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    Clinical Trial Results:
    A Phase 3, Multi-Center, Open-Label Study to Investigate Safety, Efficacy, and Tolerability of Sildenafil Citrate in Pediatric Patients With Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    		 2016-003978-41
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    12 Mar 2018

    Results information
    Results version number
    		 v3(current)
    This version publication date
    30 Aug 2018
    First version publication date
    24 Nov 2016
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    A1481298
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01642407
    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 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    20 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate changes of patient status with Sildenafil treatment for individual Japanese pediatric patients with Pulmonary artery hypertension (PAH).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (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
    24 Aug 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    0
    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)
    2
    Children (2-11 years)
    3
    Adolescents (12-17 years)
    1
    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
    		 -

    Pre-assignment
    Screening details
    		 The study was conducted at 3 sites in Japan. Data reported is based on data cut-off date of 26 December 2016.

    Period 1
    Period 1 title
    Part 1 (Screening till Week 16)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Sildenafil
    Arm description
    		 Subjects received 10 milligram (mg) or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Day 1 (Baseline), Weeks 4, 8, and 16 in Part 1 of the study. Subjects who completed Part 1 and required continuing treatment with Sildenafil, received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sildenafil 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Sildenafil 10 mg per milliliter oral suspension orally thrice on Day 1, Weeks 4, 8 and 16

    Investigational medicinal product name
    Sildenafil 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Sildenafil 20 mg tablet orally thrice on Day 1, Weeks 4, 8 and 16

    Number of subjects in period 1
    		Sildenafil
    Started
    6
    Completed
    3
    Not completed
    3
         Insufficient clinical response
    3
    Period 2
    Period 2 title
    Part 2(Week17 to maximum of 119.6 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Sildenafil
    Arm description
    		 Subjects received 10 milligram (mg) or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Day 1 (Baseline), Weeks 4, 8, and 16 in Part 1 of the study. Subjects who completed Part 1 and required continuing treatment with Sildenafil, received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sildenafil 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Sildenafil 10 mg per milliliter oral suspension orally thrice on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks).

    Investigational medicinal product name
    Sildenafil 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Sildenafil 20 mg tablet orally thrice on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks).

    Number of subjects in period 2
    		Sildenafil
    Started
    3
    Completed
    1
    Not completed
    2
         Coil Embolization
    1
         Change of treatment plan
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sildenafil
    Reporting group description
    		 Subjects received 10 milligram (mg) or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Day 1 (Baseline), Weeks 4, 8, and 16 in Part 1 of the study. Subjects who completed Part 1 and required continuing treatment with Sildenafil, received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets.

    Reporting group values
    		 Sildenafil Total
    Number of subjects
    		 6 6
    Age Categorical
    Units: Subjects
        <=18 years
    		 6 6
        Between 18 and 65 years
    		 0 0
        >=65 years
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.7 ± 5.4 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 3 3
        Male
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    Sildenafil
    Reporting group description
    		 Subjects received 10 milligram (mg) or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Day 1 (Baseline), Weeks 4, 8, and 16 in Part 1 of the study. Subjects who completed Part 1 and required continuing treatment with Sildenafil, received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets.
    Reporting group title
    Sildenafil
    Reporting group description
    		 Subjects received 10 milligram (mg) or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Day 1 (Baseline), Weeks 4, 8, and 16 in Part 1 of the study. Subjects who completed Part 1 and required continuing treatment with Sildenafil, received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks). Subjects with less than or equal to (<=) 20 kilogram (kg) of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with greater than (>) 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets.

    Primary: Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16

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    End point title
    		 Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Week 16 [1]
    End point description
    PVRI equals pulmonary vascular resistance (PVR) times body surface area (BSA) (PVRI = PVR*BSA). PVR is the resistance to blood flow through the pulmonary circulation and it was measured in Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: wood units*meter^2
    arithmetic mean (standard deviation)
        Baseline (n =6)
    18.567 ± 11.7629
        Change at Week 16 (n =4)
    -4.113 ± 6.3770
    No statistical analyses for this end point

