110.31 )
    7.5 ( 70.00 )
    Notes
    [136] - Safety Population
    [137] - Safety Population
    [138] - Safety Population
    [139] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Sex Hormone Binding Globulin at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Sex Hormone Binding Globulin at end of study [140]
    End point description
    Sex hormone binding globulin level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [140] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 2.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 7.5 mg (Safety)
    Number of subjects analysed
    6 [141]
    2 [142]
    4 [143]
    2 [144]
    Units: Nanomoles per liter
        arithmetic mean (standard deviation)
    11.8 ( 14.22 )
    -10.0 ( 1.41 )
    17.3 ( 22.31 )
    0.5 ( 0.71 )
    Notes
    [141] - Safety Population
    [142] - Safety Population
    [143] - Safety Population
    [144] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Sex Hormone Binding Globulin at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Sex Hormone Binding Globulin at 20 years of age of participants [145]
    End point description
    Sex hormone binding globulin level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [145] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    1 [146]
    3 [147]
    1 [148]
    2 [149]
    Units: Nanomoles per liter
        arithmetic mean (standard deviation)
    49.0 ( 99999 )
    1.7 ( 54.37 )
    10.0 ( 99999 )
    -15.5 ( 2.12 )
    Notes
    [146] - Safety Population
    [147] - Safety Population
    [148] - Safety Population
    [149] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Estrone at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Estrone at end of study [150]
    End point description
    Estrone level of female participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [150] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    1 [151]
    5 [152]
    2 [153]
    5 [154]
    Units: Picomole per milliliter
        arithmetic mean (standard deviation)
    0.00 ( 99999 )
    -6.80 ( 178.361 )
    -26.00 ( 209.304 )
    17.00 ( 125.913 )
    Notes
    [151] - Safety Population
    [152] - Safety Population
    [153] - Safety Population
    [154] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Estrone at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Estrone at 20 years of age of participants [155]
    End point description
    Estrone level of female participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [155] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    1 [156]
    1 [157]
    2 [158]
    2 [159]
    Units: Picomole per milliliter
        arithmetic mean (standard deviation)
    -7.00 ( 99999 )
    11.00 ( 99999 )
    179.00 ( 196.576 )
    89.00 ( 73.539 )
    Notes
    [156] - Safety Population
    [157] - Safety Population
    [158] - Safety Population
    [159] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Estradiol at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Estradiol at end of study [160]
    End point description
    Estradiol level of female participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed. Only those participants with available data at the specified time points were analyzed.99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [160] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    1 [161]
    2 [162]
    5 [163]
    4 [164]
    Units: Picomoles per liter
        arithmetic mean (standard deviation)
    -11.00 ( 99999 )
    -255.50 ( 427.800 )
    44.80 ( 264.452 )
    -77.25 ( 211.435 )
    Notes
    [161] - Safety Population
    [162] - Safety Population
    [163] - Safety Population
    [164] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Female: Estradiol at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Female: Estradiol at 20 years of age of participants [165]
    End point description
    Estradiol level of female participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [165] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    1 [166]
    1 [167]
    2 [168]
    1 [169]
    Units: Picomoles per liter
        arithmetic mean (standard deviation)
    55.50 ( 99999 )
    15.00 ( 99999 )
    387.50 ( 375.474 )
    -107.00 ( 99999 )
    Notes
    [166] - Safety Population
    [167] - Safety Population
    [168] - Safety Population
    [169] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: FSH and LH at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: FSH and LH at end of study [170]
    End point description
    FSH and LH level of participants were measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [170] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 7.5 mg (Safety)
    Number of subjects analysed
    1 [171]
    3 [172]
    2 [173]
    2 [174]
    Units: International units per Liter
    arithmetic mean (standard deviation)
        FSH
    6.000 ( 99999 )
    0.267 ( 0.3215 )
    0.850 ( 2.4749 )
    3.250 ( 3.4648 )
        LH
    3.20 ( 99999 )
    1.70 ( 1.473 )
    3.55 ( 4.738 )
    3.55 ( 2.333 )
    Notes
    [171] - Safety Population
    [172] - Safety Population
    [173] - Safety Population
    [174] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: FSH and LH at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: FSH and LH at 20 years of age of participants [175]
    End point description
    FSH and LH level of participants were measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [175] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    2 [176]
    1 [177]
    Units: International units per Liter
    arithmetic mean (standard deviation)
        FSH
    2.350 ( 3.6062 )
    0.500 ( 99999 )
        LH
    2.90 ( 2.828 )
    0.60 ( 99999 )
    Notes
    [176] - Safety Population
    [177] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: Inhibin B at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: Inhibin B at end of study [178]
    End point description
    Inhibin B level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [178] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 7.5 mg (Safety)
    Number of subjects analysed
    2 [179]
    2 [180]
    2 [181]
    Units: Nanogram per liter
        arithmetic mean (standard deviation)
    15.0 ( 5.66 )
    73.0 ( 175.36 )
    8.5 ( 6.36 )
    Notes
    [179] - Safety Population
    [180] - Safety Population
    [181] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: Inhibin B at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: Inhibin B at 20 years of age of participants [182]
    End point description
    Inhibin B level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [182] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    2 [183]
    1 [184]
    Units: Nanogram per liter
        arithmetic mean (standard deviation)
    23.0 ( 21.21 )
    -47.0 ( 99999 )
    Notes
    [183] - Safety Population
    [184] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: Sex Hormone Binding Globulin at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: Sex Hormone Binding Globulin at end of study [185]
    End point description
    Sex hormone binding globulin level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [185] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 7.5 mg (Safety)
    Number of subjects analysed
    2 [186]
    2 [187]
    2 [188]
    Units: Nanomoles per liter
        arithmetic mean (standard deviation)
    -28.5 ( 28.99 )
    -11.0 ( 39.60 )
    -11.5 ( 3.54 )
    Notes
    [186] - Safety Population
    [187] - Safety Population
    [188] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: Sex Hormone Binding Globulin at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: Sex Hormone Binding Globulin at 20 years of age of participants [189]
    End point description
    Sex hormone binding globulin level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [189] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    2 [190]
    1 [191]
    Units: Nanomoles per liter
        arithmetic mean (standard deviation)
    -2.5 ( 12.02 )
    12.0 ( 99999 )
    Notes
    [190] - Safety Population
    [191] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: Total Testosterone at end of study

