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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo Controlled, Dose Ranging, Parallel Group Study of Oral Sildenafil in the Treatment of Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension.

    Summary
    EudraCT number
    		 2006-002235-25
    Trial protocol
    		 GB   FI   SK   Outside EU/EEA  
    Global end of trial date
    05 Jun 2008

    Results information
    Results version number
    		 v1
    This version publication date
    22 Apr 2016
    First version publication date
    29 Jul 2015
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    A1481131
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00159913
    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
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 800-718-1021, 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
    27 Nov 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the efficacy of 16 weeks of chronic treatment with oral sildenafil in pediatric subjects, aged 1 to 17 years, with primary arterial hypertension (PAH). Secondary objective were- 1) To assess safety, tolerability, and pharmacokinetics of 16 weeks of chronic treatment with oral sildenafil in pediatric subjects, aged 1 to 17 years with PAH, 2) To assess the survival status of subjects who did not enter A1481156 [(NCT number: NCT00159874) and (EudraCT number: 2005-000963-25)].
    Protection of trial subjects
    The study was in compliance with 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
    28 Aug 2003
    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
    Russian Federation: 13
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    United States: 39
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Guatemala: 25
    Country: Number of subjects enrolled
    Colombia: 34
    Country: Number of subjects enrolled
    India: 27
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Malaysia: 8
    Country: Number of subjects enrolled
    Taiwan: 5
    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
    		 The study was conducted at 32 centers in North, Latin and South America, Europe and Asia.

    Pre-assignment
    Screening details
    		 Of the 324 subjects screened, 235 subjects were randomized. 234 received treatment. One subject (sildenafil medium dose group) withdrew prior to taking any study treatment as the hemodynamic entrance criteria were not met.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sildenafil Low Dose
    Arm description
    		 Day 1-7 10 milligram (mg), followed by 10 mg TID (3 times daily) for body weights greater than (>)20-45 kilogram (kg) and >45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects [that is (i.e.), subjects would receive the same dose because of the available tablet strengths]; consequently there was no low dose for the greater than or equal to (>=)8-20 kg weight group.
    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
    Day 1-7 10 mg, followed by 10 mg TID for body weights > 20-45 kg and > 45 kg, through Day 112.

    Arm title
    		 Sildenafil Medium Dose
    Arm description
    		 Day 1-7 10 mg, followed by 10, 20, 40 mg TID based on the body weight, through Day 112.
    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
    Day 1-7 10 mg, followed by 10, 20, 40 mg TID for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively through Day 112.

    Arm title
    		 Sildenafil High Dose
    Arm description
    		 Day 1-7 10 mg, followed by 20, 40, 80 mg TID based on body weight, through Day 112.
    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
    Day 1-7 10 mg, followed by 20, 40, 80 mg TID for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112.

    Arm title
    		 Placebo
    Arm description
    		 Subjects randomized to this arm received placebo TID for 112 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was given TID for 112 days.

    Number of subjects in period 1
    		Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose Placebo
    Started
    42
    55
    77
    60
    Completed
    40
    55
    75
    58
    Not completed
    2
    0
    2
    2
         Consent withdrawn by subject
    -
    -
    -
    1
         Protocol violation
    1
    -
    1
    -
         Adverse event
    1
    -
    1
    -
         Lost to follow-up
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sildenafil Low Dose
    Reporting group description
    		 Day 1-7 10 milligram (mg), followed by 10 mg TID (3 times daily) for body weights greater than (>)20-45 kilogram (kg) and >45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects [that is (i.e.), subjects would receive the same dose because of the available tablet strengths]; consequently there was no low dose for the greater than or equal to (>=)8-20 kg weight group.

    Reporting group title
    Sildenafil Medium Dose
    Reporting group description
    		 Day 1-7 10 mg, followed by 10, 20, 40 mg TID based on the body weight, through Day 112.

    Reporting group title
    Sildenafil High Dose
    Reporting group description
    		 Day 1-7 10 mg, followed by 20, 40, 80 mg TID based on body weight, through Day 112.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomized to this arm received placebo TID for 112 days.