    Primary: Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16

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    End point title
    		 Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 16 [2]
    End point description
    It was a hemodynamic parameter and measured using a pressure transducer positioned at the mid-axillary line with the subject in the supine position. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline (n =6)
    58.5 ± 22.94
        Change at Week 16 (n =4)
    -6.5 ± 15.15
    No statistical analyses for this end point

    Primary: Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 4

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    End point title
    		 Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 4 [3]
    End point description
    WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
        Baseline: Class I|
    2
        Baseline: Class II|
    3
        Baseline: Class III|
    1
        Baseline: Class IV|
    0
        Week 4: Improved|
    1
        Week 4: No change|
    5
        Week 4: Worsened|
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 8

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    End point title
    		 Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 8 [4]
    End point description
    WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here,'N' (Number of Subjects Analyzed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    5
    Units: subjects
        Improved|
    1
        No change|
    4
        Worsened|
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 16

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    End point title
    		 Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Week 16 [5]
    End point description
    WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, Number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    4
    Units: subjects
        Improved|
    1
        No change|
    3
        Worsened|
    0
    No statistical analyses for this end point

    Primary: Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16

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    End point title
    		 Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 16 [6]
    End point description
    BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: picogram per milliliter
    arithmetic mean (standard deviation)
        Baseline (n =6)
    132.62 ± 135.080
        Change at Week 16 (n =4)
    -64.10 ± 129.638
    No statistical analyses for this end point

    Primary: Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT pro-BNP) at Week 16

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    End point title
    		 Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT pro-BNP) at Week 16 [7]
    End point description
    NT pro-BNP is a cardiac marker, having the prognostic value for subjects with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = subjects evaluable for this end point at specified time points.
    End point type
    Primary
    End point timeframe
    Baseline, Week 16
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for this endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: picogram per milliliter
    arithmetic mean (standard deviation)
        Baseline (n =6)
    843.03 ± 1120.900
        Change at Week 16 (n =4)
    -546.85 ± 1107.621
    No statistical analyses for this end point

    Secondary: Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Weeks 28, 40, 52, 64, 76, 88, 100, 112 and 124

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    End point title
    		 Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With Pulmonary Arterial Hypertension (PAH) at Weeks 28, 40, 52, 64, 76, 88, 100, 112 and 124
    End point description
    WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO functional class was classified into “Improved”, “No change” and “Worsened”. Improvement = reduction in functional class, worsened = increase in functional class and no change = no change in functional class. Change from baseline in number of subjects in each functional class were reported. Efficacy analysis set was used in this analysis. Here, Number of subjects analyzed specifies number of subjects who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study and ‘n’ = subjects evaluable for this endpoint for specified categories.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
    End point values
    		 Sildenafil
    Number of subjects analysed
    3
    Units: subjects
        Baseline: Class I(n =3)
    2
        Baseline: Class II (n =3)
    3
        Baseline: Class III (n =3)
    1
        Baseline: Class IV (n =3)
    0
        Week 28: Improved (n =3)
    1
        Week 28: No Change (n =3)
    2
        Week 28: Worsened (n =3)
    0
        Week 40: Improved (n =3)
    1
        Week 40: No Change (n =3)
    2
        Week 40: Worsened (n =3)
    0
        Week 52: Improved (n =3)
    1
        Week 52: No Change (n =3)
    2
        Week 52: Worsened (n =3)
    0
        Week 64: Improved (n =2)
    1
        Week 64: No Change (n =2)
    1
        Week 64: Worsened (n =2)
    0
        Week 76: Improved (n =2)
    1
        Week 76: No Change (n =2)
    0
        Week 76: Worsened (n =2)
    1
        Week 88: Improved (n =1)
    1
        Week 88: No Change (n =1)
    0
        Week 88: Worsened (n =1)
    0
        Week 100: Improved (n =1)
    1
        Week 100: No Change (n =1)
    0
        Week 100: Worsened (n =1)
    0
        Week 112: Improved (n =1)
    1
        Week 112: No Change (n =1)
    0
        Week 112: Worsened (n =1)
    0
        Week 124: Improved (n =1)
    1
        Week 124: No Change (n =1)
    0
        Week 124:Worsened (n =1)
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT)

