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    Clinical Trial Results:
    A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil in the Treatment of Subjects Who Have Completed Study A1481131.

    Summary
    EudraCT number
    2005-000963-25
    Trial protocol
    SE   GB   FI   SK   Outside EU/EEA  
    Global end of trial date
    24 Dec 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    25 May 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A1481156
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00159874
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Clinical Trials gov Call center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Clinical Trials gov Call center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000671-PIP01-09
    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
    28 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Dec 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the safety and tolerability of oral sildenafil in the chronic treatment of pediatric subjects with Pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jan 2004
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    United States: 39
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Colombia: 34
    Country: Number of subjects enrolled
    Guatemala: 25
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    India: 27
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Malaysia: 8
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Russian Federation: 13
    Worldwide total number of subjects
    234
    EEA total number of subjects
    59
    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)
    6
    Children (2-11 years)
    129
    Adolescents (12-17 years)
    99
    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 extension study included 220 subjects at 31 sites. 14 subjects did not go from A1481131 (2006-002235-25) to A1481156. Subject from one center in Canada participated in base study A1481131 (2006-002235-25) but not in this extension study.

    Pre-assignment
    Screening details
    Sildenafil subjects remained in the same dose group as in study A1481131(2006-002235-25).Subjects randomized to placebo in 2006-002235-25 were rerandomized to sildenafil in A1481156. Placebo subjects in low weight category were rerandomized to medium or high dose(1:2) and other weight categories were re randomized to low, medium or high dose(1:1:1)

    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
    Sildenafil Low/Low Dose
    Arm description
    Subjects randomized to sildenafil low dose in study A1481131 (2006-002235-25) and in the extension study A1481156.
    Arm type
    Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 milligram (mg) thrice a day (TID) for body weights between 20-45 kilogram (kg) and >45 kg.

    Arm title
    Sildenafil Medium/ Medium Dose
    Arm description
    Subjects randomized to sildenafil medium dose in study A1481131 (2006-002235-25) and in the extension study A1481156.
    Arm type
    Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10, 20, 40 mg TID for body weights greater than or equal to (>=) 8-20 kg, > 20-45 kg, > 45 kg respectively.

    Arm title
    Sildenafil High/ High Dose
    Arm description
    Subjects randomized to sildenafil high dose in study A1481131 (2006-002235-25) and in the extension study A1481156.
    Arm type
    Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg for body weight <=20 kg or 20, 40, 80 mg TID for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively.

    Arm title
    Placebo/ Low Dose
    Arm description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil low dose in study A1481156.
    Arm type
    Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg TID for body weights between 20-45 kg and >45 kg.

    Arm title
    Placebo/ Medium Dose
    Arm description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil medium dose in study A1481156.
    Arm type
    Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10, 20, 40 mg TID for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively.

    Arm title
    Placebo/ High Dose
    Arm description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil high dose in study A1481156.
    Arm type
    Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 10 mg for body weight <=20 kg or 20, 40, 80 mg TID for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively.

    Arm title
    Placebo Non-randomized
    Arm description
    This group comprised those placebo subjects who either discontinued from base study A1481131 (2006-002235-25) or chose not to enter study A1481156 and hence not randomly assigned to a sildenafil dose group at the start of study A1481156.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Started
    42
    55
    77
    13
    19
    23
    5
    Completed
    22
    25
    34
    7
    11
    11
    0
    Not completed
    20
    30
    43
    6
    8
    12
    5
         Death
    3
    8
    15
    -
    1
    2
    -
         Lack of efficacy
    2
    -
    1
    1
    -
    3
    -
         Pregnancy
    1
    1
    -
    -
    -
    -
    -
         Not specified
    8
    8
    8
    -
    2
    1
    3
         Protocol Violation
    -
    5
    2
    -
    -
    -
    -
         Does Not Meet Entrance Criteria
    1
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    2
    6
    8
    4
    3
    2
    1
         Adverse Event
    2
    2
    5
    1
    1
    2
    -
         Lost to follow-up
    1
    -
    3
    -
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sildenafil Low/Low Dose
    Reporting group description
    Subjects randomized to sildenafil low dose in study A1481131 (2006-002235-25) and in the extension study A1481156.

    Reporting group title
    Sildenafil Medium/ Medium Dose
    Reporting group description
    Subjects randomized to sildenafil medium dose in study A1481131 (2006-002235-25) and in the extension study A1481156.

    Reporting group title
    Sildenafil High/ High Dose
    Reporting group description
    Subjects randomized to sildenafil high dose in study A1481131 (2006-002235-25) and in the extension study A1481156.

    Reporting group title
    Placebo/ Low Dose
    Reporting group description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil low dose in study A1481156.

    Reporting group title
    Placebo/ Medium Dose
    Reporting group description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil medium dose in study A1481156.

    Reporting group title
    Placebo/ High Dose
    Reporting group description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil high dose in study A1481156.

    Reporting group title
    Placebo Non-randomized
    Reporting group description
    This group comprised those placebo subjects who either discontinued from base study A1481131 (2006-002235-25) or chose not to enter study A1481156 and hence not randomly assigned to a sildenafil dose group at the start of study A1481156.

    Reporting group values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized Total
    Number of subjects
    42 55 77 13 19 23 5 234
    Age categorical
    Units: Subjects
        1-4
    0 9 19 1 3 2 1 35
        5-12
    25 28 36 11 10 14 2 126
        13-17
    17 18 22 1 6 7 2 73
        >=18
    0 0 0 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    25 31 51 9 11 15 3 145
        Male
    17 24 26 4 8 8 2 89

    End points

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    End points reporting groups
    Reporting group title
    Sildenafil Low/Low Dose
    Reporting group description
    Subjects randomized to sildenafil low dose in study A1481131 (2006-002235-25) and in the extension study A1481156.

    Reporting group title
    Sildenafil Medium/ Medium Dose
    Reporting group description
    Subjects randomized to sildenafil medium dose in study A1481131 (2006-002235-25) and in the extension study A1481156.

    Reporting group title
    Sildenafil High/ High Dose
    Reporting group description
    Subjects randomized to sildenafil high dose in study A1481131 (2006-002235-25) and in the extension study A1481156.

    Reporting group title
    Placebo/ Low Dose
    Reporting group description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil low dose in study A1481156.