    Reporting group values
    		 Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose Placebo Total
    Number of subjects
    		 42 55 77 60 234
    Age categorical
    Units: Subjects
        1-4 Years
    		 0 9 19 7 35
        5-12 Years
    		 25 28 36 37 126
        13-17 Years
    		 17 18 22 16 73
        >= 18 Years
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 25 31 51 38 145
        Male
    		 17 24 26 22 89

    End points

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    End points reporting groups
    Reporting group title
    Sildenafil Low Dose
    Reporting group description
    		 Day 1-7 10 milligram (mg), followed by 10 mg TID (3 times daily) for body weights greater than (>)20-45 kilogram (kg) and >45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects [that is (i.e.), subjects would receive the same dose because of the available tablet strengths]; consequently there was no low dose for the greater than or equal to (>=)8-20 kg weight group.

    Reporting group title
    Sildenafil Medium Dose
    Reporting group description
    		 Day 1-7 10 mg, followed by 10, 20, 40 mg TID based on the body weight, through Day 112.

    Reporting group title
    Sildenafil High Dose
    Reporting group description
    		 Day 1-7 10 mg, followed by 20, 40, 80 mg TID based on body weight, through Day 112.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomized to this arm received placebo TID for 112 days.

    Subject analysis set title
    Sildenafil Low Dose
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Day 1-7 10 mg, followed by 10 mg TID for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (ie, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group.

    Subject analysis set title
    Sildenafil High Dose
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Day 1-7 10 mg, followed by 20, 40, 80 mg TID for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112.

    Subject analysis set title
    Sildenafil Medium Dose
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Day 1-7 10 mg, followed by 10, 20, 40 mg TID for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to this arm received placebo TID for 112 days.

    Subject analysis set title
    Combined Sildenafil
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This includes all subjects in the low, medium and high dose group of sildenafil.

    Primary: Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population

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    End point title
    		 Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Intent To Treat Population
    End point description
    Peak VO2 (normalized for body weight) at trough plasma levels assessed by Cardiopulmonary excercise (CPX) testing (bicycle ergometry) at the end of treatment (Week 16 for those who completed the study). Mean Percent change = [(week 16 value minus baseline mean)/mean at baseline]*100%. Intent to treat (ITT) population included all subjects randomized and who received at least one dose of study medication. All subjects developmentally able to perform the exercise test. Subjects assumed developmentally able if they had a CPX exercise assessment at any visit during study using a LOCF (last observation carried forward) (end-of-treatment) approach for handling missing data.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    24
    29
    77
    26
    27
    Units: percent change
        arithmetic mean (standard deviation)
    6.44 ( 20.16 )
    0.53 ( 15.91 )
    10.24 ( 18.39 )
    13.4 ( 19.5 )
    10.58 ( 15.51 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance (ANCOVA) with etiology, weight and baseline peak VO2 as the covariates. No adjustments for multiple comparisons have been made.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.056
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 15.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.98
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.11
         upper limit
    		 13.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    5
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.72
         upper limit
    		 20.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.84
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.64
         upper limit
    		 17.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.85

    Primary: Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population

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    End point title
    		 Percent Change From Baseline in Peak Volume of Oxygen (VO2) Consumed : Per Protocol Population
    End point description
    Peak VO2 (normalized for body weight) at trough plasma levels assessed by CPX testing (bicycle ergometry) at the end of treatment (Week 16 for those who completed the study). Percent change = [(week 16 value minus baseline mean)/mean at baseline]*100%. Per protocol population was used for the analysis.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    23
    24
    73
    23
    27
    Units: percent change
        arithmetic mean (standard deviation)
    5.43 ( 20.69 )
    2.81 ( 13.17 )
    10.1 ( 19.87 )
    15.66 ( 21.48 )
    9.34 ( 17.13 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.179
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 14.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.35
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.49
         upper limit
    		 11.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.35
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 21.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.36
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    Analyses performed using analysis of covariance with etiology, weight and baseline peak VO2 as the covariates
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.02
         upper limit
    		 15.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.16

    Secondary: Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP)