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    End point title
    		 Change From Baseline in Brain Natriuretic Peptide (BNP) at Week 52 and End of Treatment (EOT)
    End point description
    BNP is produced by ventricular cardiomyocytes. It causes reduction in preload and blood pressure by vasodilatation. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here 'Number of subjects analyzed' specifies number of subjects who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
    End point values
    		 Sildenafil
    Number of subjects analysed
    3
    Units: picograms per milliliter
    arithmetic mean (standard deviation)
        Baseline
    100.17 ± 151.478
        Change at Week 52
    -85.17 ± 55.088
        Change at EoT
    -85.17 ± 155.088
    No statistical analyses for this end point

    Secondary: Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT pro-BNP) at Week 52 and End of Treatment (EOT)

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    End point title
    		 Change From Baseline in N-terminal Pro Brain Natriuretic Peptide (NT pro-BNP) at Week 52 and End of Treatment (EOT)
    End point description
    NT pro-BNP is a cardiac marker, having the prognostic value for subjects with heart failure or left ventricular dysfunction. Higher level of the marker was indicative of heart damage. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here 'Number of subjects analyzed' specifies number of subjects who completed Part 1 of the study and continued treatment with Sildenafil in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
    End point values
    		 Sildenafil
    Number of subjects analysed
    3
    Units: picograms per milliliter
    arithmetic mean (standard deviation)
        Baseline
    841.73 ± 1323.533
        Change at Week 52
    -754.90 ± 1335.370
        Change at EoT
    -754.90 ± 1335.370
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-serious AEs. Safety analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
        AEs|
    6
        SAEs|
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-serious AEs. Safety analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline upto 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
        AEs|
    3
        SAEs|
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124

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    End point title
    		 Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
    End point description
    BP measurement is recorded as supine and sitting systolic and diastolic systemic blood pressure: 1) Systolic blood pressure when heart is contracting and it is the maximum arterial pressure during contraction of left ventricle. 2) Diastolic BP when heart is relaxing and it is the minimum arterial pressure during relaxation and dilation of ventricles. Only those categories in which at least 1 subject had data were reported. Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint for specified categories. Standard deviation was not analyzed since only 1 subject was evaluable and has been denoted by '99999'.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline: Supine Systolic BP (n =5)
    95.4 ± 13.41
        Baseline: Supine Diastolic BP (n =5)
    55.8 ± 10.87
        Baseline: Sitting Systolic BP (n =1)
    110.0 ± 99999
        Baseline: Sitting Diastolic BP (n =1)
    60.0 ± 99999
        Change at Week 4: Supine Systolic BP (n =5)
    5.6 ± 9.91
        Change at Week 4: Supine Diastolic BP (n =5)
    1.6 ± 13.65
        Change at Week 4: Sitting Systolic BP (n =1)
    16.0 ± 99999
        Change at Week 4: Sitting Diastolic BP (n =1)
    23.0 ± 99999
        Change at Week 8: Supine Systolic BP (n =4)
    7.8 ± 14.93
        Change at Week 8: Supine Diastolic BP (n =4)
    2.3 ± 12.28
        Change at Week 8: Sitting Systolic BP (n =1)
    -6.0 ± 99999
        Change at Week 8: Sitting Diastolic BP (n =1)
    -3.0 ± 99999
        Change at Week 16: Supine Systolic BP (n =3)
    7.7 ± 17.62
        Change at Week 16: Supine Diastolic BP (n =3)
    -1.3 ± 12.22
        Change at Week 16: Sitting Systolic BP (n =1)
    8.0 ± 99999
        Change at Week 16: Sitting Diastolic BP (n =1)
    10.0 ± 99999
        Change at Week 28: Supine Systolic BP (n =3)
    7.0 ± 19.31
        Change at Week 28: Supine Diastolic BP (n =3)
    1.7 ± 9.29
        Change at Week 40: Supine Systolic BP (n =2)
    -7.5 ± 3.54
        Change at Week 40: Supine Diastolic BP (n =2)
    2.0 ± 0.00
        Change at Week 52: Supine Systolic BP (n =2)
    2.0 ± 15.56
        Change at Week 52: Supine Diastolic BP (n =2)
    10.0 ± 5.66
        Change at Week 64: Supine Systolic BP (n =1)
    1.0 ± 99999
        Change at Week 64: Supine Diastolic BP (n =1)
    8.0 ± 99999
        Change at Week 76: Supine Systolic BP (n =1)
    -13.0 ± 99999
        Change at Week 76: Supine Diastolic BP (n =1)
    3.0 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124

