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    Clinical Trial Results:
    A MULTI-CENTRE, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, TWO-ARMED, PARALLEL GROUP STUDY TO EVALUATE EFFICACY AND SAFETY OF INTRAVENOUS (IV) SILDENAFIL IN THE TREATMENT OF NEONATES WITH PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN (PPHN) OR HYPOXIC RESPIRATORY FAILURE (HRF) AND AT RISK FOR PPHN, WITH A LONG TERM FOLLOW-UP INVESTIGATION OF DEVELOPMENTAL PROGRESS 12 AND 24 MONTHS AFTER COMPLETION OF STUDY TREATMENT

    Summary
    EudraCT number
    		 2012-002619-24
    Trial protocol
    		 BE   GB   SE   ES   AT   DE   NO   IT   NL   DK   FR  
    Global end of trial date
    28 Sep 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    08 Apr 2021
    First version publication date
    17 Jul 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Basic Results being posted with final data / end of global study date need to be added to results

    Trial information

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    Trial identification
    Sponsor protocol code
    A1481316
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01720524
    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 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000671-PIP01-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of IV sildenafil when added to inhaled nitric oxide (iNO) for the treatment of neonates with PPHN or HRF and at risk for PPHN.
    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
    		 All subjects were treated with iNO.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Aug 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    59
    EEA total number of subjects
    27
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    59
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in two parts Part A (double-blind phase) and Part B (long-term, non-interventional phase).

    Pre-assignment
    Screening details
    		 Neonates with PPHN or HRF and at risk of PPHN who were receiving iNO treatment were evaluated in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IV Sildenafil
    Arm description
    		 Subjects received sildenafil intravenously based on their body weight at a loading dose of 0.1 milligrams per kg (mg/kg) for 30 minutes on Day 1 followed by a maintenance dose of 0.03 milligrams per kg per hour (mg/kg/hr), for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sildenafil Citrate
    Investigational medicinal product code
    UK-092,480
    Other name
    Revatio
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV sildenafil at a loading dose of 0.1 mg/kg, for 30 minutes, on Day 1, followed by maintenance dose of 0.03 mg/kg/hr, for a minimum of 2 days and maximum of 14 days.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo (0.9 % normal saline or dextrose 10%) at a rate matched to sildenafil infusion, intravenously, based on subject’s weight for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (0.9 percent [%] normal saline or dextrose 10%) intravenously for a minimum of 2 days and maximum of 14 days.

    Number of subjects in period 1
    		IV Sildenafil Placebo
    Started
    29
    30
    Completed
    22
    18
    Not completed
    7
    12
         Consent withdrawn by subject
    -
    1
         Missed 28 day follow-up visit
    1
    1
         Other
    -
    1
         Adverse event
    2
    2
         Insufficient Clinical Response
    2
    4
         Death (during follow-up)
    -
    1
         Death (not completed study treatment)
    2
    -
         Lost to follow-up
    -
    1
         Protocol deviation
    -
    1
    Period 2
    Period 2 title
    Part B (Non-Interventional Phase)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IV Sildenafil
    Arm description
    		 Subjects received sildenafil intravenously based on their body weight at a loading dose of 0.1 milligrams per kg (mg/kg) for 30 minutes on Day 1 followed by a maintenance dose of 0.03 milligrams per kg per hour (mg/kg/hr), for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo (0.9 % normal saline or dextrose 10%) at a rate matched to sildenafil infusion, intravenously, based on subject’s weight for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		IV Sildenafil Placebo
    Started
    22
    18
    Completed
    22
    17
    Not completed
    5
    9
         Death
    -
    2
         No longer willing to participate in study
    1
    4
         Unspecified
    2
    -
         Lost to follow-up
    2
    3
    Joined
    5
    8
         Continued to follow-up
    5
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IV Sildenafil
    Reporting group description
    		 Subjects received sildenafil intravenously based on their body weight at a loading dose of 0.1 milligrams per kg (mg/kg) for 30 minutes on Day 1 followed by a maintenance dose of 0.03 milligrams per kg per hour (mg/kg/hr), for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (0.9 % normal saline or dextrose 10%) at a rate matched to sildenafil infusion, intravenously, based on subject’s weight for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Reporting group values
    		 IV Sildenafil Placebo Total
    Number of subjects
    		 29 30 59
    Age Categorical
    Safety population included all subjects treated with study treatment.
    Units: Subjects
        Newborns (0-27 days)
    		 29 30 59
    Age Continuous
    Safety population included all subjects treated with study treatment.
    Units: days
        arithmetic mean (standard deviation)
    		 1.7 ( 0.90 ) 1.9 ( 0.75 ) -
    Gender Categorical
    Safety population included all subjects treated with study treatment.
    Units: Subjects
        Female
    		 13 13 26
        Male
    		 16 17 33
    Race
    Safety population included all subjects treated with study treatment.
    Units: Subjects
        White
    		 19 16 35
        Black
    		 1 7 8
        Asian
    		 2 5 7
        Other
    		 3 1 4
        Unspecified
    		 4 1 5

    End points

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    End points reporting groups
    Reporting group title
    IV Sildenafil
    Reporting group description
    		 Subjects received sildenafil intravenously based on their body weight at a loading dose of 0.1 milligrams per kg (mg/kg) for 30 minutes on Day 1 followed by a maintenance dose of 0.03 milligrams per kg per hour (mg/kg/hr), for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (0.9 % normal saline or dextrose 10%) at a rate matched to sildenafil infusion, intravenously, based on subject’s weight for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.
    Reporting group title
    IV Sildenafil
    Reporting group description
    		 Subjects received sildenafil intravenously based on their body weight at a loading dose of 0.1 milligrams per kg (mg/kg) for 30 minutes on Day 1 followed by a maintenance dose of 0.03 milligrams per kg per hour (mg/kg/hr), for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (0.9 % normal saline or dextrose 10%) at a rate matched to sildenafil infusion, intravenously, based on subject’s weight for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Subject analysis set title
    Part B (Non-Interventional Phase): IV Sildenafil
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received sildenafil intravenously based on their body weight at a loading dose of 0.1 milligrams per kg (mg/kg) for 30 minutes on Day 1 followed by a maintenance dose of 0.03 milligrams per kg per hour (mg/kg/hr), for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Subject analysis set title
    Part B (Non-Interventional Phase): Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received placebo (0.9 % normal saline or dextrose 10%) at a rate matched to sildenafil infusion, intravenously, based on subject’s weight for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Primary: Time on Inhaled Nitric Oxide (iNO) Treatment After Initiation of Intravenous (IV) Study Drug For Subjects Without Treatment Failure