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    End point title
    		 Change From Baseline to Week 16 in Mean Pulmonary Artery Pressure (mPAP)
    End point description
    mPAP, a hemodynamic parameter, was measured using a pressure transducer positioned at the mid-axillary line with the subject in the supine position. Change is observed value at Week 16 minus Baseline value. ITT population, using a Last Observation Carried Forward (LOCF) (end-of-treatment) approach for handling missing data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    39
    56
    165
    55
    71
    Units: mm Hg
        arithmetic mean (standard deviation)
    0.9 ( 12.3 )
    -0.4 ( 15.9 )
    -4.3 ( 13.9 )
    -3.9 ( 12 )
    -7.4 ( 15.4 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=excluding outliers.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.172
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.2
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=excluding outliers.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 7.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=excluding outliers.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.9
         upper limit
    		 1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=excluding outliers.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.4
         upper limit
    		 -2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6

    Secondary: Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI)

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    End point title
    		 Change From Baseline to Week 16 in Pulmonary Vascular Resistance Index (PVRI)
    End point description
    PVRI equals Pulmonary Vascular Resistance (PVR) times Body Surface Area (BSA). Wood unit = 80 dyn*s/cm^5. Change is observed value at Week 16 minus baseline value. ITT population, LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    36
    50
    152
    49
    67
    Units: wood units*m^2
        arithmetic mean (standard deviation)
    0.1 ( 10.9 )
    1.6 ( 9.2 )
    -3.2 ( 13 )
    -2.9 ( 11.5 )
    -5.1 ( 14.7 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=natural log transformed.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=natural log transformed.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 4.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=natural log transformed.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    Covariates: etiology, weight group, capability performing exercise test. Normality assumptions not met with main analysis: alternative=natural log transformed.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.7
         upper limit
    		 -2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3

    Secondary: Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER)

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    End point title
    		 Percent Change From Baseline to Week 16 in: Respiratory Exchange Ratio (RER)
    End point description
    RER is the ratio of carbon dioxide produced to oxygen consumed (VCO2/VO2). Percent change is ([Week 16 value minus Baseline value]/Baseline value) * 100% . ITT population, LOCF (end-of-treatment) approach for handling missing values.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    24
    29
    77
    26
    27
    Units: percent change
        arithmetic mean (standard deviation)
    0.01 ( 11.69 )
    -2.68 ( 10.37 )
    -2.04 ( 10.87 )
    -3.96 ( 10.69 )
    -2.01 ( 10.33 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.795
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.07
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.36
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.31
         upper limit
    		 8.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.99
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.09
         upper limit
    		 4.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.92
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.24
         upper limit
    		 6.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.9

    Secondary: Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2)

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    End point title
    		 Percent Change From Baseline to Week 16 in Time to Maximum Volume of Oxygen Consumed (VO2)
    End point description
    Time to maximum VO2 was assessed on the subset of subjects who are developmentally able to perform the exercise test. Percent change is [(value at Week 16 minus Baseline value)/Baseline value] * 100% . ITT population, LOCF (end-of-treatment) approach for handling missing values.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    24
    29
    77
    26
    27
    Units: percent change
        arithmetic mean (standard deviation)
    15.21 ( 26.28 )
    4.56 ( 34.85 )
    14.04 ( 25.82 )
    15.97 ( 22.92 )
    11.16 ( 28.62 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.139
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.05
         upper limit
    		 21.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.2
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.21
         upper limit
    		 25.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.84
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    11.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.78
         upper limit
    		 26.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.67
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology and weight group.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.16
         upper limit
    		 21.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.62

    Secondary: Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR)

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    End point title
    		 Change From Baseline to Week 16 in Pulmonary Vascular Resistance (PVR)
    End point description
    Change calculated as (mean PAP - pulmonary capillary wedge pressure [PCWP])/COpulm in PVR is observed value at Week 16 minus Baseline value. ITT population, using LOCF (end of treatment) approach for handling missing data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    36
    50
    152
    49
    67
    Units: woods units
        arithmetic mean (standard deviation)
    -0.1 ( 10.4 )
    0.1 ( 11.8 )
    -3.4 ( 13.1 )
    -3.3 ( 10.5 )
    -5.2 ( 15.7 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.172
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.1
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 5.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.9
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.3
         upper limit
    		 -0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.4

