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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
    v2(current)
    This version publication date
    07 May 2016
    First version publication date
    29 Jul 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    update is required regarding the unit of measurement of a secondary endpoint.

    Trial information

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    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
         Protocol violation
    1
    -
    1
    -
         Adverse event
    1
    -
    1
    -
         Consent withdrawn by subject
    -
    -
    -
    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 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
    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
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    24
    26
    29
    27
    77
    Units: percent change
        arithmetic mean (standard deviation)
    6.44 ± 20.16
    13.4 ± 19.5
    0.53 ± 15.91
    10.58 ± 15.51
    10.24 ± 18.39
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    23
    23
    24
    27
    73
    Units: percent change
        arithmetic mean (standard deviation)
    5.43 ± 20.69
    15.66 ± 21.48
    2.81 ± 13.17
    9.34 ± 17.13
    10.1 ± 19.87
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    39
    55
    56
    71
    165
    Units: mm Hg
        arithmetic mean (standard deviation)
    0.9 ± 12.3
    -3.9 ± 12
    -0.4 ± 15.9
    -7.4 ± 15.4
    -4.3 ± 13.9
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    36
    49
    50
    67
    152
    Units: wood units*m^2
        arithmetic mean (standard deviation)
    0.1 ± 10.9
    -2.9 ± 11.5
    1.6 ± 9.2
    -5.1 ± 14.7
    -3.2 ± 13
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    24
    26
    29
    27
    77
    Units: percent change
        arithmetic mean (standard deviation)
    0.01 ± 11.69
    -3.96 ± 10.69
    -2.68 ± 10.37
    -2.01 ± 10.33
    -2.04 ± 10.87
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    24
    26
    29
    27
    77
    Units: percent change
        arithmetic mean (standard deviation)
    15.21 ± 26.28
    15.97 ± 22.92
    4.56 ± 34.85
    11.16 ± 28.62
    14.04 ± 25.82
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    36
    49
    50
    67
    152
    Units: woods units
        arithmetic mean (standard deviation)
    -0.1 ± 10.4
    -3.3 ± 10.5
    0.1 ± 11.8
    -5.2 ± 15.7
    -3.4 ± 13.1
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    37
    49
    52
    68
    154
    Units: liters/minute/meters ^2
        arithmetic mean (standard deviation)
    0.2 ± 1.17
    0.02 ± 1.44
    -0.6 ± 2.12
    0.24 ± 2.19
    0.16 ± 1.76
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    39
    55
    56
    71
    165
    Units: mm Hg
        arithmetic mean (standard deviation)
    0.23 ± 3.95
    0.07 ± 4.1
    0.23 ± 4.48
    -0.96 ± 4.01
    -0.33 ± 4.04
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    31
    29
    40
    43
    103
    Units: score on scale
        arithmetic mean (standard deviation)
    14 ± 13.1
    9.8 ± 11.8
    8.3 ± 12
    5.9 ± 10.5
    9.4 ± 12.1
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    31
    29
    40
    43
    103
    Units: score on scale
        arithmetic mean (standard deviation)
    5.1 ± 6.9
    4.1 ± 8.1
    5.6 ± 10.3
    4.3 ± 10
    4.5 ± 8.6
    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 Sildenafil Medium Dose Placebo Sildenafil High Dose Combined Sildenafil
    Number of subjects analysed
    31
    34
    35
    55
    120
    Units: Subjects
    number (not applicable)
        No change
    25
    24
    31
    38
    84
        Improved by 1 class
    6
    10
    4
    16
    32
        Improved by 2 classes
    0
    0
    0
    1
    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
    Combined Sildenafil
    Reporting group description
    This includes all subjects in the low, medium and high dose groups.

    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
    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.

    Serious adverse events
    Placebo Sildenafil Low Dose Combined Sildenafil Sildenafil High Dose Sildenafil Medium Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 42 (2.38%)
    9 / 174 (5.17%)
    7 / 77 (9.09%)
    1 / 55 (1.82%)
         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%)
    1 / 174 (0.57%)
    1 / 77 (1.30%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         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%)
    1 / 174 (0.57%)
    1 / 77 (1.30%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         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%)
    1 / 174 (0.57%)
    0 / 77 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         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%)
    1 / 174 (0.57%)
    1 / 77 (1.30%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         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%)
    1 / 174 (0.57%)
    1 / 77 (1.30%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         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%)
    1 / 174 (0.57%)
    0 / 77 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         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%)
    1 / 174 (0.57%)
    1 / 77 (1.30%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         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%)
    1 / 174 (0.57%)
    0 / 77 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         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%)
    1 / 174 (0.57%)
    1 / 77 (1.30%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         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 / 174 (0.00%)
    0 / 77 (0.00%)
    0 / 55 (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%)
    1 / 174 (0.57%)
    0 / 77 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         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%)
    1 / 174 (0.57%)
    1 / 77 (1.30%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         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%)
    3 / 174 (1.72%)
    2 / 77 (2.60%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
    0 / 1
         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 / 174 (0.00%)
    0 / 77 (0.00%)
    0 / 55 (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%)
    2 / 174 (1.15%)
    1 / 77 (1.30%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         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 Combined Sildenafil Sildenafil High Dose Sildenafil Medium Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 60 (51.67%)
    21 / 42 (50.00%)
    103 / 174 (59.20%)
    45 / 77 (58.44%)
    37 / 55 (67.27%)
    Vascular disorders