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    End point title
    		 Change From Baseline in Heart Rate at Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
    End point description
    Only those categories in which at least 1 subject had data were reported. Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint for specified categories. Standard deviation was not analyzed since only 1 subject was evaluable and has been denoted by '99999'.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 16, 28, 40, 52, 64, 76, 88, 100, 112 and 124
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: beats per minute (bpm)
    arithmetic mean (standard deviation)
        Baseline: Supine Heart rate (n =5)
    100.2 ± 15.91
        Baseline: Sitting Heart rate (n =1)
    96.0 ± 99999
        Change at Week 4: Supine Heart rate (n =5)
    -1.0 ± 12.08
        Change at Week 4: Sitting Heart rate (n =1)
    -22.0 ± 99999
        Change at Week 8: Supine Heart rate (n =4)
    -0.5 ± 9.11
        Change at Week 8: Sitting Heart rate (n =1)
    0.0 ± 99999
        Change at Week 16: Supine Heart rate (n =3)
    3.0 ± 28.69
        Change at Week 16: Sitting Heart rate (n =1)
    4.0 ± 99999
        Change at Week 28: Supine Heart rate (n =3)
    6.7 ± 14.36
        Change at Week 40: Supine Heart rate (n =2)
    10.0 ± 16.97
        Change at Week 52: Supine Heart rate (n =2)
    -2.0 ± 11.31
        Change at Week 64: Supine Heart rate (n =1)
    17.0 ± 99999
        Change at Week 76: Supine Heart rate (n =1)
    -8.0 ± 99999
    No statistical analyses for this end point

    Secondary: Number of Subjects With Laboratory Abnormalities

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    End point title
    		 Number of Subjects With Laboratory Abnormalities
    End point description
    Laboratory abnormality criteria: Hematology (hemoglobin, hematocrit, red blood cell count [less than {<}]0.8*lower limit of normal [LLN]; platelets <0.5*LLN, greater than [>]1.75*upper limit of normal [ULN], white blood cells <0.6*LLN, >1.5*ULN; lymphocytes, neutrophils <0.8*LLN, >1.2*ULN, eosinophils, basophils, monocytes >1.2*ULN); liver function (total and direct bilirubin >1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase >3.0*ULN, total protein, albumin <0.8*LLN, >1.2*ULN); renal (creatinine, blood urea nitrogen >1.3*ULN); electrolytes (sodium <0.95*LLN, >1.05*ULN, potassium, chloride <0.9*LLN, >1.1*ULN; other (glucose <0.6*LLN or >1.5*ULN ); urinalysis (dipstick) urine glucose, urine protein, urine blood/Hemoglobin, [greater than or equal to {>=}1]. Safety analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up-to End of treatment (maximum duration of treatment: 119.6 weeks)
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities

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    End point title
    		 Number of Subjects With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities
    End point description
    Criteria for clinically significant abnormality in ECG parameters: Maximum corrected QT interval (QTc) from 450 millisecond (msec) to less than (<) 480 msec, Maximum QTcB interval (Bazett’s Correction) from 450 msec to <480 msec, Maximum QTcF interval (Fredericia’s Correction) from 450 msec to <480 msec, maximum QTc interval increase from baseline of 30 msec to <60 msec and >=60 msec. Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint for specified categories.
    End point type
    Secondary
    End point timeframe
    Screening, Week 16, Week 52 and End of treatment (maximum duration of treatment: 119.6 weeks)
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
        Screening (n =6)
    4
        Week 16 (n =6)
    5
        Week 52 (n =2)
    1
        End of Treatment (n =3)
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Ocular Examination Abnormalities

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    End point title
    		 Number of Subjects With Ocular Examination Abnormalities
    End point description
    Ocular examination measures included external examination of the eye, funduscopy, assessments of visual acuity, and color vision. Ocular examination findings were considered abnormal based on investigator’s decision. Safety analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Screening up to end of treatment (maximum duration of treatment: 119.6 weeks)
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16