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    End point title
    		 Time on Inhaled Nitric Oxide (iNO) Treatment After Initiation of Intravenous (IV) Study Drug For Subjects Without Treatment Failure
    End point description
    Time in days, on iNO treatment, for subjects without iNO treatment failure, was calculated 14 days from the initiation of IV study drug or hospital discharge, whichever occurred first. iNO treatment failure was defined as need for additional treatment targeting PPHN, need for extra corporeal membrane oxygenation (ECMO), or death during the study. The intent-to-treat population (ITT) included all randomized subjects treated with study treatment. Here, “Number of Subjects Analyzed” signifies number of subjects without iNO treatment failure.
    End point type
    Primary
    End point timeframe
    14 days from the initiation of IV study drug or hospital discharge, whichever occurs first
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    21
    24
    Units: days
        least squares mean (confidence interval 95%)
    4.1 (2.58 to 5.58)
    4.1 (2.70 to 5.50)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.985
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.08
         upper limit
    		 2.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.02

    Primary: Treatment Failure Rate

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    End point title
    		 Treatment Failure Rate
    End point description
    Treatment failure rate was defined as percentage of subjects who needed additional treatment targeting PPHN, needed ECMO, or died during the study. The ITT population included all randomized subjects treated with study treatment.
    End point type
    Primary
    End point timeframe
    14 days from the initiation of IV study drug or hospital discharge, whichever occurs first
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: percentage of subjects
        number (confidence interval 95%)
    27.6 (11.3 to 43.9)
    20.0 (5.7 to 34.3)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4935
    Method
    		 Chi-squared
    Parameter type
    		 Difference in percentage
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.1
         upper limit
    		 29.3

    Secondary: Time From Initiation of Intravenous (IV) Study Drug to Final Weaning of Mechanical Ventilation

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    End point title
    		 Time From Initiation of Intravenous (IV) Study Drug to Final Weaning of Mechanical Ventilation
    End point description
    Time in days, from initiation of IV study drug to final weaning of mechanical ventilation among subjects achieving final weaning of mechanical ventilation for PPHN was evaluated. Kaplan-Meier method was used for estimation. For subjects with mechanical ventilation beyond 336 hours (14 days) from initiation of IV study drug, data is censored at 14 days. The ITT population included all randomized subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    14 days from the initiation of IV study drug or hospital discharge, whichever occurs first
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: days
        median (confidence interval 95%)
    8.3 (5.46 to 11.75)
    7.3 (5.46 to 10.78)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9885
    Method
    		 Logrank
    Confidence interval

    Secondary: Time From Initiation of Intravenous (IV) Study Drug to First Treatment Failure

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    End point title
    		 Time From Initiation of Intravenous (IV) Study Drug to First Treatment Failure
    End point description
    Time in days, from initiation of IV study drug to first treatment failure (defined as need for additional treatment targeting PPHN, need for ECMO, or death) for subjects with treatment failure was evaluated. Kaplan-Meier method was used for estimation. For subjects without treatment failure by the endpoint assessment date, data is censored at the endpoint assessment date. The ITT population included all randomized subjects treated with study treatment. Due to low number of subjects with events, Kaplan-Meier estimates of median, upper and lower limit of CI could not be estimated/calculated and has been denoted by “99999”, signifying data not available.
    End point type
    Secondary
    End point timeframe
    14 days from the initiation of IV study drug or hospital discharge, whichever occurs first
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: days
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.491
    Method
    		 Logrank
    Confidence interval

    Secondary: Percentage of Subjects With Individual Components of Treatment Failure

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    End point title
    		 Percentage of Subjects With Individual Components of Treatment Failure
    End point description
    Percentage of subjects with individual components of treatment failure (need to start additional treatment targeting PPHN, need to start ECMO, or death) were evaluated. Some subjects could have had multiple qualifying events for treatment failure. The ITT population included all randomized subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    14 days from the initiation of IV study drug or hospital discharge, whichever occurs first
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: percentage of subjects
    number (confidence interval 95%)
        Additional Treatment Targeting PPHN
    13.8 (3.9 to 31.7)
    10.0 (2.1 to 26.5)
        ECMO
    10.3 (2.2 to 27.4)
    10.0 (2.1 to 26.5)
        Death
    6.9 (0.8 to 22.8)
    0.0 (0.0 to 11.6)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Additional Treatment
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7065
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Percentage
    Point estimate
    3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.2
         upper limit
    		 22.9
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: ECMO
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Percentage
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.5
         upper limit
    		 18.5
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Death
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2373
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Percentage
    Point estimate
    6.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 22.8

    Secondary: Change From Baseline in Oxygenation Index (OI) at Hour 6, 12 and 24

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    End point title
    		 Change From Baseline in Oxygenation Index (OI) at Hour 6, 12 and 24
    End point description
    Oxygenation index was calculated as the product of fraction of inspired oxygen (FiO2) and mean airway pressure divided by partial pressure of oxygen dissolved in arterial blood (PaO2) [(FiO2*mean airway pressure)/PaO2] measured in centimeter of water per millimeter of mercury (cmH2O/mmHg). FiO2 is the measure of oxygen concentration that is breathed. Mean airway pressure is defined as an average of the airway pressure throughout the respiratory cycle. PaO2 is the measure of oxygen level dissolved in the arterial blood. Here, ‘n’ = subjects evaluable for this endpoint at specified time points. The ITT population included all randomized subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Hour 6, 12 and 24 after start of infusion
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: cmH2O/mmHg
    least squares mean (confidence interval 95%)
        Change at Hour 6 (n=29,22)
    -4.2 (-11.64 to 3.34)
    -8.0 (-16.63 to 0.57)
        Change at Hour 12 (n=28,22)
    -4.1 (-10.51 to 2.23)
    -8.2 (-15.42 to -1.04)
        Change at Hour 24 (n=18,17)
    -11.6 (-15.40 to -7.83)
    -9.5 (-13.36 to -5.57)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 6
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4984
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 15.3
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 12
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3956
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 13.7
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 24
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4249
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.6
         upper limit
    		 3.3