    Secondary: Change From Baseline to Week 16 in Cardiac Index (CI)

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    End point title
    		 Change From Baseline to Week 16 in Cardiac Index (CI)
    End point description
    CI is observed value at Week 16 minus Baseline value. Calculated as cardiac output in systemic circulation (COsys) / body surface area (BSA). ITT population, using LOCF (end of treatment) approach for handling missing data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    37
    52
    154
    49
    68
    Units: liters/minute/meters ^2
        arithmetic mean (standard deviation)
    0.2 ( 1.17 )
    -0.6 ( 2.12 )
    0.16 ( 1.76 )
    0.02 ( 1.44 )
    0.24 ( 2.19 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 1.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test .
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 1.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test .
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 1.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 1.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35

    Secondary: Change From Baseline to Week 16 in Right Atrial Pressure (RAP)

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    End point title
    		 Change From Baseline to Week 16 in Right Atrial Pressure (RAP)
    End point description
    RAP was measured using a pressure transducer positioned at the mid-axillary line with the subject in the supine position. Change is observed value at Week 16 minus Baseline value. ITT population, using LOCF (end of treatment) approach for missing data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    39
    56
    165
    55
    71
    Units: mm Hg
        arithmetic mean (standard deviation)
    0.23 ( 3.95 )
    0.23 ( 4.48 )
    -0.33 ( 4.04 )
    0.07 ( 4.1 )
    -0.96 ( 4.01 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    221
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.77
         upper limit
    		 0.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.64
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.91
         upper limit
    		 1.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.88
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 1.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    The model included the covariates etiology, weight group and capability of performing the exercise test.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    127
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.61
         upper limit
    		 0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75

    Secondary: Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale

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    End point title
    		 Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Physical Scale
    End point description
    CHQ-PF28: validated generic Quality of Life (QoL) questionnaire for subjects >= 5 years. Includes 12 domain scores of QoL concepts including physical functioning, social & school activities, mental health, parent/family concepts. Scores range 0-100: lower scores = lower QoL. Change is observed value at Week 16 minus Baseline value. ITT population, includes subjects >= 5 years with a valid questionnaire available in the subject's first language.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    31
    40
    103
    29
    43
    Units: score on s scale
        arithmetic mean (standard deviation)
    14 ( 13.1 )
    8.3 ( 12 )
    9.4 ( 12.1 )
    9.8 ( 11.8 )
    5.9 ( 10.5 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    The covariates included in the model were baseline scale, etiology, weight and capability of performing the exercise test.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.45
         upper limit
    		 3.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.93
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.21
         upper limit
    		 5.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.57
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.68
         upper limit
    		 5.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.49
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.37
         upper limit
    		 1.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.23

    Secondary: Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales

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    End point title
    		 Change From Baseline to Week 16 in Child Health Questionnaire Parent Form (CHQ-PF28), Psychosocial Scales
    End point description
    CHQ-PF28: validated generic Quality of Life (QoL) questionnaire for subjects >= 5 years. Includes 12 domain scores of QoL concepts including physical functioning, social & school activities, mental health, parent/family concepts. Scores range 0-100: lower scores = lower QoL. Change is observed value at Week 16 minus Baseline value. ITT population, includes subjects >= 5 years with a valid questionnaire available in the subject's first language.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    31
    40
    103
    29
    43
    Units: score on scale
        arithmetic mean (standard deviation)
    5.1 ( 6.9 )
    5.6 ( 10.3 )
    4.5 ( 8.6 )
    4.1 ( 8.1 )
    4.3 ( 10 )
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    The covariates included in the model were baseline scale, etiology, weight and capability of performing the exercise test.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.784
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.41
         upper limit
    		 2.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.51
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.49
         upper limit
    		 4.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.97
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.99
         upper limit
    		 1.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.96
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.06
         upper limit
    		 3.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.77