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    End point title
    		 Change From Baseline in Pulmonary Artery Systolic and Diastolic Pressure at Week 16
    End point description
    Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline: Systolic Pressure (n =6)
    82.5 ± 35.51
        Baseline: Diastolic Pressure (n =6)
    42.0 ± 18.19
        Change at Week 16: Systolic Pressure (n =4)
    -9.8 ± 18.01
        Change at Week 16: Diastolic Pressure (n =4)
    -3.5 ± 13.99
    No statistical analyses for this end point

    Secondary: Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16

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    End point title
    		 Change From Baseline in Systemic Artery Systolic and Diastolic Pressure at Week 16
    End point description
    Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline: Systolic Pressure (n =6)
    95.3 ± 15.20
        Baseline: Diastolic Pressure (n =6)
    60.2 ± 19.30
        Change at Week 16: Systolic Pressure (n =4)
    0.3 ± 10.21
        Change at Week 16: Diastolic Pressure (n =4)
    -1.5 ± 14.25
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 16
    End point description
    The resistance to blood flow through the pulmonary circulation is known as PVR. It is largely influenced by the caliber of the pulmonary arteries and capillaries and was measured in terms of Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: Wood units
    arithmetic mean (standard deviation)
        Baseline (n =6)
    21.372 ± 11.3408
        Change at Week 16 (n =4)
    -6.145 ± 10.3499
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in Right Atrial Pressure (RAP) at Week 16
    End point description
    RAP is the blood pressure in the right atrium of the heart. It reflects the amount of blood returning to the heart and the ability of the heart to pump the blood into the arterial system. RAP was measured using a pressure transducer positioned at the mid-axillary line with the subject in the supine position. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (n =6)
    6.5 ± 2.88
        Change at Week 16 (n =4)
    1.3 ± 2.36
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16

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    End point title
    		 Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 16
    End point description
    PCWP was measured by pulmonary artery catheterization and provided an indirect measure of left atrial pressure. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (n =6)
    8.5 ± 0.84
        Change at Week 16 (n =4)
    2.5 ± 1.00
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cardiac Output (CO) at Week 16

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    End point title
    		 Change From Baseline in Cardiac Output (CO) at Week 16
    End point description
    Cardiac output is simply the amount of blood pumped by the heart per minute. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: liter per minute
    arithmetic mean (standard deviation)
        Baseline (n =6)
    2.620 ± 0.9879
        Change at Week 16 (n =4)
    0.420 ± 0.9076
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in Cardiac Index (CI) at Week 16
    End point description
    Cardiac index is a hemodynamic parameter that relates the cardiac output from left ventricle in one minute to BSA, thus relating heart performance to the size of the individual. CI was calculated as cardiac output in systemic circulation divided by BSA. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: liter per minute per meter square
    arithmetic mean (standard deviation)
        Baseline (n =6)
    3.070 ± 0.7460
        Change at Week 16 (n=4)
    0.658 ± 1.8912
    No statistical analyses for this end point

    Secondary: Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16

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    End point title
    		 Change From Baseline in Systemic Vascular Resistance (SVR) at Week 16
    End point description
    The resistance to blood flow through the systemic circulation is known as SVR. This can be used in measuring blood pressure, blood flow and cardiac function and measured in terms of Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: Wood units
    arithmetic mean (standard deviation)
        Baseline (n =6)
    26.545 ± 3.0768
        Change at Week 16 (n =4)
    -3.403 ± 4.4409
    No statistical analyses for this end point

    Secondary: Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16

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    End point title
    		 Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Week 16
    End point description
    SVRI equals systemic vascular resistance (SVR) times BSA. SVR is the resistance to blood flow through the systemic circulation and it was measured in Wood units. Wood unit =80 dyne*seconds per centimetre^5 (dyne*sec/cm^5). Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: Wood units*meter^2
    arithmetic mean (standard deviation)
        Baseline (n =6)
    23.855 ± 12.1480
        Change at Week 16 (n =4)
    -2.378 ± 3.9096
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16