    Secondary: Change From Baseline in Differential Saturation at Hour 6, 12 and 24

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    End point title
    		 Change From Baseline in Differential Saturation at Hour 6, 12 and 24
    End point description
    Differential oxygenation saturation is a simple way to detect the right-to-left shunting at ductus arteriosus using 2 pulse oximeters. It is the difference between pre-ductal and post-ductal sites pulse oxygen saturation (SpO2). Where, pre-duct refers to right upper extremity and post-duct refers to lower limb. Oxygenation saturation is measured as percentage of hemoglobin binding sites occupied by oxygen in the blood. Here, ‘n’ = subjects evaluable for this endpoint at specified time points. The ITT population included all randomized subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Hour 6, 12 and 24 after start of infusion
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: percentage of hemoglobin
    least squares mean (confidence interval 95%)
        Change at Hour 6 (n=26,19)
    1.5 (-1.79 to 4.80)
    0.8 (-3.10 to 4.62)
        Change at Hour 12 (n=25,19)
    -1.2 (-7.65 to 5.21)
    6.7 (-0.65 to 14.12)
        Change at Hour 24 (n=19,14)
    1.2 (-7.15 to 9.49)
    9.3 (-0.40 to 19.08)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 6
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7686
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 5.8
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 12
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1112
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.8
         upper limit
    		 1.9
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 24
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2089
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    -8.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.2
         upper limit
    		 4.8

    Secondary: Change From Baseline in Ratio of Partial Pressure of Oxygen in Arterial Blood to Fraction of Inspired Oxygen (P/F) at Hour 6, 12 and 24

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    End point title
    		 Change From Baseline in Ratio of Partial Pressure of Oxygen in Arterial Blood to Fraction of Inspired Oxygen (P/F) at Hour 6, 12 and 24
    End point description
    The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen is a ratio between the oxygen level in the arterial blood and the oxygen concentration that is breathed. It helps to determine the degree of any problems with how the lungs transfer oxygen to the blood. Here, ‘n’ = subjects evaluable for this endpoint at specified time points. The ITT population consisted of all randomized subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Hour 6, 12 and 24 after start of infusion
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: ratio
    least squares mean (confidence interval 95%)
        Change at Hour 6 (n=29,23)
    45.3 (17.21 to 73.37)
    8.1 (-23.48 to 39.60)
        Change at Hour 12 (n=28,24)
    43.4 (16.76 to 70.13)
    16.9 (-11.97 to 45.68)
        Change at Hour 24 (n=20,17)
    94.6 (18.52 to 170.69)
    14.7 (-67.83 to 97.25)
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 6
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0829
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    37.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 79.5
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 12
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1802
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    26.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.7
         upper limit
    		 65.9
    Statistical analysis title
    		 IV Sildenafil vs. Placebo: Hour 24
    Statistical analysis description
    Field appearing in section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analyzed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis. Only subjects without treatment failure were included in the analysis.
    Comparison groups
    IV Sildenafil v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1576
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    79.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.5
         upper limit
    		 192.2

    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 in a subject who received study drug without regard to possibility of causal relationship. A 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; medically important events. Treatment-emergent are events between first infusion of study drug and up to 31 days after end of study drug infusion (up to 45 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. The safety population included all subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 31 days after end of study drug infusion (up to 45 days)
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: subjects
        AEs
    22
    19
        SAEs
    7
    2
    No statistical analyses for this end point

    Secondary: Number of Treatment-Emergent Adverse Events (AEs) According to Severity

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    End point title
    		 Number of Treatment-Emergent Adverse Events (AEs) According to Severity
    End point description
    AE: untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. Treatment-emergent are events between first infusion of study drug and up to 31 days after end of study drug infusion (up to 45 days) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. Severity criteria: mild=did not interfere with subject's usual function; moderate=interfered to some extent with subject's usual function and severe=interfered significantly with subject's usual function. Missing baseline severities were imputed as mild. The safety population included all subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 31 days after end of study drug infusion (up to 45 days)
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    30
    Units: events
        Mild
    49
    42
        Moderate
    29
    24
        Severe
    12
    17
    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
    Criteria for laboratory values: Hematology: hemoglobin, hematocrit, red blood cell count <0.8*lower limit of normal (LLN), platelets<0.5*LLN, >1.75*upper limit of normal (ULN), white blood cells count <0.6*LLN, >1.5*ULN; Liver function: total and direct bilirubin >1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase >3.0*ULN, total protein <0.8*LLN, >1.2*ULN; Renal function: blood urea nitrogen, creatinine >1.3*ULN; Electrolytes: sodium <0.95*LLN, >1.05*ULN, potassium, chloride, calcium, bicarbonate (venous) <0.9*LLN, >1.1*ULN. Here, “number of subjects analyzed” signifies those subjects who were evaluable for this endpoint. The safety population included all subjects treated with study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 14 days from initiation of study drug infusion
    End point values
    		 IV Sildenafil Placebo
    Number of subjects analysed
    29
    28
    Units: subjects
    27
    22
    No statistical analyses for this end point

    Secondary: Part B: Composite Scores of Cognitive, Language, and Motor Developmental Progress of Subjects as Assessed by Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)

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    End point title
    		 Part B: Composite Scores of Cognitive, Language, and Motor Developmental Progress of Subjects as Assessed by Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)
    End point description
    Bayley-III assesses infant and toddler development across five domains: cognitive, language, motor, social-emotional (SE), and adaptive behavior (AB). Assessments of the cognitive, language, and motor domains conducted using items administered to the child; assessments of the SE and AB domains conducted using the primary caregiver’s responses to a questionnaire. Score ranges: cognitive scale 0-91, language scale 0-97 and motor scale 0-132, where higher scores indicated better cognitive function, communication and motor skills respectively. Raw scores of cognitive, language and motor domains were converted to composite scores. Composite scores of cognitive, language and motor developmental scales ranged from a scale of 40 to 160, where higher score indicated stronger skills and abilities. Part-B safety analysis set. Number Analysed =subjects evaluable for this end point, n =subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    19
    13
    Units: units on a scale
    arithmetic mean (standard deviation)
        Cognitive Development: Month 12 (n =19, 12)
    97.5 ( 16.14 )
    94.5 ( 14.18 )
        Cognitive Development: Month 24 (n =17, 13)
    97.4 ( 18.12 )
    97.3 ( 14.95 )
        Language Development: Month 12 (n =18, 12)
    99.5 ( 16.86 )
    94.7 ( 10.25 )
        Language Development: Month 24 (n =16, 11)
    96.7 ( 21.91 )
    95.8 ( 17.70 )
        Motor Development: Month 12 (n =19, 12)
    93.1 ( 16.10 )
    88.2 ( 14.61 )
        Motor Development: Month 24 (n =17, 12)
    99.0 ( 19.59 )
    105.3 ( 24.00 )
    No statistical analyses for this end point