    Reporting group title
    Placebo/ Medium Dose
    Reporting group description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil medium dose in study A1481156.

    Reporting group title
    Placebo/ High Dose
    Reporting group description
    Subjects randomized to placebo in study A1481131 (2006-002235-25) and randomized to sildenafil high dose in study A1481156.

    Reporting group title
    Placebo Non-randomized
    Reporting group description
    This group comprised those placebo subjects who either discontinued from base study A1481131 (2006-002235-25) or chose not to enter study A1481156 and hence not randomly assigned to a sildenafil dose group at the start of study A1481156.

    Subject analysis set title
    Sildenafil Low Dose
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects randomized to sildenafil low dose in study A1481131 (2006-­002235-­25) and continued in the low dose group in the extension study A1481156, and subjects randomized to placebo dose in study A1481131 (2006-­002235-­25) and randomized to sildenafil low dose in the extension study A1481156.

    Subject analysis set title
    Sildenafil Medium Dose
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects randomized to sildenafil medium dose in study A1481131 (2006-­002235­-25) and continued in the medium dose group in the extension study A1481156, and subjects randomized to placebo dose in study A1481131 (2006-­002235-­25) and randomized to sildenafil medium dose in the extension study A1481156.

    Subject analysis set title
    Sildenafil High Dose
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects randomized to sildenafil high dose in study A1481131 (2006-­002235-­25)and continued in the high dose group in the extension study A1481156, and subjects randomized to placebo dose in study A1481131 (2006-­002235-­25) and randomized to sildenafil high dose in the extension study A1481156.

    Primary: Number of Subjects Reporting at Least One Adverse Event

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    End point title
    Number of Subjects Reporting at Least One Adverse Event [1]
    End point description
    Safety was measured according to standard adverse event collection as described in the adverse event (AE) section of the results. Complete tables of the AEs according to the A1481156 treatment groups are provided in the reported AE section.The safety population consisted of all subjects who had taken at least one dose of study medication in A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
    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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
    41
    55
    73
    13
    19
    22
    3
    No statistical analyses for this end point

    Primary: Number of Subjects Reporting Treatment-related Adverse Events

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    End point title
    Number of Subjects Reporting Treatment-related Adverse Events [2]
    End point description
    Safety was measured according to standard AE collection as described in the AE section of the results. The safety population consisted of all subjects who had taken at least one dose of study medication in A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
    20
    24
    41
    9
    9
    11
    3
    No statistical analyses for this end point

    Primary: Number of Subjects Reporting at Least One Serious Adverse Event

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    End point title
    Number of Subjects Reporting at Least One Serious Adverse Event [3]
    End point description
    Safety was measured according to standard AE collection as described in the adverse event section of the results. Complete tables of the serious adverse events (SAEs) according to the A1481156 treatment groups are provided in the reported AE section. The safety population consisted of all subjects who had taken at least one dose of study medication in A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: subjects
    13
    33
    38
    1
    4
    10
    0
    No statistical analyses for this end point

    Primary: Number of Subjects Reporting Treatment-related Serious Adverse Events

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    End point title
    Number of Subjects Reporting Treatment-related Serious Adverse Events [4]
    End point description
    All SAEs regardless of treatment group or suspected relationship to study drug were reported. Investigators were to provide independent determination of possible causality of any SAE. The safety population consisted of all subjects who had taken at least one dose of study medication in A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
    1
    1
    4
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Deaths Reported in the Study Prior to the Data Monitoring Committee (DMC) Recommendation of Dose Down Titration

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    End point title
    Number of Deaths Reported in the Study Prior to the Data Monitoring Committee (DMC) Recommendation of Dose Down Titration [5]
    End point description
    Deaths were reported immediately independent of the circumstances or suspected cause at any time during the study through the last follow-up visit or 30 days after the last administration of study drug, whichever comes later.The safety population consisted of all subjects who had taken at least one dose of study medication in A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Pre-DMC Recommendation dose down titration (04 August 2011)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
    5
    10
    22
    No statistical analyses for this end point

    Primary: Number of Deaths Reported During This Study

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    End point title
    Number of Deaths Reported During This Study [6]
    End point description
    Deaths were reported immediately independent of the circumstances or suspected cause at any time during the study through the last follow-up visit or 30 days after the last administration of study drug, whichever comes later. The safety population consisted of all subjects who had taken at least one dose of study medication in A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Last follow-up visit or 30 days after the last administration of study drug
    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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
    5
    13
    24
    No statistical analyses for this end point

    Primary: Discontinuation Due to Intolerability

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    End point title
    Discontinuation Due to Intolerability [7]
    End point description
    Subject who experienced drug-related intolerance, the subject’s dose was reduced by 50 percent (%). If, after a dose reduction, the subject continued to appear intolerant, they were discontinued from study treatment. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Throughout the treatment duration (median treatment duration 1689 to 1744 days)
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
    2
    1
    3
    No statistical analyses for this end point

    Primary: Down Titration in Dose Due to Intolerability

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    End point title
    Down Titration in Dose Due to Intolerability [8]
    End point description
    Based on review of the survival data, DMC concluded that the high dose of sildenafil was associated with a harmful effect on survival when compared to the low dose. The DMC also expressed concern as to the potential dose-response relationship between increasing dose and mortality. Therefore, on 04 August 2011, the DMC recommended discontinuation of the 40 mg and 80 mg TID doses, as well as the 20 mg TID dose in children with body weight less than (<=)20 kg. The protocol was amended per DMC recommendations. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Pre-DMC recommendation (04 August 2011)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
    0
    0
    3
    0
    2
    1
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Deterioration Post Baseline in Visual Acuity Safety Tests

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    End point title
    Number of Subjects With Deterioration Post Baseline in Visual Acuity Safety Tests [9]
    End point description
    Visual Acuity is measured either using the reduced Snellen test or via Teller cards, and was assessed in the left and right eyes separately. There were 9 lines on the reduced Snellen chart which were coded as 6/60, 6/36, 6/24, 6/18, 6/12, 6/9, 6/6, 6/5, 6/4 (where 6/60 was the easiest to read and 6/4 was the most difficult to read). If a subject experienced a visual AE the investigator was asked to perform additional ocular assessments either at the visit when the subject reported the visual Ae or at an unplanned visit. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Week 36
    Notes
    [9] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
    10
    11
    17
    0
    4
    4
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Deterioration Post Baseline in Color Vision Monitoring Safety Tests