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    End point title
    		 Change From Baseline in Mixed Venous Oxygen Saturation (SvO2) at Week 16
    End point description
    SvO2 is the percentage of mixed venous oxygen (amount of oxygen bound to hemoglobin in venous blood). Change from baseline in percentage of mixed venous oxygen was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: percentage of mixed venous oxygen
    arithmetic mean (standard deviation)
        Baseline (n =6)
    65.30 ± 8.549
        Change at Week 16 (n =4)
    5.38 ± 12.426
    No statistical analyses for this end point

    Secondary: Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16

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    End point title
    		 Change From Baseline in Arterial Oxygen Saturation (SaO2) at Week 16
    End point description
    SaO2 is the percentage of arterial oxygen (amount of oxygen bound to hemoglobin in arterial blood). Change from baseline in percentage of arterial oxygen was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: percentage of arterial oxygen
    arithmetic mean (standard deviation)
        Baseline (n =6)
    95.08 ± 2.730
        Change at Week 16 (n =4)
    -0.80 ± 1.691
    No statistical analyses for this end point

    Other pre-specified: Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Sildenafil and UK-103,320
    End point description
    UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4. Pharmacokinetic (PK) parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Sildenafil|
    138.1 ± 73
        UK-103,320|
    73.66 ± 48
    No statistical analyses for this end point

    Other pre-specified: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320

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    End point title
    		 Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Sildenafil and UK-103,320
    End point description
    UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: nanogram*hour per millimeter
    geometric mean (geometric coefficient of variation)
        Sildenafil|
    338.9 ± 54
        UK-103,320|
    210.2 ± 74
    No statistical analyses for this end point

    Other pre-specified: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320

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    End point title
    		 Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sildenafil and UK-103,320
    End point description
    UK-103,320 was the main metabolite of Sildenafil and was produced by cytochrome P450 3A4. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: hour
    median (full range (min-max))
        Sildenafil|
    1.00 (1.00 to 1.97)
        UK-103,320|
    1.00 (1.00 to 1.97)
    No statistical analyses for this end point

    Other pre-specified: Terminal Half Life (t1/2) of Sildenafil and UK-103,320

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    End point title
    		 Terminal Half Life (t1/2) of Sildenafil and UK-103,320
    End point description
    Terminal half-life is the time measured for the plasma concentration to decrease by one half of its original concentration. UK-103,320 was a main metabolite of sildenafil and was produced by cytochrome P450 3A4. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: hour
    median (full range (min-max))
        Sildenafil (n =2)
    1.785 (1.63 to 1.94)
        UK-103,320 (n =3)
    2.110 (2.04 to 3.26)
    No statistical analyses for this end point

    Other pre-specified: Apparent Oral Clearance (CL/F) of Sildenafil

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    End point title
    		 Apparent Oral Clearance (CL/F) of Sildenafil
    End point description
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: liter per hour
        geometric mean (geometric coefficient of variation)
    41.73 ± 77
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16

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    End point title
    		 Change From Baseline in Ratio of Acceleration Time to Ejection Time (AcT/ET) at Week 16
    End point description
    Acceleration time and ejection time are quantitative Doppler parameters and ratio of acceleration time to ejection time is a useful tool to evaluate the severity of aortic stenosis. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n =6)
    0.3038 ± 0.09675
        Change at Week 16 (n =4)
    0.0175 ± 0.10261
    No statistical analyses for this end point

    Other pre-specified: Apparent Volume of Distribution (Vz/F) of Sildenafil

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    End point title
    		 Apparent Volume of Distribution (Vz/F) of Sildenafil
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed. PK parameter analysis set included all subjects who have at least 1 of PK parameters of interest. Here, Number of subjects analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Pre-dose (0 hour) on Week 4, 8, 16 and 1, 2, 4, 8 hours post-dose on Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    2
    Units: liter
        median (full range (min-max))
    77.90 (62.4 to 93.4)
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Right Ventricular Tei Index at Week 16

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    End point title
    		 Change From Baseline in Right Ventricular Tei Index at Week 16
    End point description
    The right ventricular Tei Index is an index of myocardial performance. It is defined as the sum of isovolumic contraction time and isovolumic relaxation time divided by the ejection time. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n =3)
    0.7540 ± 0.48602
        Change at Week 16 (n =2)
    -0.0440 ± 0.37618
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Right Ventricular Size at Week 16

