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    Clinical Trial Results:
    Multicenter, double-blind, placebo-controlled, randomized, prospective study of bosentan as adjunctive therapy to inhaled nitric oxide in the management of persistent pulmonary hypertension of the newborn (PPHN)

    Summary
    EudraCT number
    		 2011-000203-41
    Trial protocol
    		 DE   NL   CZ   GB   FR   BE   PL   Outside EU/EEA  
    Global end of trial date
    05 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 May 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-052-391
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01389856
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com
    Scientific contact
    Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@actelion.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000425-PIP02-10
    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
    08 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the efficacy of bosentan in neonates with persistent pulmonary hypertension of the newborn (PPHN) who were in need of continued inhaled nitric oxide (iNO) after at least 4 hours of continuous iNO treatment.
    Protection of trial subjects
    This clinical study was conducted within the framework of the pediatric development program agreed with the Pediatric Committee at the European Medicines Agency, and designed in compliance with the EMA pediatric guidelines for PPHN, which recommend an add-on trials in patients failing treatment with iNO (EMA/CHMP/213972/2010) Parent(s) or the legal representative(s) were asked if they agreed that their baby took part in the study.
    Background therapy
    		 Inhaled nitric oxide (iNO) was administered concurrently with the study drug as per the standard care at the center, and as as per protocol requirements at randomization and weaning. The following standard treatments for conditions associated with PPHN were permitted to be administered along with the study drugs: • Milrinone • Vasopressors (e.g., dopamine, dobutamine, terlipressin, epinephrine or norepinephrine) • Neuromuscular blocking agents (e.g., Pancuronium/Pavulon) • Surfactant • Sodium bicarbonate or tromethamine to correct metabolic acidosis • Other therapies to correct or avoid hypothermia, hypovolemia, hypoglycemia, hypocalcemia or anemia should have been applied as per best medical practice, including magnesium sulfate (MgSO4) if it was used to treat hypomagnesemia.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Dec 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    21
    EEA total number of subjects
    17
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    21
    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
    		 The study was conducted in expert pediatric centers with neonatal intensive care unit facilities at which inhaled nitric oxide (iNO) was used as standard of care for PPHN. 23 patients were randomized but 2 were not treated and not included in any analyses

    Pre-assignment
    Screening details
    		 Term or near-term (gestational age > 34 weeks) hypoxic newborns with respiratory distress refractory to supplemental oxygen were considered, provided they had no significant structural cardiac anomalies documented in the pre-natal period and no immediate need for extra corporeal membrane oxygenation.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Only the members of the independent data monitoring committee reviewed data unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bosentan
    Arm description
    		 This arm includes neonates who received bosentan on top of iNO
    Arm type
    		 Experimental

    Investigational medicinal product name
    bosentan
    Investigational medicinal product code
    ACT-050088
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Nasogastric use
    Dosage and administration details
    Quadrisectable 32 mg tablet of bosentan dispersed in sterile water and administered by nasogastric or orogastric tube at a dose of 2 mg/kg of weight at birth twice daily (b.i.d) for a minimum of 2 days and up to 14 days (planned duration)

    Arm title
    		 Placebo
    Arm description
    		 This arm includes neonates who received matching placebo on top of iNO
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Nasogastric use
    Dosage and administration details
    matching placebo tablets dispersed in sterile water and administered by nasogastric or orogastric tube according to the same schedule as the active compound

    Number of subjects in period 1
    		Bosentan Placebo
    Started
    13
    8
    Completed
    13
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bosentan
    Reporting group description
    		 This arm includes neonates who received bosentan on top of iNO

    Reporting group title
    Placebo
    Reporting group description
    		 This arm includes neonates who received matching placebo on top of iNO

    Reporting group values
    		 Bosentan Placebo Total
    Number of subjects
    		 13 8 21
    Age categorical
    Age at first dosing in all patients who received at least one dose of study drug
    Units: Subjects
        Newborns (0-27 days)
    		 13 8 21
    Age Continuous
    Median age at first dosing in all patients who received at least one dose of study drug
    Units: days
        median (full range (min-max))
    		 1.4 (0.6 to 5.6) 1.7 (0.6 to 5.9) -
    Gender categorical
    Units: Subjects
        Female
    		 9 6 15
        Male
    		 4 2 6
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian/white
    		 11 6 17
        Asian
    		 1 0 1
        Hispanic
    		 1 1 2
        Other
    		 0 1 1
    Primary PPHN etiology
    Among the 9 patients reported to have neonatal aspiration in the Bosentan group, 4 also had another parenchymal lung disease: 3 had respiratory distress syndrome and one had sepsis. So, data reported in the table below for the Bosentan arm must be read as follows: neonatal aspiration n = 9, neonatal respiratory distress syndrome n = 4, pneumonia/sepsis n = 4 since these different conditions are not mutually exclusive
    Units: Subjects
        Idiopathic
    		 0 3 3
        Neonatal aspiration
    		 9 3 12
        Neonatal respiratory distress syndrome
    		 1 0 1
        Pneumonia / Sepsis
    		 3 2 5
    Gestational age
    Median gestational age in all patients who received at least one of study drug
    Units: weeks
        median (full range (min-max))
    		 40 (36 to 41) 38.5 (36 to 42) -
    Oxygenation index (OI) at first dosing
    OI is a measure of the severity of pulmonary dysfunction: The higher OI is, the more severe is the disease.
    Units: none
        median (full range (min-max))
    		 18.3 (5.9 to 44.3) 13.2 (7.1 to 39.4) -