    Secondary: Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class

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    End point title
    		 Change From Baseline to Week 16 in World Health Organization (WHO) Pulmonary Hypertension (PH) Functional Class
    End point description
    WHO PH functional class definitions adapted from New York Heart Association Criteria for Functional Capacity and Therapeutic Class Definitions. Class I = PH without resulting limitation of physical activity, Class II = PH resulting in slight limitation of physical activity, Class III = PH resulting in marked limitation of physical activity, Class IV = PH with inability to carry out any physical activity without symptoms. Improved by 1 class = Class 4 to 3, Class 3 to 2, Class 2 to 1. Improved by 2 classes = Class 4 to 2, Class 3 to 1. Change is observed value at Week 16 minus Baseline value. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil Low Dose Placebo Combined Sildenafil Sildenafil Medium Dose Sildenafil High Dose
    Number of subjects analysed
    31
    35
    120
    34
    55
    Units: Subjects
    number (not applicable)
        No change
    25
    31
    84
    24
    38
        Improved by 1 class
    6
    4
    32
    10
    16
        Improved by 2 classes
    0
    0
    1
    0
    1
    Statistical analysis title
    		 Combined Sildenafil vs. Placebo
    Statistical analysis description
    Proportional odds method (LOCF). Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. Number of subjects displayed in the table is number of subjects with observations at Week 16. For the treatment comparison, results were based on LOCF analyses, with N=230.
    Comparison groups
    Combined Sildenafil v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.184
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 4.45
    Statistical analysis title
    		 Sildenafil Low Dose vs. Placebo
    Statistical analysis description
    Proportional odds method (LOCF). Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. Number of subjects displayed in the table is number of subjects with observations at Week 16. For the treatment comparison, results were based on LOCF analyses, with N=100.
    Comparison groups
    Sildenafil Low Dose v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.409
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 2.01
    Statistical analysis title
    		 Sildenafil Medium Dose vs. Placebo
    Statistical analysis description
    Proportional odds method (LOCF). Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. Number of subjects displayed in the table is number of subjects with observations at Week 16. For the treatment comparison, results were based on LOCF analyses, with N=114.
    Comparison groups
    Sildenafil Medium Dose v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.146
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 6.69
    Statistical analysis title
    		 Sildenafil High Dose vs. Placebo
    Statistical analysis description
    Proportional odds method (LOCF). Model covariates were baseline WHO functional class, etiology, weight group and capability of performing the exercise test. Number of subjects displayed in the table is number of subjects with observations at Week 16. For the treatment comparison, results were based on LOCF analyses, with N=136.
    Comparison groups
    Sildenafil High Dose v Placebo
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.56
         upper limit
    		 13.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 7 days after last dose of study drug
    Adverse event reporting additional description
    EU BR specific AE tables were generated separately as per EU format. Latest coding dictionary has been used for EU BR tables.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects randomized to this arm received placebo TID (three times daily) for 112 days.

    Reporting group title
    Sildenafil Low Dose
    Reporting group description
    		 Day 1-7 10 mg, followed by 10 mg TID (3 times daily) for body weights > 20-45 kg and > 45 kg, through Day 112. Modeling of the plasma concentrations for each dose level showed that the low and medium doses were predicted to be similar for the 8 to 20 kg subjects (i.e, subjects would receive the same dose because of the available tablet strengths); consequently there was no low dose for the >= 8-20 kg weight group.

    Reporting group title
    Sildenafil Medium Dose
    Reporting group description
    		 Day 1-7 10 mg, followed by 10, 20, 40 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112.

    Reporting group title
    Sildenafil High Dose
    Reporting group description
    		 Day 1-7 10 mg, followed by 20, 40, 80 mg TID (3 times daily) for body weights >= 8-20 kg, > 20-45 kg, > 45 kg respectively, through Day 112.

    Reporting group title
    Combined Sildenafil
    Reporting group description
    		 This includes all subjects in the low, medium and high dose groups.