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: Total Testosterone at end of study [192]
    End point description
    Total Testosterone level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [192] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 7.5 mg (Safety)
    Number of subjects analysed
    1 [193]
    3 [194]
    2 [195]
    2 [196]
    Units: Nanomoles per liter
        arithmetic mean (standard deviation)
    10.650 ( 99999 )
    2.900 ( 7.1190 )
    17.175 ( 0.1061 )
    7.300 ( 1.6971 )
    Notes
    [193] - Safety Population
    [194] - Safety Population
    [195] - Safety Population
    [196] - Safety Population
    No statistical analyses for this end point

    Primary: Change from Baseline in Plasma Endocrine Parameters - Male: Total Testosterone at 20 years of age of participants

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    End point title
    		 Change from Baseline in Plasma Endocrine Parameters - Male: Total Testosterone at 20 years of age of participants [197]
    End point description
    Total Testosterone level of participants was measured. Only those parameters having status as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with available data at the specified time points were analyzed. 99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [197] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    2 [198]
    1 [199]
    Units: Nanomoles per liter
        arithmetic mean (standard deviation)
    4.000 ( 10.7480 )
    6.600 ( 99999 )
    Notes
    [198] - Safety Population
    [199] - Safety Population
    No statistical analyses for this end point

    Primary: Change From Baseline of Pubertal Development in Male: Testicular volume at end of study

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    End point title
    		 Change From Baseline of Pubertal Development in Male: Testicular volume at end of study [200]
    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. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles).99999 indicates standard deviation could not be calculated due to single participant.Data reported for left and right testicular volume.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [200] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 7.5 mg (Safety)
    Number of subjects analysed
    2 [201]
    2 [202]
    2 [203]
    Units: Milliliter
    arithmetic mean (standard deviation)
        Right TV, n=1, 2, 2
    0.0 ( 99999 )
    11.5 ( 16.26 )
    15.0 ( 7.07 )
        Left TV, n= 2, 2, 2
    6.0 ( 8.49 )
    13.0 ( 14.14 )
    16.5 ( 4.95 )
    Notes
    [201] - Safety Population
    [202] - Safety Population
    [203] - Safety Population
    No statistical analyses for this end point

    Primary: Change From Baseline of Pubertal Development in Male: Testicular volume at 20 years of age of participants

