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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

    Results information
    Results version number
    		 v2
    This version publication date
    17 Mar 2017
    First version publication date
    24 Nov 2016
    Other versions
    		 v1 , v3
    Version creation reason
    • Correction of full data set
    Update to indicate Yes for Article 46 and that the study remains ONGOING.

    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, 110017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, 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
    Interim
    Date of interim/final analysis
    20 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 May 2016
    Global end of trial reached?
    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
    		 Study was conducted at 11 sites in japan. 

    Period 1
    Period 1 title
    Overall Study (overall period)
    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), Week 4, 8 and 16. 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 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, Week 4, 8 and 16

    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, Week 4, 8 and 16

    Number of subjects in period 1
    		Sildenafil
    Started
    6
    Completed
    4
    Not completed
    2
         Insufficient clinical response
    2

    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), Week 4, 8 and 16. 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 ) -
    Gender, Male/Female
    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), Week 4, 8 and 16. 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’ signifies those subjects who were evaluable 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 analysed for this primary 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 ( 6.377 )
    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’ signifies those subjects who were evaluable 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 analysed for this primary endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: millimeters 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 analysed for this primary 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' signifies those subjects who were evaluable for this measure.
    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 analysed for this primary 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,'N' subjects those subjects who were evaluable for this measure.
    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 analysed for this primary 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’ signifies those subjects who were evaluable 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 analysed for this primary endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: picogram per milliliter
    arithmetic mean (standard deviation)
        Baseline (n =6)
    132.62 ( 135.08 )
        Change at Week 16 (n =4)
    -64.1 ( 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 participants 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’ signifies those subjects who were evaluable 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 analysed for this primary endpoint.
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: picogram per milliliter
    arithmetic mean (standard deviation)
        Baseline (n =6)
    843.03 ( 1120.9 )
        Change at Week 16 (n =4)
    -546.85 ( 1107.621 )
    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 subjects 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 pretreatment state. 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 28 days after last dose of study drug (up to 20 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-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Related 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. 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 28 days after last dose of study drug (up to 20 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 Week 4, 8 and 16

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    End point title
    		 Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Week 4, 8 and 16
    End point description
    BP measurement is recorded as 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. Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 16
    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 ( 99999 )
        Baseline: Sitting Diastolic BP (n =1)
    60 ( 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 ( 99999 )
        Change at Week 4: Sitting Diastolic BP (n =1)
    23 ( 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 ( 99999 )
        Change at Week 8: Sitting Diastolic BP(n =1)
    -3 ( 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 ( 99999 )
        Change at Week 16: Sitting Diastolic BP (n =1)
    10 ( 99999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Heart Rate at Week 4, 8 and 16

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    End point title
    		 Change From Baseline in Heart Rate at Week 4, 8 and 16
    End point description
    Safety analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, 8, 16
    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 ( 99999 )
        Change at Week 4: Supine Heart rate (n =5)
    -1 ( 12.08 )
        Change at Week 4: Sitting Heart rate (n =1)
    -22 ( 99999 )
        Change at Week 8: Supine Heart rate (n =4)
    -0.5 ( 9.11 )
        Change at Week 8: Sitting Heart rate (n =1)
    0 ( 99999 )
        Change at Week 16: Supine Heart rate (n =3)
    3 ( 28.69 )
        Change at Week 16: Sitting Heart rate (n =1)
    4 ( 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 atleast 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
    3
    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.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 16
    End point values
    		 Sildenafil
    Number of subjects analysed
    6
    Units: subjects
    5
    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
    Baseline up to Week 16
    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’ signifies those subjects who were evaluable 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 ( 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’ signifies those subjects who were evaluable 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 ( 15.2 )
        Baseline: Diastolic Pressure (n =6)
    60.2 ( 19.3 )
        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’ signifies those subjects who were evaluable 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’ signifies those subjects who were evaluable 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’ signifies those subjects who were evaluable 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 )
    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’ signifies those subjects who were evaluable 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)
    2.62 ( 0.9879 )
        Change at Week 16 (n =4)
    0.42 ( 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’ signifies those subjects who were evaluable 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)
    3.07 ( 0.746 )
        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’ signifies those subjects who were evaluable 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’ signifies those subjects who were evaluable 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 ( 12.148 )
        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 outcome measure. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable 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)
    65.3 ( 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 outcome measure. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable 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 ( 2.73 )
        Change at Week 16 (n =4)
    -0.8 ( 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
    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 (1 to 1.97)
        UK-103,320
    1 (1 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.
    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)
    2.11 (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: 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,'N' signifies those subjects who were evaluable for this measure.
    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))
    77.9 (62.4 to 93.4)
    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’ signifies those subjects who were evaluable 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: 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’ signifies those subjects who were evaluable 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)
    0.754 ( 0.48602 )
        Change at Week 16 (n =2)
    -0.044 ( 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’ signifies those subjects who were evaluable 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)
    -0.4 ( 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. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable 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)
    2.19 ( 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. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable 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 ( 39.31 )
        Change at Week 16 (n =2)
    -6 ( 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. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable 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 ( 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. Efficacy analysis set included all subjects who received at least 1 dose of study drug. Here, ‘n’ signifies those subjects who were evaluable 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 ( 0.32 )
    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 (up to 20 weeks)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    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), Week 4, 8 and 16. 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.

    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
    0
    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
    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
    Ammonia increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Weight increased
         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
    4
    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
    Gastrointestinal disorders
    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
    Vomiting
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
    Additional description: As the event is gender specific, only female participants were evaluated.
         subjects affected / exposed [1]
    1 / 3 (33.33%)
         occurrences all number
    1
    Erection increased
    Additional description: As the event is gender specific, only female participants were evaluated.
         subjects affected / exposed [2]
    1 / 3 (33.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Rhinitis allergic
         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
    Dermatitis diaper
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Dry skin
         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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    3
    Gastroenteritis
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    6
    Nasopharyngitis
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    4
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: As the event is gender specific, only female participants were evaluated.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: As the event is gender specific, only female participants were evaluated.

    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)

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

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