    Serious adverse events
    		 Placebo Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose Combined Sildenafil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 42 (2.38%)
    1 / 55 (1.82%)
    7 / 77 (9.09%)
    9 / 174 (5.17%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cyanosis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stridor
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    2 / 77 (2.60%)
    3 / 174 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    1 / 77 (1.30%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo Sildenafil Low Dose Sildenafil Medium Dose Sildenafil High Dose Combined Sildenafil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 60 (51.67%)
    21 / 42 (50.00%)
    37 / 55 (67.27%)
    45 / 77 (58.44%)
    103 / 174 (59.20%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 42 (2.38%)
    1 / 55 (1.82%)
    0 / 77 (0.00%)
    2 / 174 (1.15%)
         occurrences all number
    8
    6
    1
    0
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 42 (4.76%)
    2 / 55 (3.64%)
    2 / 77 (2.60%)
    6 / 174 (3.45%)
         occurrences all number
    4
    2
    2
    4
    9
    Headache
         subjects affected / exposed
    8 / 60 (13.33%)
    5 / 42 (11.90%)
    6 / 55 (10.91%)
    12 / 77 (15.58%)
    23 / 174 (13.22%)
         occurrences all number
    20
    6
    11
    14
    31
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    0 / 77 (0.00%)
    2 / 174 (1.15%)
         occurrences all number
    2
    0
    2
    0
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 42 (4.76%)
    1 / 55 (1.82%)
    2 / 77 (2.60%)
    5 / 174 (2.87%)
         occurrences all number
    4
    2
    2
    2
    6
    Fatigue
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 42 (4.76%)
    0 / 55 (0.00%)
    2 / 77 (2.60%)
    4 / 174 (2.30%)
         occurrences all number
    4
    2
    0
    2
    4
    Pyrexia
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 42 (7.14%)
    8 / 55 (14.55%)
    8 / 77 (10.39%)
    19 / 174 (10.92%)
         occurrences all number
    2
    3
    10
    8
    21
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    2 / 77 (2.60%)
    3 / 174 (1.72%)
         occurrences all number
    6
    1
    0
    2
    3
    Abdominal pain lower
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    3 / 77 (3.90%)
    3 / 174 (1.72%)
         occurrences all number
    0
    0
    0
    3
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 42 (0.00%)
    3 / 55 (5.45%)
    3 / 77 (3.90%)
    6 / 174 (3.45%)
         occurrences all number
    2
    0
    3
    3
    6
    Diarrhoea
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 42 (4.76%)
    3 / 55 (5.45%)
    7 / 77 (9.09%)
    12 / 174 (6.90%)
         occurrences all number
    8
    2
    3
    10
    15
    Dyspepsia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    0 / 77 (0.00%)
    2 / 174 (1.15%)
         occurrences all number
    2
    0
    2
    0
    2
    Nausea
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    4 / 55 (7.27%)
    4 / 77 (5.19%)
    8 / 174 (4.60%)
         occurrences all number
    0
    0
    4
    4
    8
    Vomiting
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 42 (7.14%)
    5 / 55 (9.09%)
    11 / 77 (14.29%)
    19 / 174 (10.92%)
         occurrences all number
    10
    7
    6
    14
    27
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 42 (2.38%)
    1 / 55 (1.82%)
    1 / 77 (1.30%)
    3 / 174 (1.72%)
         occurrences all number
    0
    1
    1
    1
    3
    Erection increased
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
    2 / 77 (2.60%)
    3 / 174 (1.72%)
         occurrences all number
    0
    0
    1
    2
    3
    Priapism
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    1 / 174 (0.57%)
         occurrences all number
    0
    0
    0
    1
    1
    Spontaneous penile erection
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    1 / 77 (1.30%)
    3 / 174 (1.72%)
         occurrences all number
    0
    0
    2
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 42 (4.76%)
    4 / 55 (7.27%)
    2 / 77 (2.60%)
    8 / 174 (4.60%)
         occurrences all number
    8
    2
    4
    3
    9
    Epistaxis
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 42 (2.38%)
    2 / 55 (3.64%)
    3 / 77 (3.90%)
    6 / 174 (3.45%)
         occurrences all number
    4
    1
    3
    3
    7
    Haemoptysis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 42 (2.38%)
    2 / 55 (3.64%)
    0 / 77 (0.00%)
    3 / 174 (1.72%)
         occurrences all number
    2
    1
    2
    0
    3
    Nasal congestion
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    0 / 174 (0.00%)