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    End point title
    		 Change From Baseline of Pubertal Development in Male: Testicular volume at 20 years of age of participants [204]
    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 as overall were presented. Baseline was the last value recorded prior to start of study treatment from AMB112529.Change from Baseline was calculated by subtracting the Baseline value from the specified time point value. Only participants with data at 20 year visit is presented. When participants reached pubertal maturity prior to being 20 years of age then these tests were not repeated at 20-years of age of participants. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles). 99999 indicates standard deviation could not be calculated due to single participant.88888 indicates data is not available as no participants were analyzed. Data reported for left and right testicular volume.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and at 20 years of age of participants
    Notes
    [204] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 7.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    2 [205]
    1 [206]
    1 [207]
    Units: Milliliter
    arithmetic mean (standard deviation)
        Right TV, n=0, 2, 1
    15.0 ( 7.07 )
    88888 ( 88888 )
    8.0 ( 99999 )
        Left TV, n= 1, 2, 1
    16.5 ( 4.95 )
    17.0 ( 99999 )
    8.0 ( 99999 )
    Notes
    [205] - Safety Population
    [206] - Safety Population
    [207] - Safety Population
    No statistical analyses for this end point

    Primary: Time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, Phosphodiesterase type 5 [PDE-5] inhibitors) due to tolerability issues

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    End point title
    		 Time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, Phosphodiesterase type 5 [PDE-5] inhibitors) due to tolerability issues [208]
    End point description
    Time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, Phosphodiesterase type 5 [PDE-5] inhibitors) due to tolerability issues was defined as the time from randomization to the first occurrence of a dose change due to tolerability issues.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    Notes
    [208] - 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: There are no statistical data to report
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety) Ambrisentan 5 mg (Safety)
    Number of subjects analysed
    1 [209]
    1 [210]
    3 [211]
    2 [212]
    Units: Days
        arithmetic mean (standard deviation)
    393.0 ( 99999 )
    354.0 ( 99999 )
    1448.7 ( 745.09 )
    468.5 ( 41.72 )
    Notes
    [209] - Safety Population
    [210] - Safety Population
    [211] - Safety Population
    [212] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with all-cause death

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    End point title
    		 Number of participants with all-cause death
    End point description
    Number of participants with all-cause death is presented.
    End point type
    Secondary
    End point timeframe
    Up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Number of subjects analysed
    4 [213]
    16 [214]
    6 [215]
    12 [216]
    Units: Participants
    0
    4
    1
    2
    Notes
    [213] - Safety Population
    [214] - Safety Population
    [215] - Safety Population
    [216] - Safety Population
    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 6 MWD data has been presented into three categories as overall, with oxygen use and without oxygen use. The 6-minute walk test measures the distance that a participant can walk in 6 minutes. All participants were given standardized instructions and the distance walked was measured.Baseline which is the last value recorded prior to start of study treatment in AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Intent-to-Treat (ITT) Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to their treatment group at the start of study AMB114588. Only those participants with data available at the specified data points were analyzed (represented by n=X in category titles). 88888 indicates data is not available as no participants were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Number of subjects analysed
    9 [217]
    11 [218]
    4 [219]
    5 [220]
    Units: Meters
    arithmetic mean (standard deviation)
        Overall, n=9, 11, 4, 5
    98.53 ( 115.355 )
    56.74 ( 58.069 )
    3.05 ( 94.659 )
    34.24 ( 72.135 )
        With oxygen use, n=2, 0, 0, 0
    -13.05 ( 96.944 )
    88888 ( 88888 )
    88888 ( 88888 )
    88888 ( 88888 )
        Without oxygen use, n=7, 11, 4, 5
    130.41 ( 104.115 )
    56.74 ( 58.069 )
    3.05 ( 94.659 )
    34.24 ( 72.135 )
    Notes
    [217] - ITT Population
    [218] - ITT Population
    [219] - ITT Population
    [220] - ITT Population
    No statistical analyses for this end point