    Secondary: Part B: Composite Scores of Social-Emotional and Adaptive Behavior Questionnaire of Subjects as Assessed by Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)

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    End point title
    		 Part B: Composite Scores of Social-Emotional and Adaptive Behavior Questionnaire of Subjects as Assessed by Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III)
    End point description
    The Bayley-III assesses infant and toddler development across five domains: cognitive, language, motor, social-emotional (SE), and adaptive behavior (AB). Assessments of the cognitive, language, and motor domains conducted using items administered to the child; assessments of the SE and AB domains conducted using the primary caregiver’s responses to a questionnaire. The questionnaire comprises the SE scale (35 items) and the AB scale (241 items). Raw scores of SE and AB were converted to composite scores. Composite scores for SE and AB scale ranged from 40 to 160, where higher scores indicated better social-emotional skills and adaptive behavior in child. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. 'Number Analysed' = subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Month 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    15
    8
    Units: units on a scale
    arithmetic mean (standard deviation)
        Social-Emotional Development
    104.5 ( 21.40 )
    112.5 ( 18.13 )
        Adaptive Behavior Development
    91.6 ( 15.66 )
    98.3 ( 12.44 )
    No statistical analyses for this end point

    Secondary: Part B: Number of Subjects With Eye Movement Disorders as Assessed by Eye Examination

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    End point title
    		 Part B: Number of Subjects With Eye Movement Disorders as Assessed by Eye Examination
    End point description
    Standard age-appropriate ophthalmological examinations of subjects were used to assess eye movement disorders (presence of amblyopia, strabismus, and nystagmus) at month 12 and 24. In this end point, data have been reported for right and left eye separately. Rows according to eye movement disorder categories at specified time points are reported in this end point, only when there was a non-zero data for at least 1 reporting arm. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    16
    14
    Units: subjects
        Strabismus Present,Right Eye: Month 12 (n =16, 14)
    0
    1
        Strabismus Present,Left Eye: Month 12 (n =16, 14)
    0
    1
        Strabismus Present,Right Eye: Month 24 (n =12, 12)
    1
    0
        Strabismus Present,Left Eye: Month 24 (n =12, 12)
    1
    0
        Nystagmus Present,Left Eye: Month 24 (n =12, 12)
    0
    1
    No statistical analyses for this end point

    Secondary: Part B: Visual Acuity of Verbal Subjects as Assessed by Ophthalmological Assessment

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    End point title
    		 Part B: Visual Acuity of Verbal Subjects as Assessed by Ophthalmological Assessment
    End point description
    Standard age-appropriate ophthalmological examinations were used to assess visual acuity (performed differently for children able of verbal interaction) through visual acuity chart (VAC) quantitative, counting finger (CF), hand motion (HM), light perception (LP), no light perception (NLP) and missing at month 12 and 24. In this end point, data have been reported for right and left eye separately. Rows according to visual acuity categories at specified time points are reported in this end point, only when there was a non-zero data for at least 1 reporting arm. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    16
    14
    Units: subjects
        VAC Quantitative, Right Eye: Month 12 (n =16, 14)
    2
    1
        HM, Right Eye: Month 12 (n =16, 14)
    0
    2
        LP, Right Eye: Month 12 (n =16, 14)
    1
    0
        Missing, Right Eye: Month 12 (n =16, 14)
    13
    11
        VAC Quantitative, Left Eye: Month 12 (n =16, 14)
    2
    1
        HM, Left Eye: Month 12 (n =16, 14)
    0
    2
        LP, Left Eye: Month 12 (n =16, 14)
    1
    0
        Missing, Left Eye: Month 12 (n =16, 14)
    13
    11
        VAC Quantitative, Right Eye: Month 24 (n =12, 12)
    6
    5
        HM, Right Eye: Month 24 (n =12, 12)
    1
    0
        Missing, Right Eye: Month 24 (n =12, 12)
    5
    7
        VAC Quantitative, Left Eye: Month 24 (n =12, 12)
    6
    5
        Missing, Left Eye: Month 24 (n =12, 12)
    6
    7
    No statistical analyses for this end point

    Secondary: Part B: Visual Acuity of Non-Verbal Subjects as Assessed by Ophthalmological Assessment

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    End point title
    		 Part B: Visual Acuity of Non-Verbal Subjects as Assessed by Ophthalmological Assessment
    End point description
    Standard age-appropriate ophthalmological examinations were used to assess visual acuity (performed differently for children unable of verbal interaction) through fixates and follows [F&F] (included central, steady and maintained), light perception [LP] (wince to light), no light perception [NLP], and missing at month 12 and 24. In this end point, data have been reported for right and left eye separately. Rows according to visual acuity categories at specified time points are reported in this end point, only when there was a non-zero data for at least 1 reporting arm. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    16
    14
    Units: subjects
        F&F, Right Eye: Month 12 (n =16, 14)
    15
    13
        LP, Right Eye: Month 12 (n =16, 14)
    0
    1
        Missing, Right Eye: Month 12 (n =16, 14)
    1
    0
        F&F, Left Eye: Month 12 (n =16, 14)
    15
    13
        LP, Left Eye: Month 12 (n =16, 14)
    0
    1
        Missing, Left Eye: Month 12 (n =16, 14)
    1
    0
        F&F, Right Eye: Month 24 (n =12, 12)
    5
    9
        Missing, Right Eye: Month 24 (n =12, 12)
    7
    3
        F&F, Left Eye: Month 24 (n =12, 12)
    5
    9
        Missing, Left Eye: Month 24 (n =12, 12)
    7
    3
    No statistical analyses for this end point