    End points

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    End points reporting groups
    Reporting group title
    Bosentan
    Reporting group description
    		 This arm includes neonates who received bosentan on top of iNO

    Reporting group title
    Placebo
    Reporting group description
    		 This arm includes neonates who received matching placebo on top of iNO

    Subject analysis set title
    all-treated set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This set consists of all patients who received at least one dose of study drug (bosentan or matching placebo) and was used for the analysis of all efficacy endpoints. The "full analysis" set, the "safety" set and the "All -treated" set were identical. This set was used for the analysis of all efficacy endpoints.

    Subject analysis set title
    pharmacokinetic set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This set comprised all bosentan-treated patients included in the all treated set who were able to provide at least 5 of the 7 blood samples requested for at least one evaluable profile of PK assessment and who did not violate the protocol in a way that might affect the evaluation of the PK endpoints. Pharmacokinetic analyses were performed using this set.

    Primary: Proportion of patients with treatment failure

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    End point title
    		 Proportion of patients with treatment failure
    End point description
    Treatment failure was defined as the need for extra corporeal membrane oxygenation or initiation of alternative pulmonary vasodilator treatment
    End point type
    Primary
    End point timeframe
    From the first dose of study drug up to end of study (maximum = 21 days)
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    13
    8
    Units: Percentage of patients
        number (not applicable)
    7.7
    0
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - No formal statistical hypothesis on expected treatment difference was defined

    Primary: Time to complete weaning from iNO

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    End point title
    		 Time to complete weaning from iNO
    End point description
    Calculated from the time from first study drug administration to complete weaning from iNO. Weaning from iNO was considered complete if there was no requirement for the re-initiation of iNO within 24 h after stopping
    End point type
    Primary
    End point timeframe
    From first study drug administration up to end of study (maximum = 21 days)
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    13
    8
    Units: Days
        median (confidence interval 95%)
    3.7 (1.17 to 6.95)
    2.9 (1.26 to 4.23)
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.3407
    Method
    		 Logrank
    Confidence interval
    Notes
    [2] - No formal statistical hypothesis on expected treatment difference was defined

    Primary: Time to complete weaning from mechanical ventilation

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    End point title
    		 Time to complete weaning from mechanical ventilation
    End point description
    Calculated from the time from first study drug administration to complete weaning from mechanical ventilation
    End point type
    Primary
    End point timeframe
    From first study drug administration up to end of study (maximum = 21 days)
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    13
    8
    Units: Days
        median (confidence interval 95%)
    10.8 (3.21 to 12.21)
    8.6 (3.71 to 9.66)
    Statistical analysis title
    		 Treatment comparison
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.2399
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - No formal statistical hypothesis on expected treatment difference was defined

    Secondary: Proportion of patients requiring re-initiation of iNO therapy

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    End point title
    		 Proportion of patients requiring re-initiation of iNO therapy
    End point description
    Re-initiation of iNO therapy following weaning from iNO therapy
    End point type
    Secondary
    End point timeframe
    From first study drug administration up to end of study (maximum = 21 days)
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    13
    8
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Proportion of patients with pulmonary hypertension (PH) at end of treatment

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    End point title
    		 Proportion of patients with pulmonary hypertension (PH) at end of treatment
    End point description
    The presence of PH was assessed by echocardiography. PH was reported as ‘present’ if at least one of the following criteria was met: • Shunt through ductus arteriosus was either ‘predominant right to left’ or ‘bidirectional’ • Shunt through foramen ovale was either ‘predominant right to left’ or ‘bidirectional’ • Marked right ventricular dilation was ticked ‘present’ • Paradoxical shift of intraventricular septum was ticked ‘present’ • Right ventricular systolic pressure (mmHg) was > 2/3 of the reported systemic blood pressure
    End point type
    Secondary
    End point timeframe
    From first study drug administraton up to end of treatment (maximum = 14 days)
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    13
    8
    Units: Percentage of patients
        number (not applicable)
    41.7
    37.5
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [4] - No formal statistical hypothesis on expected treatment difference was defined.