    Secondary: Time to the First Clinical Worsening of PAH

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    End point title
    		 Time to the First Clinical Worsening of PAH
    End point description
    Time to clinical worsening of PAH is defined as time from randomization to first occurrence of death(all cause),placed on active list for lung transplant, &/or atrial septostomy,hospitalization due to PAH deterioration,addition of another targeted PAH therapeutic agents (prostanoids,PDE-5 inhibitors) due to deterioration of clinical condition,change in dose of ambrisentan/other targeted PAH therapeutic agents(prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition, PAH related deterioration identified by increase in WHO functional class,deterioration in exercise testing (i.e.20% decrease in 6MWD on 2 consecutive tests -1 week apart, clinical signs or symptoms of right sided heart failure (i.e.new peripheral edema,increase in liver size,ascites,increase in jugular venous pressure, pericardial effusion increased dyspnea).Only participants with available data at specified time points were analyzed.99999 indicate SD could not be calculated due to single participant.
    End point type
    Secondary
    End point timeframe
    Up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Number of subjects analysed
    2 [221]
    5 [222]
    3 [223]
    1 [224]
    Units: Days
        arithmetic mean (standard deviation)
    315.5 ( 2.12 )
    896.2 ( 721.33 )
    1122.0 ( 704.09 )
    228.0 ( 99999 )
    Notes
    [221] - ITT Population
    [222] - ITT Population
    [223] - ITT Population
    [224] - ITT Population
    No statistical analyses for this end point

    Secondary: Time to the addition of another targeted PAH therapeutic agent due to deterioration of clinical condition

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    End point title
    		 Time to the addition of another targeted PAH therapeutic agent due to deterioration of clinical condition
    End point description
    Time to addition of another targeted PAH therapeutics agents due to deterioration of clinical condition was defined as the time from randomization to the first occurrence of deterioration of clinical condition.
    End point type
    Secondary
    End point timeframe
    Up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Number of subjects analysed
    1 [225]
    2 [226]
    1 [227]
    2 [228]
    Units: Days
        arithmetic mean (standard deviation)
    510.0 ( 99999 )
    697.5 ( 863.38 )
    909.0 ( 99999 )
    345.5 ( 109.60 )
    Notes
    [225] - ITT Population
    [226] - ITT Population
    [227] - ITT Population
    [228] - ITT Population
    No statistical analyses for this end point

    Secondary: Time to the addition of another targeted PAH therapeutic agent due to lack of beneficial effect with previous therapy

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    End point title
    		 Time to the addition of another targeted PAH therapeutic agent due to lack of beneficial effect with previous therapy [229]
    End point description
    The time to addition of another targeted PAH therapeutic agents due to lack of beneficial effect with previous therapy was defined as the time from randomization to the first occurrence of lack of beneficial effect with previous therapy (not reaching set treatment goals).Only those participants with available data at the specified time points were analyzed.99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Secondary
    End point timeframe
    Up to 10 years and 11 months
    Notes
    [229] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is only reporting on a subset of the arms that are contained in the baseline period
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT)
    Number of subjects analysed
    2 [230]
    1 [231]
    Units: Days
        arithmetic mean (standard deviation)
    315.5 ( 2.12 )
    173.0 ( 99999 )
    Notes
    [230] - ITT Population
    [231] - ITT Population
    No statistical analyses for this end point

    Secondary: Time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition

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    End point title
    		 Time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition
    End point description
    Time to change in dose of ambrisentan or other targeted PAH therapeutic agents (prostanoids, PDE-5 inhibitors) due to deterioration of clinical condition was defined as the time from randomization to the first occurrence of a dose change due to deterioration of clinical condition. Only those participants with available data at the specified time points were analyzed.99999 indicates standard deviation could not be calculated due to single participant.
    End point type
    Secondary
    End point timeframe
    Up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Number of subjects analysed
    3 [232]
    3 [233]
    1 [234]
    2 [235]
    Units: Days
        arithmetic mean (standard deviation)
    1247.3 ( 1051.97 )
    1097.0 ( 922.77 )
    909.0 ( 99999 )
    345.5 ( 109.60 )
    Notes
    [232] - ITT Population
    [233] - ITT Population
    [234] - ITT Population
    [235] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in Subject Global Assessment (SF-10) Health Survey for Children