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    End point title
    Number of Subjects With Deterioration Post Baseline in Color Vision Monitoring Safety Tests [10]
    End point description
    Color vision was measured where appropriate via the Farnsworth-Munsell D-15 Hue test. This test was performed in both eyes simultaneously or just in a single specific eye. If using a single eye the same eye was used throughout the study. In case of young subjects an age-and-ability-appropriate evaluation such as the Ishihara Test for Unlettered Persons were conducted. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006-002235-25).
    End point type
    Primary
    End point timeframe
    Week 36
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
    2
    2
    1
    0
    0
    1
    1
    No statistical analyses for this end point

    Primary: Pediatric Cognitive Development Status at Week 16

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    End point title
    Pediatric Cognitive Development Status at Week 16 [11]
    End point description
    Subject's cognitive development status was assessed at A1481156 baseline (Week 16 in A1481131; 2006­-002235-­25) using the physician assessment questions. Assessment question (i.e., compared to other children the subject’s age group is this subject’s cognitive development limited?) included the following criteria: severely limited, moderately limited, mildly limited and not limited. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006­-002235-­25). Subjects with observed data were included in table.
    End point type
    Primary
    End point timeframe
    Week 16
    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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
        Severely Limited
    2
    4
    2
    0
    1
    1
    0
        Moderately Limited
    5
    6
    8
    1
    5
    2
    1
        Mildly Limited
    6
    7
    12
    1
    1
    1
    0
        Not limited
    26
    38
    54
    11
    12
    19
    1
    No statistical analyses for this end point

    Primary: Pediatric Cognitive Development Status at Week 52

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    End point title
    Pediatric Cognitive Development Status at Week 52 [12] [13]
    End point description
    Subject's cognitive development status was assessed at Week 52 using the physician assessment questions. Assessment question (i.e., compared to other children the subject’s age group is this subject’s cognitive development limited?) included the following criteria: severely limited, moderately limited, mildly limited and not limited. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006-002235-25). Subjects with observed data were included in table.
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [12] - 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: Only descriptive data was planned to be reported for this endpoint.
    [13] - 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: Placebo Non-randomized group was not assigned any treatment in the extension study. Hence no data was analyzed for it at Week 52.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    Units: Subjects
        Severely limited
    1
    1
    2
    0
    0
    0
        Moderately Limited
    5
    10
    6
    1
    5
    2
        Mildly Limited
    3
    5
    8
    0
    3
    3
        Not Limited
    27
    36
    50
    11
    10
    15
    No statistical analyses for this end point

    Primary: Pediatric Motor Development Status at Week 16

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    End point title
    Pediatric Motor Development Status at Week 16 [14]
    End point description
    Subject's motor development status was assessed at A1481156 baseline (Week 16 in A1481131; 2006-002235-25) using the physician assessment questions. Assessment question (i.e., compared to other children the subject’s age group is this subject’s motor development limited?) included the following criteria: severely limited, moderately limited, mildly limited and not limited. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006-002235-25). Subjects with observed data were included in table.
    End point type
    Primary
    End point timeframe
    Week 16
    Notes
    [14] - 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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
        Severely Limited
    0
    0
    0
    0
    1
    0
    0
        Moderately Limited
    5
    5
    7
    0
    4
    1
    1
        Mildly Limited
    10
    11
    20
    1
    5
    2
    0
        Not Limited
    24
    39
    49
    12
    9
    20
    1
    No statistical analyses for this end point

    Primary: Pediatric Motor Development Status at Week 52

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    End point title
    Pediatric Motor Development Status at Week 52 [15] [16]
    End point description
    Subject's motor development status was assessed at Week 52 using the physician assessment questions. Assessment question (i.e., compared to other children the subject’s age group is this subject’s motor development limited?) included the following criteria: severely limited, moderately limited, mildly limited and not limited. Safety population included all randomly assigned subjects who took at least 1 dose of study medication in Study A1481131 (2006-002235-25). Subjects with observed data were included in table.
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [15] - 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: Only descriptive data was planned to be reported for this endpoint.
    [16] - 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: Placebo Non-randomized group was not assigned any treatment in the extension study. Hence no data was analyzed for it at Week 52.
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    Units: Subjects
        Severely Limited
    0
    0
    0
    0
    0
    0
        Moderately Limited
    4
    9
    5
    0
    2
    0
        Mildly Limited
    8
    8
    15
    3
    6
    3
        Not Limited
    24
    35
    46
    9
    10
    17
    No statistical analyses for this end point

    Secondary: Peak Volume of Oxygen (VO2) Consumed at Year 1 Using a Bicycle Ergometry Cardiopulmonary Exercise Test (CPX)

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    End point title
    Peak Volume of Oxygen (VO2) Consumed at Year 1 Using a Bicycle Ergometry Cardiopulmonary Exercise Test (CPX)
    End point description
    Exercise Tolerance Test (CPX test) was performed on developmentally able subjects to determine peak volume of VO2 consumed. Subjects were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131(N2006-002235-25). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after previous dose.If subjects were able to perform CPX test in Study A1481131(2006-002235-25), they were expected to be able to perform the exercise paradigm in extension study (A1481156) unless their clinical condition had deteriorated and investigator considered this was unsafe for the subject. An intent to treat (ITT) population included all randomized subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points:1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131(2006-002235-25) baseline.
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    38
    36
    40
    Units: milliliter/Kilogram/minute (mL/kg/min)
        arithmetic mean (standard error)
    19.97 ± 5.17
    18.69 ± 5.92
    17.93 ± 4.02
    Statistical analysis title
    Sildenafil Low Dose vs. Sildenafil Medium Dose
    Statistical analysis description
    Analyses were performed using analysis of covariance (ANCOVA) with etiology, weight, day of assessment and baseline peak VO2 as the covariates. Least square mean difference of -7.02 was calculated as ‘ Sildenafil Medium Dose – Low Dose’ for percent change from baseline in Peak VO2. For the treatment comparison, results were based on total 65 subjects, 33 from low dose and 32 from medium dose Sildenfil reporting groups.
    Comparison groups
    Sildenafil Low Dose v Sildenafil Medium Dose
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.253
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -7.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -19.13
         upper limit
    5.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.1
    Statistical analysis title
    Sildenafil Low Dose vs. Sildenafil High Dose
    Statistical analysis description
    Analyses were performed using ANCOVA with etiology, weight, day of assessment and baseline peak VO2 as the covariates. Least square mean difference of -9.84 was calculated as ‘ Sildenafil High Dose – Low Dose’ for percent change from baseline in Peak VO2. For the treatment comparison, results were based on total 68 subjects, 33 from low dose and 35 from high dose Sildenafil reporting groups.
    Comparison groups
    Sildenafil High Dose v Sildenafil Low Dose
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1
    Method
    ANCOVA
    Parameter type
    Least Square Mean Difference
    Point estimate
    -9.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.6
         upper limit
    1.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.92
    Statistical analysis title
    Sildenafil Medium Dose vs. Sildenafil High Dose
    Statistical analysis description
    Analyses were performed using ANCOVA with etiology, weight, day of assessment and baseline peak VO2 as the covariates.Least square mean difference of -2.82 was calculated as ‘ Sildenafil High Dose – Medium Dose’ for percent change from baseline in Peak VO2. For the treatment comparison, results were based on total 67 subjects, 32 from medium dose and 35 from high dose Sildenafil reporting groups.
    Comparison groups
    Sildenafil Medium Dose v Sildenafil High Dose
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.64
    Method
    ANCOVA
    Parameter type
    Least square mean difference
    Point estimate
    -2.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.75
         upper limit
    9.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.01