    Secondary: Part B: Visual Acuity of Verbal Subjects as Assessed by LogMAR Through Visual Acuity Chart

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    End point title
    		 Part B: Visual Acuity of Verbal Subjects as Assessed by LogMAR Through Visual Acuity Chart
    End point description
    Standard age-appropriate ophthalmological examinations were used to assess visual acuity (performed differently for children able of verbal interaction) at month 12 and 24. Visual acuity (VA) of verbal children was assessed for each eye using the Snellen method, where logarithm of minimum angle of resolution (logMAR) units were derived from the Snellen ratios. Subjects had to read letters from the chart at a distance of 20 feet/6 meter or 4 meter. VA (Snellen ratio) = distance between the chart and subject, divided by distance at which subject was able to see/read chart without impairment; expressed as decimal, logMAR = log10 (1/decimal VA). In this end point, data have been reported for right and left eye separately. Part B safety analysis. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    6
    6
    Units: LogMAR
    arithmetic mean (standard deviation)
        Right Eye: Month 12 (n =6, 3)
    0.45 ( 0.394 )
    0.57 ( 0.513 )
        Left Eye: Month 12 (n =6, 3)
    0.47 ( 0.372 )
    0.57 ( 0.513 )
        Right Eye: Month 24 (n =6, 4)
    0.20 ( 0.155 )
    0.28 ( 0.299 )
        Left Eye: Month 24 (n =6, 6)
    0.20 ( 0.155 )
    0.35 ( 0.409 )
    No statistical analyses for this end point

    Secondary: Part B: Visual Status of Subjects With Abnormality as Assessed by Eye Examination of the Anterior and Posterior Segments

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    End point title
    		 Part B: Visual Status of Subjects With Abnormality as Assessed by Eye Examination of the Anterior and Posterior Segments
    End point description
    Standard age-appropriate ophthalmological examinations were used to assess examination of anterior and posterior chamber for abnormality in lids, conjunctiva, cornea, anterior chamber, lens, iris, pupil, extraocular muscle movement (EMM) and eye movements at month 12 and 24. In this end point, data have been reported for right and left eye separately. Rows according to visual status categories at specified time points are reported in this end point, only when there was a non-zero data for at least 1 reporting arm. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    17
    15
    Units: subjects
        Anterior (Lids), Right Eye: Month 12 (n =17, 15)
    0
    1
        Anterior (Lids), Left Eye: Month 12 (n =17, 15)
    0
    1
        Anterior (EMM), Right Eye: Month 24 (n =13, 11)
    1
    0
        Anterior (EMM), Left Eye: Month 24 (n =13, 11)
    1
    0
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Behavior Hearing Assessment Through Pure Tone Audiometry Test

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Behavior Hearing Assessment Through Pure Tone Audiometry Test
    End point description
    Audiological evaluations of subjects were recorded and reported using behavior hearing assessment through pure tone audiometry test which included subjects with normal, abnormal, incomplete/inconclusive behavior at month 12 and 24. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here ‘Number of Subjects Analysed’ signifies number of subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    16
    12
    Units: subjects
        Normal Behavior: Month12
    11
    8
        Abnormal Behavior: Month 12
    1
    4
        Incomplete/Inconclusive Behavior: Month 12
    4
    0
        Normal Behavior: Month 24
    13
    8
        Abnormal Behavior: Month 24
    0
    2
        Incomplete/Inconclusive Behavior: Month 24
    3
    2
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Bone Conduction Through Pure Tone Audiometry Test

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Bone Conduction Through Pure Tone Audiometry Test
    End point description
    Audiological evaluations of subjects were recorded and reported by bone conduction assessment through pure tone audiometry test which included subjects with sensorineural hearing loss, conductive hearing loss, mixed hearing loss, neural, and unspecified. Rows according to bone conduction categories at specified time points are reported in this end point, only when there was a non-zero data for at least 1 reporting arm. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    1
    2
    Units: subjects
        Conductive Hearing Loss: Month 12 (n =1, 2)
    0
    1
        Unspecified: Month 12 (n =1, 2)
    1
    1
        Conductive Hearing Loss: Month 24 (n =0, 1)
    0
    1
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Air Conduction via Phones/Headphones Through Pure Tone Audiometry Test