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    End point title
    		 Change From Baseline in Right Ventricular Size at Week 16
    End point description
    Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: centimeter (cm)
    arithmetic mean (standard deviation)
        Baseline (n =6)
    3.37 ± 1.216
        Change at Week 16 (n=4)
    -0.40 ± 0.408
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Tricuspid Valve Annulus Size at Week 16

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    End point title
    		 Change From Baseline in Tricuspid Valve Annulus Size at Week 16
    End point description
    The tricuspid valve lies between the right atrium and the right ventricle and is placed in a more apical position than the mitral valve. The annulus separates the right atrium from the right ventricle. Change from baseline in tricuspid valve annulus size (in cm) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n =6)
    2.190 ± 0.5636
        Change at Week 16 (n =4)
    -0.103 ± 0.3727
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at Week 16

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    End point title
    		 Change From Baseline in Tricuspid Regurgitation - Pressure Gradient (TR-PG) Peak at Week 16
    End point description
    Tricuspid regurgitation (insufficiency) is the failure of the tricuspid valve to close properly during systole, leading to the leaking of blood from the right ventricle into the right atrium. Change from baseline in TR-PG peak (in mmHg) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (n =5)
    73.0 ± 39.31
        Change at Week 16 (n =2)
    -6.0 ± 33.94
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at Week 16

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    End point title
    		 Change From Baseline in Pulmonary Regurgitation - Pressure Gradient (PR-PG) End-Diastole at Week 16
    End point description
    Pulmonary regurgitation (PR) or insufficiency is a valvular heart disease characterized by an incomplete closure of the pulmonary valve leading to a diastolic reflux into the right ventricle. Change from baseline in PR-PG end-diastole (in mmHg) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: mmHg
    arithmetic mean (standard deviation)
        Baseline (n =3)
    29.0 ± 14.73
        Change at Week 16 (n =2)
    3.5 ± 13.44
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Pericardial Effusion

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    End point title
    		 Number of Subjects With Pericardial Effusion
    End point description
    Pericardial effusion is the presence of an abnormal amount of fluid in the pericardial cavity, as determined by echocardiography. Efficacy analysis set included all subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
    0
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 16

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    End point title
    		 Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 16
    End point description
    Tricuspid annular plane systolic excursion is a parameter depicting global right ventricular function. Change from baseline in TAPSE (in cm) was reported in this endpoint. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ = Subjects evaluable for this endpoint at specified time points.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n =6)
    1.47 ± 0.437
        Change at Week 16 (n =4)
    0.18 ± 0.320
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 28 days after last dose of study drug (maximum duration of treatment: 119.6 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Sildenafil
    Reporting group description
    		 Subjects received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Day 1 (Baseline), Weeks 4, 8, and 16 in Part 1 of the study. Subjects who completed Part 1 and required continuing treatment with Sildenafil, received 10 mg or 20 mg of Sildenafil (based on their body weight) orally, thrice daily on Weeks 28, 40, 52 and thereafter every 12 weeks until Sildenafil obtained marketing approval (up to a maximum of 119.6 weeks). Subjects with <= 20 kg of body weight received 10 mg dose, thrice daily as powder for oral suspension and subjects with > 20 kg of body weight received 20 mg dose, thrice daily as film-coated tablets.

    Serious adverse events
    		 Sildenafil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Sildenafil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    Investigations
    Ammonia increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Weight increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Blood urine present
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    7
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Feeling abnormal
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Visual acuity reduced transiently
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Vision blurred
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Dental caries
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Colitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
    Additional description: As the event is gender specific, only female subjects were evaluated.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Erection increased
    Additional description: As the event is gender specific, only female subjects were evaluated.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    6
    Bronchitis
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    4
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    6
    Molluscum contagiosum
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Streptococcal infection
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2012
    Addition of Part 2 (Long­ term administration of the investigational drug)
    20 Jan 2016
    Changed the target sample size of subjects.
    25 Aug 2017
    Addition that after approval for additional indication for pediatric PAH, "clinical study" was read as "post-marketing clinical study", Changed the treatment period of Part 2.

    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.
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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