    Secondary: Percentage Change From Baseline in Percent Predicted Peak VO2 at Year 1

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    End point title
    Percentage Change From Baseline in Percent Predicted Peak VO2 at Year 1
    End point description
    CPX test was performed on developmentally able subjects to measure the percent predicted peak VO2 at Week 16, and Year 1. Subjects were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (2006-002235-25). CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after previous dose. If subjects were able to perform CPX test in Study A1481131(2006-002235-25), they were expected to be able to perform exercise paradigm in extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the subject. ITT population. Only developmentally able subjects were used for this analysis. Here,99999 in the arithmetic mean and standard deviation signifies "Not estimable".Since number of subjects in the reporting group(Placebo Non-randomized) was 1, arithmetic mean and standard deviation could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    28
    28
    29
    10
    8
    11
    1
    Units: percent
        arithmetic mean (standard deviation)
    12.79 ± 22.71
    7.65 ± 34.57
    5.83 ± 23.54
    8.7 ± 25.99
    0.2 ± 22.32
    -6.13 ± 7.46
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Time to Maximum VO2 at Year 1

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    End point title
    Percent Change From Baseline in Time to Maximum VO2 at Year 1
    End point description
    CPX testwas performed on developmentally able subjects to determine the time to maximum VO2. Subjects were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (2006-002235-25). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If subjects were able to perform the CPX test in Study A1481131 (2006-002235-25), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the subject. ITT population. Only developmentally able subjects were used for this analysis. Here, 99999 in the arithmetic mean and standard deviation signifies "Not estimable". Since number of subjects in the reporting group (Placebo Non-randomized) was 1, arithmetic mean and standard deviation could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    28
    28
    29
    10
    8
    11
    1
    Units: percent
        arithmetic mean (standard deviation)
    25.47 ± 35.67
    13.08 ± 33.42
    7.7 ± 33.01
    21.17 ± 57.25
    36.68 ± 101.65
    -9.64 ± 15.21
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Respiratory Exchange Ratio at Year 1

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    End point title
    Percent Change From Baseline in Respiratory Exchange Ratio at Year 1
    End point description
    This is the ratio of carbon dioxide (CO2) produced to O2 consumed [VCO2/VO2]. Exercise Tolerance Test was performed on developmentally able subjects to determine the respiratory exchange ratio on week 16 and Year 1. Subjects were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (2006-002235-25). An ITT population included all randomized subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131 (2006-002235-25) baseline. Only developmentally able subjects were used for this analysis.Here, 99999 in the arithmetic mean and standard deviation signifies "Not estimable". Since number of subjects in the reporting group (Placebo Non-randomized) was 1, arithmetic mean and standard deviation could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    28
    28
    29
    10
    8
    11
    1
    Units: percent
        arithmetic mean (standard deviation)
    2.15 ± 8.73
    5.63 ± 13.37
    0.68 ± 11.5
    -3.69 ± 7.24
    0.27 ± 11.04
    10.75 ± 17.76
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Percent Change From Start of Sildenafil in Total Ventilation (VE) to Year 1

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    End point title
    Percent Change From Start of Sildenafil in Total Ventilation (VE) to Year 1
    End point description
    CPX test was performed on developmentally able subjects to determine total ventilation. Subjects were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131(2006-002235-25). The CPX tests were performed as close to trough plasma levels of sildenafil possible,i.e., prior to dosing and at least 4 hours after the previous dose. If subjects were able to perform CPX test in Study A1481131(2006-002235-25), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and investigator considered this was unsafe for the subject. ITT population included all randomized subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1,2 years and 3,4 and 5 years(where data quantity allowed) from A1481131(2006-002235-25) baseline. Only developmentally able subjects were used for this analysis.
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    38
    36
    40
    Units: percent
        arithmetic mean (standard deviation)
    14.29 ± 21.38
    12.38 ± 32.64
    11.8 ± 19.79
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in End Tidal Oxygen (O2) at Year 1

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    End point title
    Percentage Change From Baseline in End Tidal Oxygen (O2) at Year 1
    End point description
    CPX test was performed on developmentally able subjects to measure the End Tidal O2 at Year 1. Subjects were assumed to be developmentally able if they had CPX exercise assessment at any visit during study A1481131(2006-002235-25). The CPX tests were performed as close to trough plasma levels of sildenafil possible,i.e., prior to dosing and at least 4 hours after previous dose. If subjects were able to perform the CPX test in Study A148113(2006-002235-25), they were expected to be able to perform exercise paradigm in extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the subject. ITT population included all randomized subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1,2 years and 3,4, 5 years(where data quantity allowed) from A1481131(2006-002235-25) baseline. Only developmentally able subjects were used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    25
    22
    24
    Units: percent
        arithmetic mean (standard deviation)
    0.59 ± 3.79
    -0.52 ± 3.55
    0.08 ± 3.68
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in End Tidal Carbon Dioxide (CO2) at Year 1