    Secondary: Change from baseline in oxygenation index (OI) over time

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    End point title
    		 Change from baseline in oxygenation index (OI) over time
    End point description
    OI was calculated as the mean airway pressure multiplied by the fraction of inspired oxygen (expressed in %), and the product was divided by the partial pressure of oxygen in arterial blood. OI changed in a similar manner from baseline over time in the bosentan and placebo groups, with large inter-subject variability. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: one patient in the bosentan group was not analyzed after time 24 hours because of treatment failure.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    12
    8
    Units: oxygenation index
    median (confidence interval 95%)
        Baseline for timepoint 72 hours
    19.4 (8.2 to 35.4)
    13.2 (7.9 to 39.4)
        Change from baseline to 72 hours
    -8.9 (-23.1 to -1.8)
    -9.4 (-17.7 to 2.2)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.1015
    Method
    		 Non-parametric ANCOVA
    Confidence interval
    Notes
    [5] - No formal statistical hypothesis on expected treatment difference was defined

    Secondary: Change from baseline in arterial pH over time

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    End point title
    		 Change from baseline in arterial pH over time
    End point description
    Arterial pH changed in a similar manner from baseline over time in the bosentan and placebo groups. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: one patient in the bosentan group was not analyzed after time 24 hours because of treatment failure.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    12
    8
    Units: pH
    median (confidence interval 95%)
        baseline for timepoint 72 hours
    7.37 (7.3 to 7.43)
    7.31 (7.21 to 7.49)
        change from baseline to 72 hours
    0.04 (-0.06 to 0.07)
    0.02 (-0.09 to 0.19)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.0824
    Method
    		 Non-parametric ANCOVA
    Confidence interval
    Notes
    [6] - No formal statistical hypothesis on expected treatment difference was defined

    Secondary: Change from baseline in arterial blood oxygen saturation (SaO2) over time

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    End point title
    		 Change from baseline in arterial blood oxygen saturation (SaO2) over time
    End point description
    Arterial SaO2 changed in a similar manner from baseline over time in the bosentan and placebo groups. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: Data from 2 patients in the bosentan group were missing at time 72 hours and another one had no value available.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    11
    8
    Units: percentage saturation
    median (confidence interval 95%)
        Baseline for timepoint 72 hours
    95 (92 to 99)
    95.5 (89 to 99)
        change from baseline to 72 hours
    1 (0 to 8)
    0 (-4 to 21)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.3863
    Method
    		 Non-parametric ANCOVA
    Confidence interval
    Notes
    [7] - No formal statistical hypothesis on expected treatment difference was defined.

    Secondary: Change from baseline in partial pressure of oxygen (PaO2) in arterial blood over time

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    End point title
    		 Change from baseline in partial pressure of oxygen (PaO2) in arterial blood over time
    End point description
    PaO2 changed in a similar manner from baseline over time in the bosentan and placebo groups, with both groups plateauing at 24 hours and retaining almost identical median values out to 72 hours. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: One patient in the bosentan group was not analyzed after time 24 hours because of treatment failure.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    12
    8
    Units: mmHg
    median (confidence interval 95%)
        Baselin for timepoint 72 hours
    61 (53 to 132)
    69.5 (46 to 111)
        Change from baseline to 72 hours
    18 (-13 to 32)
    6 (-12 to 115)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.3936
    Method
    		 Nonparametric ANCOVA
    Confidence interval
    Notes
    [8] - No formal statistical hypothesis on expected treatment difference was defined.

    Secondary: Change from baseline in partial pressure of carbon dioxide (PaCO2) in arterial blood over time

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    End point title
    		 Change from baseline in partial pressure of carbon dioxide (PaCO2) in arterial blood over time
    End point description
    PaCO2 changed in a similar manner from baseline over time in the bosentan and placebo groups. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: one patient in the bosentan group was not analyzed after time 24 hours because of treatment failure.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    12
    8
    Units: mmHg
    median (confidence interval 95%)
        Baseline for timepoint 72 hours
    40.5 (31 to 47)
    46 (35 to 57)
        Change from baseline to 72 hours
    6 (-1 to 12)
    8 (-8 to 21)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.2436
    Method
    		 Non-parametric ANCOVA
    Confidence interval
    Notes
    [9] - No formal statistical hypothesis on expected treatment difference was defined.