         occurrences all number
    4
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    4 / 55 (7.27%)
    2 / 77 (2.60%)
    6 / 174 (3.45%)
         occurrences all number
    0
    0
    4
    2
    6
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    1 / 77 (1.30%)
    3 / 174 (1.72%)
         occurrences all number
    0
    0
    2
    1
    3
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    0 / 77 (0.00%)
    2 / 174 (1.15%)
         occurrences all number
    0
    0
    2
    0
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 42 (4.76%)
    0 / 55 (0.00%)
    0 / 77 (0.00%)
    2 / 174 (1.15%)
         occurrences all number
    4
    2
    0
    0
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 42 (2.38%)
    5 / 55 (9.09%)
    2 / 77 (2.60%)
    8 / 174 (4.60%)
         occurrences all number
    2
    1
    6
    2
    9
    Influenza
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    0 / 77 (0.00%)
    2 / 174 (1.15%)
         occurrences all number
    0
    0
    2
    0
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
    2 / 77 (2.60%)
    2 / 174 (1.15%)
         occurrences all number
    4
    0
    0
    2
    2
    Laryngitis
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    2 / 174 (1.15%)
         occurrences all number
    4
    1
    0
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 42 (7.14%)
    3 / 55 (5.45%)
    2 / 77 (2.60%)
    8 / 174 (4.60%)
         occurrences all number
    10
    3
    5
    3
    11
    Pharyngitis
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 42 (7.14%)
    3 / 55 (5.45%)
    1 / 77 (1.30%)
    7 / 174 (4.02%)
         occurrences all number
    0
    4
    3
    1
    8
    Pneumonia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 42 (0.00%)
    2 / 55 (3.64%)
    0 / 77 (0.00%)
    2 / 174 (1.15%)
         occurrences all number
    0
    0
    2
    0
    2
    Rhinitis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 42 (2.38%)
    3 / 55 (5.45%)
    1 / 77 (1.30%)
    5 / 174 (2.87%)
         occurrences all number
    2
    1
    3
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 42 (9.52%)
    8 / 55 (14.55%)
    6 / 77 (7.79%)
    18 / 174 (10.34%)
         occurrences all number
    10
    6
    12
    7
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
    1 / 77 (1.30%)
    2 / 174 (1.15%)
         occurrences all number
    4
    1
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2003
    1) Safety follow-up days were increased from 30 days to 40 days for the subjects who were not electing to participate in the extension study. 2) Funduscopy was added instead of contrast sensitivity to the ocular safety measurement parameter. 3) Discontinuation criteria was updated to include unexpected pregnancy.
    18 May 2004
    1) Adverse event section was updated to include Abnormal test findings; Clinically significant symptoms and signs; Changes in physical examination findings; Hypersensitivity; Progression/worsening of underlying disease Drug overdose; Drug withdrawal; Drug abuse; Drug misuse; Drug interactions; Drug dependency; Extravasation; Exposure in utero. 2)Severity Assessment was distinctively defined to mild, moderate and severe. 3) Exposure in utero was defined.
    27 Sep 2005
    1) Causality assessment definition was added wherein the investigators assessment of causality must be provided for all adverse events (serious and non-serious). If the investigator’s final determination of causality was unknown and the investigator does not know whether or not investigational product caused the event, then the event was handled as “related to investigational product” for reporting purposes. If the investigator's causality assessment was "unknown but not related to investigational product", this was clearly documented on trial records. 2) Serious adverse event Reporting Requirements were defined. 3) Clarification to the methodology for the Farnsworth-Munsell test and other ocular safety assessments were made.
    07 Jul 2006
    1) The amendment clarified the assessments that should be undertaken by subjects who permanently discontinue study drug (but have not withdrawn consent). 2) The addition of annual follow-up of subjects for the evaluation of survival status was done. 3) Addition of "male exposure, either due to treatment or environmental, to the investigational product prior to or around the time of conception and/or is exposed during the partner pregnancy (paternal exposure)" was done in in-utero section.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/22963001
    http://www.ncbi.nlm.nih.gov/pubmed/22128226
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