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Air Conduction via Phones/Headphones Through Pure Tone Audiometry Test
    End point description
    Audiological evaluations of subjects were recorded and reported by air conduction via phones/headphones through pure tone audiometry test which included subjects with hearing loss ranged from less than or equal to (<=) 20 decibel hearing loss (DB HL), 21-40 DB HL, 41-70 DB HL, 71-90 DB HL, greater than (>) 90 DB HL or no response, and missing at frequencies ranged from 500 Hertz (Hz) to 8000 Hz at month 12 and 24. In this end point, data have been reported for right and left ear separately. Rows according to air conduction categories at specified time points are reported in this end point, only when there was a non-zero data for at least 1 reporting arm. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. 'Number of Subjects Analysed = subjects evaluable for this end point and ‘n’ = number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    8
    5
    Units: subjects
        Right Ear,500 Hz,<=20 DB HL: Month 12 (n =5, 5)
    3
    4
        Right Ear,500 Hz, 21-40 DB HL: Month 12 (n =5, 5)
    2
    1
        Right Ear,1000 Hz,<=20 DB HL: Month 12 (n =5, 5)
    4
    5
        Right Ear,1000 Hz,21-40 DB HL: Month 12 (n =5, 5)
    1
    0
        Right Ear,2000 Hz,<=20 DB HL: Month 12 (n =5, 5)
    3
    4
        Right Ear,2000 Hz,21-40 DB HL: Month 12 (n =5, 5)
    2
    0
        Right Ear,4000 Hz,<=20 DB HL: Month 12 (n =5, 5)
    4
    5
        Right Ear,4000 Hz,21-40 DB HL: Month 12 (n =5, 5)
    1
    0
        Right Ear,8000 Hz,<=20 DB HL: Month 12 (n =5, 5)
    3
    4
        Right Ear,8000 Hz, Missing: Month 12 (n =5, 5)
    2
    0
        Left Ear,500 Hz, <=20 DB HL: Month 12 (n =5, 5)
    3
    3
        Left Ear,500 Hz, 21-40 DB HL: Month 12 (n =5, 5)
    2
    1
        Left Ear,1000 Hz, <=20 DB HL: Month 12 (n =5, 5)
    3
    5
        Left Ear,1000 Hz, 21-40 DB HL: Month 12 (n =5, 5)
    2
    0
        Left Ear,2000 Hz, <=20 DB HL: Month 12 (n =5, 5)
    3
    4
        Left Ear,2000 Hz, 21-40 DB HL: Month 12 (n =5, 5)
    2
    0
        Left Ear,4000 Hz, <=20 DB HL: Month 12 (n =5, 5)
    4
    5
        Left Ear,4000 Hz, 21-40 DB HL: Month 12 (n =5, 5)
    1
    0
        Left Ear,8000 Hz, <=20 DB HL: Month 12 (n =5, 5)
    3
    4
        Left Ear,8000 Hz, Missing: Month 24 (n =5, 5)
    2
    1
        Right Ear,500 Hz, <=20 DB HL: Month 24 (n =8, 4)
    5
    3
        Right Ear,500 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    2
    0
        Right Ear,1000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    5
    2
        Right Ear,1000 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    1
    0
        Right Ear,2000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    6
    3
        Right Ear,2000 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    1
    0
        Right Ear,4000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    7
    3
        Right Ear,8000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    4
    3
        Right Ear,8000 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    1
    0
        Right Ear,8000 Hz, Missing: Month 24 (n =8, 4)
    1
    0
        Left Ear,500 Hz, <=20 DB HL: Month 24 (n =8, 4)
    6
    3
        Left Ear,500 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    1
    0
        Left Ear,1000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    4
    3
        Left Ear,1000 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    1
    0
        Left Ear,2000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    6
    2
        Left Ear,2000 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    1
    0
        Left Ear,4000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    7
    4
        Left Ear,8000 Hz, <=20 DB HL: Month 24 (n =8, 4)
    3
    3
        Left Ear,8000 Hz, 21-40 DB HL: Month 24 (n =8, 4)
    1
    0
        Left Ear,8000 Hz, Missing: Month 24 (n =8, 4)
    1
    0
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Air Conduction via Soundfield Through Pure Tone Audiometry Test

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Air Conduction via Soundfield Through Pure Tone Audiometry Test
    End point description
    Audiological evaluations of subjects were recorded and reported by air conduction via soundfield through pure tone audiometry test which included subjects with hearing loss ranged from <=20 DB HL, 21-40 DB HL, 41-70 DB HL, 71-90 DB HL, >90 DB HL or no response, and missing at frequencies ranged from 500 Hz to 4000 Hz at month 12 and 24. Rows according to air conduction categories at specified time points are reported in this end point, only when there was a non-zero data for at least 1 reporting arm. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' = number of subjects evaluable for this end point and ‘n’ = number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    13
    9
    Units: subjects
        500 Hz, <=20 DB HL: Month 12 (n =13, 9)
    6
    2
        500 Hz, 21-40 DB HL: Month 12 (n =13, 9)
    5
    6
        500 Hz, 71-90 DB HL: Month 12 (n =13, 9)
    1
    0
        1000 Hz, <=20 DB HL: Month 12 (n =13, 9)
    9
    3
        1000 Hz, 21-40 DB HL: Month 12 (n =13, 9)
    1
    5
        1000 Hz, 71-90 DB HL: Month 12 (n =13, 9)
    1
    0
        2000 Hz, <=20 DB HL: Month 12 (n =13, 9)
    7
    2
        2000 Hz, 21-40 DB HL: Month 12 (n =13, 9)
    3
    4
        2000 Hz, Missing: Month 12 (n =13, 9)
    1
    0
        4000 Hz, <=20 DB HL: Month 12 (n =13, 9)
    6
    4
        4000 Hz, 21-40 DB HL: Month 12 (n =13, 9)
    4
    4
        4000 Hz, 71-90 DB HL: Month 12 (n =13, 9)
    1
    0
        500 Hz, <=20 DB HL: Month 24 (n =11, 9)
    6
    2
        500 Hz, 21-40 DB HL: Month 24 (n =11, 9)
    2
    5
        1000 Hz, <=20 DB HL: Month 24 (n =11, 9)
    6
    6
        1000 Hz, 21-40 DB HL: Month 24 (n =11, 9)
    4
    3
        2000 Hz, <=20 DB HL: Month 24 (n =11, 9)
    6
    3
        2000 Hz, 21-40 DB HL: Month 24 (n =11, 9)
    2
    4
        4000 Hz, <=20 DB HL: Month 24 (n =11, 9)
    5
    4
        4000 Hz, 21-40 DB HL: Month 24 (n =11, 9)
    4
    3
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Tympanometry Assessment (Peak Pressure) Through Immittance Audiometry Test

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Tympanometry Assessment (Peak Pressure) Through Immittance Audiometry Test
    End point description
    Audiological evaluations of subjects were recorded and reported by tympanometry assessment through immittance audiometry test which included subjects with peak pressure (PP) signs (+) and (-) at month 12 and 24. In this end point, data have been reported for right and left ear separately. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    9
    8
    Units: decapascals
    arithmetic mean (standard deviation)
        PP for Sign (+), Right Ear: Month 12 (n =7, 3)
    51.89 ( 63.024 )
    27.33 ( 26.539 )
        PP for Sign (+), Left Ear: Month 12 (n =3, 4)
    5.07 ( 4.900 )
    73.75 ( 28.987 )
        PP for Sign (+), Right Ear: Month 24 (n =3, 4)
    44.00 ( 46.130 )
    33.50 ( 44.125 )
        PP for Sign (+), Left Ear: Month 24 (n =7, 5)
    42.71 ( 50.112 )
    35.00 ( 46.578 )
        PP for Sign (-), Right Ear: Month 12 (n =6, 8)
    149.3 ( 144.34 )
    67.75 ( 57.350 )
        PP for Sign (-), Left Ear: Month 12 (n =9, 5)
    79.89 ( 64.367 )
    46.80 ( 46.912 )
        PP for Sign (-), Right Ear: Month 24 (n =8, 3)
    98.00 ( 55.685 )
    83.67 ( 107.38 )
        PP for Sign (-), Left Ear: Month 24 (n =6, 2)
    102.2 ( 84.781 )
    135.0 ( 70.711 )
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Tympanometry Assessment (Static Acoustic Admittance) Through Immittance Audiometry Test