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    End point title
    Percentage Change From Baseline in End Tidal Carbon Dioxide (CO2) at Year 1
    End point description
    CPX test was performed on developmentally able subjects to measure the End Tidal CO2 at Year 1. Subjects were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131(2006-002235-25). The CPX tests were performed as close to trough plasma levels of sildenafil possible,i.e., prior to dosing and at least 4 hours after previous dose. If subjects were able to perform the CPX test in Study A1481131(2006-002235-25), they were expected to be able to perform exercise paradigm in extension study (A1481156) unless their clinical condition had deteriorated and investigator considered this was unsafe for the subject. ITT population included all randomized subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points:1, 2 years and 3, 4, 5 years (where data quantity allowed) from A1481131(2006-002235-25) baseline. Only developmentally able subjects were used for this analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    24
    20
    22
    Units: percent
        arithmetic mean (standard deviation)
    7.83 ± 16.35
    7.68 ± 18.74
    13.16 ± 31.38
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline in Anaerobic Threshold at Year 1

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    End point title
    Percentage Change From Baseline in Anaerobic Threshold at Year 1
    End point description
    CPX test was performed on developmentally able subjects to measure the anaerobic threshold at Week 16 and Year 1. Subjects were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131(2006-002235-25). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If subjects were able to perform the CPX test in Study A1481131(2006-002235-25), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the subject. ITT population. Only developmentally able subjects were used for this analysis. Here, 99999 in the arithmetic mean and standard deviation signifies "Not estimable". Since there was no observation at year 1 for reporting group (Placebo Non-randomized).
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    26
    27
    28
    10
    7
    10
    1
    Units: Percent Mean
        arithmetic mean (standard deviation)
    -1.22 ± 23.06
    1.99 ± 29.54
    3.28 ± 29.36
    7.23 ± 12.31
    -3.59 ± 28.29
    8.96 ± 32.55
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Summary of Shift in Changes From Start of Sildenafil in World Health Organization Pulmonary Hypertension (WHO PH) Functional Class by A1481156 Treatment Group at Year 1

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    End point title
    Summary of Shift in Changes From Start of Sildenafil in World Health Organization Pulmonary Hypertension (WHO PH) Functional Class by A1481156 Treatment Group at Year 1
    End point description
    The WHO PH functional classification was as follows: Class I: Subjects with PH but without resulting limitation of physical activity. Class II: Subjects with PH resulting in slight limitation of physical activity. Class III: Subjects with PH resulting in marked limitation of physical activity. Class IV: Subjects with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarized at Years 1, 2, 3 and 4. Numbers of subjects improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated. An ITT population included all randomly assigned subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131 (2006-002235-25) baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
        Improved by 3 Classes
    0
    0
    0
        Improved by 2 Classes
    1
    0
    1
        Improved by 1 Class
    13
    15
    19
        No change
    30
    48
    64
        Worsened by 1 Class
    4
    6
    3
        Worsened by 2 Classes
    1
    0
    0
        Worsened by 3 Classes
    0
    0
    0
        Discontinued
    5
    4
    10
        Died
    0
    0
    1
        Missing
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 2

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    End point title
    Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 2
    End point description
    The WHO PH functional classification was as follows: Class I: Subjects with PH but without resulting limitation of physical activity. Class II: Subjects with PH resulting in slight limitation of physical activity. Class III: Subjects with PH resulting in marked limitation of physical activity. Class IV: Subjects with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarized at Years 1, 2, 3, and 4. Numbers of subjects improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated. An ITT population included all randomly assigned subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131 (2006-002235-25) baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 2
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
        Improved by 3 Classes
    0
    0
    0
        Improved by 2 Classes
    0
    1
    1
        Improved by 1 Class
    11
    11
    16
        No change
    28
    47
    55
        Worsened by 1 Class
    3
    2
    5
        Worsened by 2 Classes
    0
    0
    0
        Worsened by 3 Classes
    0
    0
    0
        Discontinued
    9
    9
    16
        Died
    1
    2
    5
        Missing
    3
    2
    2
    No statistical analyses for this end point

    Secondary: Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 3

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    End point title
    Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 3
    End point description
    The WHO PH functional classification was as follows: Class I:Subjects with PH but without resulting limitation of physical activity. Class II:Subjects with PH resulting in slight limitation of physical activity. Class III:Subjects with PH resulting in marked limitation of physical activity. Class IV:Subjects with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1,2,3, and 4. Numbers of subjects improving by 3 classes, improving by 2 classes,improving by 1 class,not changing, worsening by 1 class,worsening by 2 classes or worsening by 3 classes from A1481131 (2006-002235-25)baseline at Years 1,2,3 and 4 were evaluated. An ITT population included all randomized subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years(where data quantity allowed)from A1481131 (2006-002235-25) baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 3
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
        Improved by 3 Classes
    0
    0
    0
        Improved by 2 Classes
    1
    0
    1
        Improved by 1 Class
    11
    16
    17
        No change
    21
    36
    44
        Worsened by 1 Class
    3
    3
    5
        Worsened by 2 Classes
    1
    0
    1
        Worsened by 3 Classes
    0
    0
    0
        Discontinued
    14
    13
    19
        Died
    2
    3
    9
        Missing
    2
    3
    4
    No statistical analyses for this end point

    Secondary: Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 4

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    End point title
    Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 4
    End point description
    The WHO PH functional classification was as follows: Class I : Subjects with PH but without resulting limitation of physical activity. Class II : Subjects with PH resulting in slight limitation of physical activity. Class III:Subjects with PH resulting in marked limitation of physical activity. Class IV:Subjects with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1, 2, 3, and 4. Numbers of subjects improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated. An ITT population included all randomly assigned subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131(2006-002235-25) baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Year 4
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
        Improved by 3 Classes
    0
    0
    0
        Improved by 2 Classes
    0
    0
    2
        Improved by 1 Class
    13
    14
    16
        No change
    15
    29
    41
        Worsened by 1 Class
    6
    4
    5
        Worsened by 2 Classes
    1
    2
    1
        Worsened by 3 Classes
    0
    0
    0
        Discontinued
    15
    18
    20
        Died
    2
    5
    13
        Missing
    3
    2
    2
    No statistical analyses for this end point