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    End point title
    		 Change from Baseline in Subject Global Assessment (SF-10) Health Survey for Children
    End point description
    The short-form 10 (SF-10) Health Survey for children is a 10-item, 4-week recall, parent-completed health assessment that measures physical and psychosocial functioning for children ages five and over. Two summary scores were calculated: a Physical Summary Score (PHS) and a Psychosocial Summary Score (PSS) with a range of 5 to 30 points for each 5-item score. The aggregate score was then standardized and transformed to a norm-based scoring metric in accordance with the developer’s guidelines. This generated the final standardized norm-based scores for PHS (range -10.90 to 57.21) and for PSS (range 8.81 to 62.28), respectively. A higher value on each summary score indicates better functioning. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value.Only those participants with available data at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Number of subjects analysed
    8 [236]
    9 [237]
    4 [238]
    5 [239]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Physical health summary
    -1.618 ( 7.4650 )
    -0.967 ( 16.4890 )
    -1.788 ( 12.0104 )
    -0.272 ( 15.1029 )
        Psychosocial summary
    -0.336 ( 5.4290 )
    -1.880 ( 7.9810 )
    2.225 ( 6.2357 )
    6.766 ( 6.5080 )
    Notes
    [236] - ITT Population
    [237] - ITT Population
    [238] - ITT Population
    [239] - ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants with change from Baseline in World Health Organization (WHO) Functional Class of PAH

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    End point title
    		 Number of participants with change from Baseline in World Health Organization (WHO) Functional Class of PAH
    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 mapped to numeric scale for which scores ranged from 1-4 (i.e. Class I=1 and IV=4). Change categorization was based on change from Baseline scores: -2, -1, 0, +1, +2. Data was categorized as No Change (0), Improved (-1,-2), Deteriorated (+1,+2). Higher score indicated higher severity.Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting the Baseline value from the end of study post-dose visit value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Number of subjects analysed
    9 [240]
    11 [241]
    4 [242]
    5 [243]
    Units: Participants
        Improved
    5
    5
    3
    0
        No Change
    4
    6
    1
    5
        Deteriorated
    0
    0
    0
    0
    Notes
    [240] - ITT Population
    [241] - ITT Population
    [242] - ITT Population
    [243] - ITT Population
    No statistical analyses for this end point

    Secondary: Percentage change from Baseline in Plasma N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) concentration

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    End point title
    		 Percentage change from Baseline in Plasma N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) concentration
    End point description
    Blood samples were collected to analyze NT-Pro BNP concentration at specific time points. Baseline was the last value recorded prior to start of study treatment from AMB112529. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Only those participants with available data at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and up to 10 years and 11 months
    End point values
    		 Ambrisentan 2.5 mg (ITT) Ambrisentan 5 mg (ITT) Ambrisentan 7.5 mg (ITT) Ambrisentan 10 mg (ITT)
    Number of subjects analysed
    7 [244]
    11 [245]
    2 [246]
    5 [247]
    Units: Percentage Change
        geometric mean (full range (min-max))
    -62.59 (-97.6 to 116.3)
    -56.02 (-99.0 to 2227.1)
    59.06 (-22.6 to 226.8)
    101.96 (-2.1 to 214.4)
    Notes
    [244] - ITT Population
    [245] - ITT Population
    [246] - ITT Population
    [247] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality, non-STEAEs and STEAEs were collected from the start of study treatment up to 10 years and 11 months
    Adverse event reporting additional description
    All-cause mortality, non-STEAEs and STEAEs were collected in Safety Population which consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 25.0
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Ambrisentan 2.5 mg (Safety)
    Reporting group description
    		 Participants received ambrisentan 2.5 mg tablet orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Reporting group title
    Ambrisentan 5 mg (Safety)
    Reporting group description
    		 Participants received ambrisentan 5 mg tablet orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Reporting group title
    Ambrisentan 7.5 mg (Safety)
    Reporting group description
    		 Participants received ambrisentan 7.5 mg tablet orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Reporting group title
    Ambrisentan 10 mg (Safety)
    Reporting group description
    		 Participants received ambrisentan 10 mg tablet orally once daily. The Safety Population consisted of all participants who received at least 1 dose of study drug. Participants were considered as belonging to the treatment group according to the highest dose received in the extension study (AMB114588).