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Tympanometry Assessment (Static Acoustic Admittance) Through Immittance Audiometry Test
    End point description
    Audiological evaluations of subjects were recorded and reported by tympanometry assessment through immittance audiometry test which included subjects with static acoustic admittance at month 12 and 24. In this end point, data have been reported for right and left ear separately. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    9
    11
    Units: millimho
    arithmetic mean (standard deviation)
        Right Ear: Month 12 (n =9, 11)
    0.241 ( 0.1403 )
    0.403 ( 0.1691 )
        Left Ear: Month 12 (n =8, 9)
    0.364 ( 0.1513 )
    0.330 ( 0.1595 )
        Right Ear: Month 24 (n =6, 6)
    0.273 ( 0.0784 )
    0.400 ( 0.1321 )
        Left Ear: Month 24 (n =8, 6)
    0.295 ( 0.0691 )
    0.585 ( 0.5558 )
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Ipsilateral Stapedial Reflex Through Immittance Audiometry Test

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Ipsilateral Stapedial Reflex Through Immittance Audiometry Test
    End point description
    Audiological evaluations of subjects were recorded and reported by ipsilateral stapedial reflex through immittance audiometry test which included subjects with presence of ipsilateral stapedial reflex at frequencies ranged from 500 Hz to 2000 Hz at month 12 and 24. Ipsilateral stapedial reflex measures are used to assess the neural pathway surrounding the stapedial reflex, which occurs in response to a loud sound (70 to 90 decibel above threshold). In this end point, data have been reported for right and left ear separately. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    14
    12
    Units: subjects
        500 Hz, Right Ear: Month 12 (n =14, 12)
    5
    1
        500 Hz, Left Ear: Month 12 (n =14, 12)
    6
    1
        1000 Hz, Right Ear: Month 12 (n =14, 12)
    5
    1
        1000 Hz, Left Ear: Month 12 (n =14, 12)
    6
    1
        2000 Hz, Right Ear: Month 12 (n =14, 12)
    5
    1
        2000 Hz, Left Ear: Month 12 (n =14, 12)
    6
    1
        500 Hz, Right Ear: Month 24 (n =13, 9)
    4
    2
        500 Hz, Left Ear: Month 24 (n =13, 9)
    4
    2
        1000 Hz, Right Ear: Month 24 (n =13, 9)
    4
    2
        1000 Hz, Left Ear: Month 24 (n =13, 9)
    5
    2
        2000 Hz, Right Ear: Month 24 (n =13, 9)
    4
    2
        2000 Hz, Left Ear: Month 24 (n =13, 9)
    4
    2
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Transient Evoked Emission Through Otoacoustic Emissions Assessment

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Transient Evoked Emission Through Otoacoustic Emissions Assessment
    End point description
    Audiological evaluations of subjects were recorded and reported by transient evoked emission through otoacoustic emissions assessment which included subjects with presence of transient evoked emissions at frequencies ranged from 1000 Hz to 4000 Hz at month 12 and 24. In this end point, data have been reported for right and left ear separately. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    7
    3
    Units: subjects
        1000 Hz, Right Ear: Month 12
    3
    2
        1000 Hz, Left Ear: Month 12
    2
    1
        1500 Hz, Right Ear: Month 12
    3
    2
        1500 Hz, Left Ear: Month 12
    2
    2
        2000 Hz, Right Ear: Month 12
    5
    2
        2000 Hz, Left Ear: Month 12
    5
    2
        3000 Hz, Right Ear: Month 12
    4
    2
        3000 Hz, Left Ear: Month 12
    4
    2
        4000 Hz, Right Ear: Month 12
    6
    2
        4000 Hz, Left Ear: Month 12
    5
    3
        1000 Hz, Right Ear: Month 24
    3
    2
        1000 Hz, Left Ear: Month 24
    2
    2
        1500 Hz, Right Ear: Month 24
    2
    3
        1500 Hz, Left Ear: Month 24
    2
    3
        2000 Hz, Right Ear: Month 24
    7
    3
        2000 Hz, Left Ear: Month 24
    6
    3
        3000 Hz, Right Ear: Month 24
    6
    3
        3000 Hz, Left Ear: Month 24
    4
    3
        4000 Hz, Right Ear: Month 24
    7
    3
        4000 Hz, Left Ear: Month 24
    5
    3
    No statistical analyses for this end point

    Secondary: Part B: Audiological Status of Subjects as Assessed by Distort Product Through Otoacoustic Emissions Assessment

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    End point title
    		 Part B: Audiological Status of Subjects as Assessed by Distort Product Through Otoacoustic Emissions Assessment
    End point description
    Audiological evaluations of subjects were recorded and reported by distort product through otoacoustic emissions assessment which included subjects with presence of distort product at frequencies ranged from 2000 Hz to 8000 Hz at month 12 and 24. Distortion-product otoacoustic emissions (DPOAEs) are generated in the cochlea in response to two tones of a given frequency and sound pressure level presented in the ear canal. Distort product otoacoustic emissions are an objective indicator of normally functioning cochlea outer hair cells. In this end point, data have been reported for right and left ear separately. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    7
    7
    Units: subjects
        2000 Hz, Right Ear: Month 12 (n =6, 6)
    4
    4
        2000 Hz, Left Ear: Month 12 (n =6, 6)
    5
    3
        3000 Hz, Right Ear: Month 12 (n =6, 6)
    5
    4
        3000 Hz, Left Ear: Month 12 (n =6, 6)
    5
    3
        4000 Hz, Right Ear: Month 12 (n =6, 6)
    5
    4
        4000 Hz, Left Ear: Month 12 (n =6, 6)
    5
    3
        6000 Hz, Right Ear: Month 12 (n =6, 6)
    4
    4
        6000 Hz, Left Ear: Month 12 (n =6, 6)
    5
    4
        8000 Hz, Right Ear: Month 12 (n =6, 6)
    4
    2
        8000 Hz, Left Ear: Month 12 (n =6, 6)
    5
    2
        2000 Hz, Right Ear: Month 24 (n =7, 7)
    4
    7
        2000 Hz, Left Ear: Month 24 (n =7, 7)
    4
    6
        3000 Hz, Right Ear: Month 24 (n =7, 7)
    7
    5
        3000 Hz, Left Ear: Month 24 (n =7, 7)
    6
    5
        4000 Hz, Right Ear: Month 24 (n =7, 7)
    6
    5
        4000 Hz, Left Ear: Month 24 (n =7, 7)
    6
    5
        6000 Hz, Right Ear: Month 24 (n =7, 7)
    4
    6
        6000 Hz, Left Ear: Month 24 (n =7, 7)
    5
    6
        8000 Hz, Right Ear: Month 24 (n =7, 7)
    3
    2
        8000 Hz, Left Ear: Month 24 (n =7, 7)
    4
    2
    No statistical analyses for this end point