    Secondary: Additions From Baseline in Background Therapy up to the End of Study

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    End point title
    Additions From Baseline in Background Therapy up to the End of Study
    End point description
    This was defined as an addition or discontinuation in the class(es) of drugs used as background medication (e.g., anticoagulants, oxygen, diuretics, calcium channel blockers, and digoxin) compared to baseline of Study A1481131 (2006-002235-25). An ITT population included all randomly assigned subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131 (2006-002235-25) baseline.
    End point type
    Secondary
    End point timeframe
    Up to the end of study
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    42
    55
    77
    13
    19
    23
    5
    Units: Subjects
        All Classes (N = 18, 26, 43, 7, 8, 14, 4)
    6
    5
    11
    2
    1
    2
    1
        At least one class (N = 42, 55, 77, 13, 19, 23, 5)
    13
    13
    23
    3
    5
    2
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Psychosocial Scale at Year 1

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    End point title
    Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Psychosocial Scale at Year 1
    End point description
    CHQ:50-item, 15 subscale parent or legal guardian assessed instrument of child's physical, emotional, social well-being,and relative burden of disease on the parents; rated on Likert-type scale: range 0 to 100; higher scores indicate a more positive health status. Global indicators for Physical Health and Psychosocial Health are weighted composites derived from subscale items using scoring algorithms(transformed scores); range 0 to 100:higher scores indicate more positive health status. ITT population included all randomized subjects who took at least 1 dose of study drug in base study; certain analyses were conducted at pre-specified time points:1, 2 years and 3, 4, 5 years(where data quantity allowed) from A1481131(2006-002235-25) baseline. Subjects >=5 years at baseline with questionnaire translated were included.Here, 99999 in the arithmetic mean and standard deviation signifies "Not estimable". Since there was no observation at year 1 for reporting group (Placebo Non-randomized).
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    34
    30
    45
    11
    14
    15
    1
    Units: Units on a scale
        arithmetic mean (standard deviation)
    5.63 ± 7.7
    3.92 ± 10.25
    3.48 ± 12.55
    13.74 ± 12.42
    5.3 ± 9.3
    4.27 ± 12.19
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Physical Scale at Year 1

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    End point title
    Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Physical Scale at Year 1
    End point description
    CHQ: 50-item, 15 subscale parent or legal guardian assessed instrument of child's physical, emotional, social well-being,and relative burden of disease on the parents; rated on Likert-type scale:range 0 to 100; higher scores indicate a more positive health status. Global indicators for Physical Health and Psychosocial Health are weighted composites derived from subscale items using scoring algorithms(transformed scores); range 0 to 100:higher scores indicate more positive health status.ITT population included all randomized subjects who took at least 1 dose of study drug in base study; certain analyses were conducted at pre-specified time points:1, 2 years and 3, 4, 5 years(where data quantity allowed) from A1481131(2006-002235-25) baseline.Subjects >= 5 years at baseline with questionnaire translated were included. Here, 99999 in the arithmetic mean and standard deviation signifies "Not estimable". Since there was no observation at year 1 for reporting group (Placebo Non-randomized).
    End point type
    Secondary
    End point timeframe
    Baseline, Year 1
    End point values
    Sildenafil Low/Low Dose Sildenafil Medium/ Medium Dose Sildenafil High/ High Dose Placebo/ Low Dose Placebo/ Medium Dose Placebo/ High Dose Placebo Non-randomized
    Number of subjects analysed
    34
    30
    45
    11
    14
    15
    1
    Units: Units on a scale
        arithmetic mean (standard deviation)
    14.29 ± 11.06
    9.34 ± 13.45
    5.91 ± 10.17
    8.51 ± 13.27
    9.86 ± 17.93
    4.64 ± 12.03
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Subject (Parent) Global Assessment at Year 1

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    End point title
    Subject (Parent) Global Assessment at Year 1
    End point description
    The subject (parent) global assessment of disease severity was assessed at Year 1 in this extension study. The number and percentage of subjects markedly improved, moderately improved, mild improvement, no change, slightly worse, moderately worse, markedly worse were evaluated. Subjects who withdrew from study treatment after at least 10 weeks of treatment were requested to perform the global assessments. An ITT population included all randomly assigned subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131 (2006-002235-25) baseline.
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
        Markedly Improved
    9
    14
    21
        Moderately Improved
    13
    27
    26
        Mild Improvement
    12
    15
    15
        No Change
    13
    6
    21
        Slightly Worse
    1
    2
    0
        Moderately Worse
    0
    1
    0
        Markedly Worse
    0
    0
    0
        Discontinued
    5
    4
    10
        Died
    0
    0
    1
        Missing
    2
    5
    6
    No statistical analyses for this end point

    Secondary: Physician Global Assessment at Year 1

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    End point title
    Physician Global Assessment at Year 1
    End point description
    The physician global assessment of disease severity was assessed at Year 1 in this extension study. The number and percentage of subjects with markedly improved, moderately improved, mild improvement, no change, slightly worse, moderately worse, markedly worse were evaluated. Subjects who withdrew from study treatment after at least 10 weeks of treatment were requested to perform the global assessments. An ITT population included all randomly assigned subjects who took at least 1 dose of study medication in base study and certain analyses were conducted at pre-specified time points: 1, 2 years and 3, 4 and 5 years (where data quantity allowed) from A1481131 (2006­-002235-­25) baseline.
    End point type
    Secondary
    End point timeframe
    Year 1
    End point values
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    55
    74
    100
    Units: Subjects
        Markedly Improved
    6
    6
    6
        Moderately Improved
    8
    18
    27
        Mild Improvement
    19
    26
    37
        No Change
    15
    16
    17
        Slightly Worse
    1
    1
    0
        Moderately Worse
    0
    1
    0
        Markedly Worse
    0
    0
    0
        Discontinued
    5
    4
    10
        Died
    0
    0
    1
        Missing
    1
    2
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Follow­-Up visit (30 to 40 days after study completion or treatment discontinuation)
    Adverse event reporting additional description
    The same event may appear as both an AE/SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as nonserious in another subject, or 1 subject may have experienced both a serious/nonserious event during the study. On treatment deaths during the study were reported in SAE section.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Sildenafil Low Dose
    Reporting group description
    Subjects randomized to sildenafil low dose in study A1481131 (2006­002235­25) and continued in the low dose group in the extension study A1481156, and subjects randomized to placebo dose in study A1481131 (2006­002235­25) and randomized to sildenafil low dose in the extension study A1481156.