    Serious adverse events
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    7 / 16 (43.75%)
    4 / 6 (66.67%)
    8 / 12 (66.67%)
         number of deaths (all causes)
    0
    4
    1
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Illness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hyperventilation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    3 / 12 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Autoimmune lymphoproliferative syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute right ventricular failure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Conduction disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wandering pacemaker
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Scoliosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myringitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media acute
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ambrisentan 2.5 mg (Safety) Ambrisentan 5 mg (Safety) Ambrisentan 7.5 mg (Safety) Ambrisentan 10 mg (Safety)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    13 / 16 (81.25%)
    5 / 6 (83.33%)
    10 / 12 (83.33%)
    Vascular disorders
    Cyanosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Surgical and medical procedures
    Therapeutic procedure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Catheter site discharge
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Chills
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Localised oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    0
    1
    Puncture site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    3
    2
    Swelling face
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    Allergy to vaccine
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Immunisation reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Erection increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Bronchospasm
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    2 / 6 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    3
    1
    Hypoxia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasal inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Nasal obstruction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 16 (18.75%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    1
    1
    Pleurisy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Respiratory symptom
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Adenoidal hypertrophy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Automatism
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Device leakage
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood parathyroid hormone increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood pressure diastolic decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Foot fracture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gingival injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Hand fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    3
    Limb injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Ear procedural complication
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Pulmonary valve stenosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Facial paralysis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 16 (18.75%)
    2 / 6 (33.33%)
    2 / 12 (16.67%)
         occurrences all number
    0
    3
    3
    7
    Hypoaesthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Lethargy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Seizure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Speech disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tardive dyskinesia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 16 (18.75%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Lymphoid tissue hyperplasia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    1
    0
    9
    Ear and labyrinth disorders
    Conductive deafness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Deafness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Ear congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eustachian tube dysfunction
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Motion sickness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    2
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    2
    Eye disorders
    Astigmatism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cataract
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    3
    Eye pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Strabismus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    0
    3
    Abdominal pain lower
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Dry mouth
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    2 / 6 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    5
    3
    1
    Stomatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tooth disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Angioedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    1
    Eczema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Eczema asteatotic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Erythema
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Lichen sclerosus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Urticaria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Bone cyst
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Coccydynia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fistula
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    2 / 6 (33.33%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    3
    1
    Pain in jaw
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Sacral pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    7
    1
    0
    Bronchitis viral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Epididymitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Folliculitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    0
    3
    Gastroenteritis viral
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 16 (18.75%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 16 (31.25%)
    1 / 6 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    0
    18
    3
    9
    Oral candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otitis externa
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    3
    Otitis media chronic
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Periodontitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Pharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 16 (18.75%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    2
    4
    0
    4
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    4
    Pneumonia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    3
    4
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    3
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tinea pedis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    0
    5
    Tooth infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tracheobronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 16 (18.75%)
    4 / 6 (66.67%)
    2 / 12 (16.67%)
         occurrences all number
    4
    8
    7
    5
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    2
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Oct 2010
    Amendment 01: The intents of this amendment are to clarify procedural issues to insure a better global understanding of intent of the protocol and to correctly categorize alkaline phosphatase as a clinical chemistry parameter rather than a liver function test.
    08 Feb 2011
    Amendment 02: The intents of this amendment are to add oestrogen and remove testosterone from laboratory assessments being conducted on female participants and to align the storage conditions requirements in the protocol with those that are printed on the study medication package.
    10 Jun 2020
    Amendment 03: The intents of this amendment are primarily to modify the testing schedule for liver functions tests and to modify the locale for performing monthly pregnancy tests that do not occur at the quarterly visits, in light of the Coronavirus disease 2019 (COVID-19) pandemic to minimize the participants need to travel to the site while maintaining appropriate monitoring to ensure participant safety. In addition, the amendment seeks to clarify protocol language on the 30-day follow-up and on the dose groups to which the participants will be considered to belong for the analysis displays, as well as updating the Medical Monitor and Sponsor Signatory
    25 May 2021
    Amendment 04: The primary intent of this amendment is to include changes to when participants can leave the study and the timing of the pubertal development assessment. Specifically, the amendment seeks to clarify that any participants who reached pubertal maturity before 18 years of age and ambrisentan can be supplied through a named participant or expanded access program until the participant reaches 18 years of age will complete their end of study visit at the investigator site. No further pubertal development assessments will be required for these participants. All participants who have reached the age of 18 and who have reached pubertal maturity at a previous visit will complete their final study visit in the form of a telephone follow-up in order to notify the participants of the end of the study and that no further study visits and assessments will take place. All participants who have reached the age of 18 and who have not reached pubertal maturity in previous visits will complete their final study visit at the investigator site and will have their pubertal development assessed. These participants may return at any point and do not need to wait until 20 years of age to have their pubertal maturity evaluated.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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