    Secondary: Part B: Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), and Deaths

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    End point title
    		 Part B: Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), and Deaths
    End point description
    An AE was any untoward medical occurrence in a subject who received study medication without regard to possibility of causal relationship to it. 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. AEs included both serious and all non-serious AEs. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    27
    26
    Units: subjects
        AEs
    17
    17
        SAEs
    9
    6
        Deaths
    0
    2
    No statistical analyses for this end point

    Secondary: Part B: Neurological Progress of Subjects as Assessed by the Neurology Optimality Score

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    End point title
    		 Part B: Neurological Progress of Subjects as Assessed by the Neurology Optimality Score
    End point description
    The Hammersmith Infant Neurological Examination (HINE) was a standard scoring examination to assess development of cranial nerve; posture; movement; tone; and reflexes and reaction. HINE exam global score is a sum of subset (cranial nerve, posture, movement, tone, reflexes and reactions) scores, ranged from 0 to 78, where higher score represents better outcome. Here, the HINE global scores were reported at month 12 and 24. Part B safety analysis set included all subjects enrolled in Part B of the study for data analyses on developmental progress, audiological, neurological and ophthalmological assessment, and safety. Here 'Number of Subjects Analysed' signifies number of subjects evaluable for this end point and ‘n’ signifies number of subjects evaluable for each specified rows.
    End point type
    Secondary
    End point timeframe
    Month 12 and 24 after end of study treatment in Part A (Day 1 to 14)
    End point values
    		 Part B (Non-Interventional Phase): IV Sildenafil Part B (Non-Interventional Phase): Placebo
    Number of subjects analysed
    21
    12
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 12 (n =21, 12)
    69.9 ( 14.97 )
    75.6 ( 3.45 )
        Month 24 (n =17, 10)
    65.6 ( 19.71 )
    76.5 ( 2.42 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part A: Baseline up to 31 days after end of study drug infusion (up to 45 days); Part B: up to 24 months after end of study treatment in Part A (maximum up to 26 months)
    Adverse event reporting additional description
    Same event may appear as both an AE and SAE. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event. Deaths (all causes) included only treatment emergent serious events. For Part-B (non-interventional) only SAEs and death data was collected.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Part A: IV Sildenafil
    Reporting group description
    		 Subjects received sildenafil intravenously based on their body weight at a loading dose of 0.1 milligrams per kg (mg/kg) for 30 minutes on Day 1 followed by a maintenance dose of 0.03 milligrams per kg per hour (mg/kg/hr), for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Reporting group title
    Part A: Placebo
    Reporting group description
    		 Subjects received placebo (0.9 % normal saline or dextrose 10%) at a rate matched to sildenafil infusion, intravenously, based on subject’s weight for a minimum of 2 days and maximum of 14 days. Infusion continuation was upon investigator discretion in view of subjects’ safety and well-being.

    Reporting group title
    Part B: IV Sildenafil
    Reporting group description
    		 Subjects who started Part A (not necessarily completed Part A) and who were eligible and consented, continued to be followed up in part B of the study.

    Reporting group title
    Part B: Placebo
    Reporting group description
    		 Subjects who started Part A (not necessarily completed Part A) and who were eligible and consented, continued to be followed up in part B of the study.

    Serious adverse events
    		 Part A: IV Sildenafil Part A: Placebo Part B: IV Sildenafil Part B: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 29 (24.14%)
    2 / 30 (6.67%)
    9 / 27 (33.33%)
    6 / 26 (23.08%)
         number of deaths (all causes)
    1
    1
    0
    2
         number of deaths resulting from adverse events
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Skull fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pulmonary malformation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Congenital heart disease
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Myoclonus
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroesophageal Reflux
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension crisis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 27 (7.41%)
    3 / 26 (11.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Part A: IV Sildenafil Part A: Placebo Part B: IV Sildenafil Part B: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 29 (68.97%)
    19 / 30 (63.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    Vascular disorders
    Haemodynamic instability
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypotension
         subjects affected / exposed
    7 / 29 (24.14%)
    3 / 30 (10.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    7
    3
    0
    0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Drug withdrawal syndrome
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Drug withdrawal syndrome neonatal
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Generalised oedema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infusion site extravasation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oedema
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Secretion discharge
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Withdrawal syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Oedema genital
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Choking
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hiccups
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lung disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Neonatal asphyxia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumothorax
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 30 (13.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    4
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary air leakage
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary interstitial emphysema syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary oedema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory distress
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Respiratory tract oedema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Stridor
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Selective eating disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood methaemoglobin present
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Blood urea increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 30 (10.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    PCO2 decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thyroid function test abnormal
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Procedural hypertension
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Procedural hypotension
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Transfusion reaction
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Underdose
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Congenital, familial and genetic disorders
    Persistent foetal circulation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Bradycardia neonatal
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Junctional ectopic tachycardia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypertonia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Motor dysfunction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Seizure
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 30 (10.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    5
    3
    0
    0
    Leukocytosis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Eye oedema
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Periorbital oedema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pupil fixed
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Intestinal perforation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Rash
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin irritation
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lung infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nosocomial infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Tracheitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Alkalosis hypochloraemic
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Feeding intolerance
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fluid overload
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Fluid retention
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hyperchloraemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypochloraemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    7 / 29 (24.14%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    8
    0
    0
    0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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