    Reporting group title
    Sildenafil Medium Dose
    Reporting group description
    Subjects randomized to sildenafil medium dose in study A1481131 (2006­002235­25) and continued in the medium dose group in the extension study A1481156, and subjects randomized to placebo dose in study A1481131 (2006­002235­25) and randomized to sildenafil medium dose in the extension study A1481156.

    Reporting group title
    Sildenafil High Dose
    Reporting group description
    Subjects randomized to sildenafil high dose in study A1481131 (2006­002235­25) and continued in the high dose group in the extension study A1481156, and subjects randomized to placebo dose in study A1481131 (2006­002235­25) and randomized to sildenafil high dose in the extension study A1481156.

    Serious adverse events
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 55 (25.45%)
    37 / 74 (50.00%)
    48 / 100 (48.00%)
         number of deaths (all causes)
    3
    8
    17
         number of deaths resulting from adverse events
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac operation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 74 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anorexia nervosa
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exposure via father
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Catheterisation cardiac
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial pressure increased
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 55 (3.64%)
    2 / 74 (2.70%)
    6 / 100 (6.00%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cyanosis
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 74 (4.05%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eisenmenger's syndrome
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip dysplasia
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular septal defect
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 74 (2.70%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 74 (2.70%)
    7 / 100 (7.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 74 (5.41%)
    5 / 100 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 55 (3.64%)
    2 / 74 (2.70%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Corneal oedema
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratoconus
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 55 (0.00%)
    2 / 74 (2.70%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Excessive granulation tissue
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 74 (1.35%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 74 (1.35%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 55 (0.00%)
    3 / 74 (4.05%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 55 (1.82%)
    7 / 74 (9.46%)
    10 / 100 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 11
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 74 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    6 / 100 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 74 (0.00%)
    3 / 100 (3.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Viral infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 74 (1.35%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 55 (92.73%)
    70 / 74 (94.59%)
    87 / 100 (87.00%)
    Investigations
    Blood pressure diastolic decreased
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 74 (4.05%)
    4 / 100 (4.00%)
         occurrences all number
    4
    6
    5
    Weight decreased
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 74 (2.70%)
    3 / 100 (3.00%)
         occurrences all number
    5
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 55 (7.27%)
    6 / 74 (8.11%)
    6 / 100 (6.00%)
         occurrences all number
    4
    6
    8
    Cough
         subjects affected / exposed
    11 / 55 (20.00%)
    14 / 74 (18.92%)
    17 / 100 (17.00%)
         occurrences all number
    14
    22
    34
    Haemoptysis
         subjects affected / exposed
    3 / 55 (5.45%)
    4 / 74 (5.41%)
    2 / 100 (2.00%)
         occurrences all number
    3
    5
    3
    Epistaxis
         subjects affected / exposed
    6 / 55 (10.91%)
    12 / 74 (16.22%)
    9 / 100 (9.00%)
         occurrences all number
    8
    18
    18
    Pulmonary arterial hypertension
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 74 (5.41%)
    9 / 100 (9.00%)
         occurrences all number
    4
    5
    9
    Oropharyngeal pain
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 74 (6.76%)
    5 / 100 (5.00%)
         occurrences all number
    3
    6
    6
    Rhinitis allergic
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 74 (1.35%)
    2 / 100 (2.00%)
         occurrences all number
    4
    1
    2
    Pulmonary hypertension
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 74 (5.41%)
    3 / 100 (3.00%)
         occurrences all number
    4
    6
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 55 (0.00%)
    5 / 74 (6.76%)
    2 / 100 (2.00%)
         occurrences all number
    0
    7
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 55 (12.73%)
    4 / 74 (5.41%)
    10 / 100 (10.00%)
         occurrences all number
    9
    7
    17
    Headache
         subjects affected / exposed
    18 / 55 (32.73%)
    18 / 74 (24.32%)
    26 / 100 (26.00%)
         occurrences all number
    39
    36
    43
    Syncope
         subjects affected / exposed
    5 / 55 (9.09%)
    7 / 74 (9.46%)
    5 / 100 (5.00%)
         occurrences all number
    7
    12
    7
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 74 (6.76%)
    6 / 100 (6.00%)
         occurrences all number
    6
    6
    6
    Conjunctivitis
         subjects affected / exposed
    1 / 55 (1.82%)
    3 / 74 (4.05%)
    9 / 100 (9.00%)
         occurrences all number
    1
    3
    13
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 74 (5.41%)
    3 / 100 (3.00%)
         occurrences all number
    0
    4
    3
    Retinal vascular disorder
         subjects affected / exposed
    1 / 55 (1.82%)
    4 / 74 (5.41%)
    6 / 100 (6.00%)
         occurrences all number
    2
    5
    6
    Visual impairment
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 74 (1.35%)
    2 / 100 (2.00%)
         occurrences all number
    3
    1
    3
    Visual acuity reduced
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 74 (5.41%)
    5 / 100 (5.00%)
         occurrences all number
    3
    7
    9
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 55 (7.27%)
    8 / 74 (10.81%)
    7 / 100 (7.00%)
         occurrences all number
    5
    12
    15
    Chest pain
         subjects affected / exposed
    5 / 55 (9.09%)
    4 / 74 (5.41%)
    12 / 100 (12.00%)
         occurrences all number
    7
    5
    21
    Pyrexia
         subjects affected / exposed
    7 / 55 (12.73%)
    16 / 74 (21.62%)
    16 / 100 (16.00%)
         occurrences all number
    9
    40
    31
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    3
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 74 (5.41%)
    13 / 100 (13.00%)
         occurrences all number
    5
    5
    15
    Abdominal pain upper
         subjects affected / exposed
    3 / 55 (5.45%)
    5 / 74 (6.76%)
    9 / 100 (9.00%)
         occurrences all number
    5
    6
    12
    Dental caries
         subjects affected / exposed
    6 / 55 (10.91%)
    3 / 74 (4.05%)
    2 / 100 (2.00%)
         occurrences all number
    8
    8
    2
    Diarrhoea
         subjects affected / exposed
    10 / 55 (18.18%)
    11 / 74 (14.86%)
    16 / 100 (16.00%)
         occurrences all number
    11
    18
    41
    Dyspepsia
         subjects affected / exposed
    3 / 55 (5.45%)
    6 / 74 (8.11%)
    5 / 100 (5.00%)
         occurrences all number
    3
    7
    6
    Gastritis
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 74 (5.41%)
    5 / 100 (5.00%)
         occurrences all number
    2
    4
    11
    Vomiting
         subjects affected / exposed
    14 / 55 (25.45%)
    13 / 74 (17.57%)
    24 / 100 (24.00%)
         occurrences all number
    29
    18
    45
    Nausea
         subjects affected / exposed
    2 / 55 (3.64%)
    5 / 74 (6.76%)
    12 / 100 (12.00%)
         occurrences all number
    3
    7
    14
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 74 (1.35%)
    3 / 100 (3.00%)
         occurrences all number
    3
    1
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 74 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    4
    0
    1
    Pain in extremity
         subjects affected / exposed
    5 / 55 (9.09%)
    3 / 74 (4.05%)
    2 / 100 (2.00%)
         occurrences all number
    6
    4
    6
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 74 (5.41%)
    0 / 100 (0.00%)
         occurrences all number
    0
    5
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 55 (18.18%)
    16 / 74 (21.62%)
    16 / 100 (16.00%)
         occurrences all number
    27
    38
    28
    Gastroenteritis
         subjects affected / exposed
    4 / 55 (7.27%)
    3 / 74 (4.05%)
    7 / 100 (7.00%)
         occurrences all number
    4
    3
    12
    Bronchopneumonia
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 74 (5.41%)
    2 / 100 (2.00%)
         occurrences all number
    0
    5
    2
    Ear infection
         subjects affected / exposed
    3 / 55 (5.45%)
    8 / 74 (10.81%)
    4 / 100 (4.00%)
         occurrences all number
    5
    17
    4
    Laryngitis
         subjects affected / exposed
    5 / 55 (9.09%)
    1 / 74 (1.35%)
    4 / 100 (4.00%)
         occurrences all number
    8
    4
    4
    Influenza
         subjects affected / exposed
    10 / 55 (18.18%)
    6 / 74 (8.11%)
    12 / 100 (12.00%)
         occurrences all number
    16
    12
    20
    Otitis media
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 74 (5.41%)
    4 / 100 (4.00%)
         occurrences all number
    2
    5
    6
    Nasopharyngitis
         subjects affected / exposed
    15 / 55 (27.27%)
    11 / 74 (14.86%)
    17 / 100 (17.00%)
         occurrences all number
    23
    29
    39
    Pharyngitis
         subjects affected / exposed
    16 / 55 (29.09%)
    13 / 74 (17.57%)
    13 / 100 (13.00%)
         occurrences all number
    73
    63
    45
    Pharyngitis streptococcal
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 74 (4.05%)
    2 / 100 (2.00%)
         occurrences all number
    4
    5
    4
    Respiratory tract infection
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 74 (5.41%)
    5 / 100 (5.00%)
         occurrences all number
    2
    4
    7
    Pneumonia
         subjects affected / exposed
    2 / 55 (3.64%)
    4 / 74 (5.41%)
    0 / 100 (0.00%)
         occurrences all number
    2
    5
    0
    Rhinitis
         subjects affected / exposed
    6 / 55 (10.91%)
    10 / 74 (13.51%)
    7 / 100 (7.00%)
         occurrences all number
    9
    19
    9
    Sinusitis
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 74 (4.05%)
    8 / 100 (8.00%)
         occurrences all number
    2
    4
    10
    Tonsillitis
         subjects affected / exposed
    9 / 55 (16.36%)
    6 / 74 (8.11%)
    13 / 100 (13.00%)
         occurrences all number
    15
    12
    17
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 55 (16.36%)
    22 / 74 (29.73%)
    37 / 100 (37.00%)
         occurrences all number
    30
    68
    93
    Urinary tract infection
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 74 (2.70%)
    6 / 100 (6.00%)
         occurrences all number
    3
    2
    7
    Varicella
         subjects affected / exposed
    3 / 55 (5.45%)
    3 / 74 (4.05%)
    4 / 100 (4.00%)
         occurrences all number
    3
    3
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jun 2006
    1. Made revisions to address the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use guideline on the exposure to medicinal products during pregnancy, need for post-authorization data. 2. Made revisions to address the European Commission Decision in June 2006 that Revatio and Viagra (sildenafil citrate) should be contraindicated in the EU in subjects who have loss of vision in 1 eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous Phosphodiesterase 5 (PDE5) inhibitor exposure (new exclusion criterion added and safety information provided).
    15 Apr 2009
    1. Increased survival follow up frequency from yearly to every 3 months.
    19 Aug 2011
    1. The DMC concluded that in the context of this clinical trial the high dose of sildenafil was associated with a harmful effect on survival when compared to the low dose. The DMC also expressed concern as to the apparent dose response relationship between increasing dose and mortality, including when comparing the medium dose to the low dose. Therefore, the DMC recommended immediate discontinuation of the 40 mg and 80 mg doses, as well as the 20 mg dose in children with body weight <=20 kg. Those subjects on ''High Dose", irrespective of weight group, were to be immediately down-titrated based on the clear relationship between mortality and "High Dose" use. Advised physicians to exercise great caution in prescribing "Medium Dose" sildenafil for children weighing <45 kg, but to evaluate the responses of each subject individually in order to make an assessment of risk:benefit. The Summary of dosing based on weight groups is listed below: - For children <20 kg in weight: Either consider using alternative therapies if available, or use sildenafil in a dose no greater than 10 mg TID. - For children between 20 and 45 kg, consider using 'Low Dose" (10 mg TID) and under no circumstances should the dose exceed 20 mg TID. - For children greater than 45 kg a dose of 20 mg TID is the maximal dose that should be used. 2. Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in the absence of other causes of liver injury are considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and should always be considered important medical events. 3. If the trial subject’s partner becomes or is found to be pregnant while receiving the investigational product, the investigator should obtain agreement from the subject’s partner for the release of their pregnancy information for the purpose of safety monitoring.

    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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