    Secondary: Change from baseline in pre-ductal peripheral oxygen saturation (SpO2) over time

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    End point title
    		 Change from baseline in pre-ductal peripheral oxygen saturation (SpO2) over time
    End point description
    Simultaneous pre- (right hand) and post-ductal (lower extremities) SpO2 were measured using pulse oximetry device. Changes from baseline in SpO2 over time were similar in the bosentan and placebo groups. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: one patient in the bosentan group was not analyzed after time 24 hours because of treatment failure.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    12
    8
    Units: percentage saturation
    median (confidence interval 95%)
        Baseline for time 72 hours
    95 (91 to 99)
    97 (91 to 99)
        Change from baseline to 72 hours
    0.5 (-2 to 2)
    -1 (-10 to 2)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug adminsitration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.1756
    Method
    		 Non-parametric ANCOVA
    Confidence interval
    Notes
    [10] - No formal statistical hypothesis on expected treatment difference was defined.

    Secondary: Change from baseline in post-ductal peripheral oxygen saturation (SpO2) over time

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    End point title
    		 Change from baseline in post-ductal peripheral oxygen saturation (SpO2) over time
    End point description
    Simultaneous pre- (right hand) and post-ductal (lower extremities) SpO2 were measured using pulse oximetry device. Changes from baseline in SpO2 over time were similar in the bosentan and placebo groups. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: one patient in the bosentan group was not analyzed after time 24 hours because of treatment failure.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    12
    8
    Units: percentage saturation
    median (confidence interval 95%)
        Baseline for time 72 hours
    96.5 (92 to 99)
    96 (89 to 98)
        Change from baseline to 72 hours
    0 (-2 to 3)
    2 (1 to 12)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.1155
    Method
    		 Non-parametric ANCOVA
    Confidence interval
    Notes
    [11] - No formal statistical hypothesis on expected treatment difference was defined.

    Secondary: Change from baseline in fraction of inspired oxygen (FiO2) over time

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    End point title
    		 Change from baseline in fraction of inspired oxygen (FiO2) over time
    End point description
    FiO2 was determined according to each study centers’ standard procedure. Changes from baseline in FiO2 over time were similar in the bosentan and placebo groups. So, only the statistical analysis for changes from baseline to 72 hours is reported here. Note: one patient in the bosentan group was not analyzed after time 24 hours because of treatment failure.
    End point type
    Secondary
    End point timeframe
    At baseline and at scheduled time points up to end of treatment. The data presented show changes from baseline to 72 hours because most patients were exposed at least 3 days and had measurements available during this period.
    End point values
    		 Bosentan Placebo
    Number of subjects analysed
    12
    8
    Units: percentage of oxygen
    median (confidence interval 95%)
        Baseline for time 72 hous
    90 (62 to 97)
    78 (60 to 100)
        Change from baseline to 72 hours
    -33.5 (-50 to -15)
    -35.5 (-60 to 0)
    Statistical analysis title
    		 Treatment comparison
    Statistical analysis description
    Treatment comparison 72 hours after first study drug administration
    Comparison groups
    Bosentan v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.14
    Method
    		 Non-parametric ANCOVA
    Confidence interval
    Notes
    [12] - No formal statistical hypothesis on expected treatment difference was defined.

    Secondary: Maximum whole blood concentration (Cmax) on Day 1 for bosentan and its metabolites (Ro 47-8634, Ro 48-5033, Ro 64-1056)

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    End point title
    		 Maximum whole blood concentration (Cmax) on Day 1 for bosentan and its metabolites (Ro 47-8634, Ro 48-5033, Ro 64-1056) [13]
    End point description
    This is the maximum concentration of bosentan or its metaboites measured directly from the whole blood samples (dried blood spot samples) scheduled to be taken immediately prior to study drug administration and 0.5, 1, 2, 3, 7.5, and 12 hours after first study drug administration on Day 1. As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg bosentan in all patients. Therefore Cmax was corrected to a dose of 2 mg/kg bosentan (Cmaxc = Cmax / actual dose x 2 mg/kg)
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    11
    Units: ng/mL
    geometric mean (confidence interval 95%)
        Bosentan
    30.1 (2.4 to 372.2)
        Ro 47-8634
    0.1 (0 to 1.1)
        Ro 48-5033
    0.6 (0 to 18.3)
        Ro 64-1056
    0.9 (0 to 16.2)
    No statistical analyses for this end point

    Secondary: Maximum whole blood concentration (Cmax) on Day 5 for bosentan and its metabolites (Ro 47-8634, Ro 48-5033, Ro 64-1056)

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    End point title
    		 Maximum whole blood concentration (Cmax) on Day 5 for bosentan and its metabolites (Ro 47-8634, Ro 48-5033, Ro 64-1056) [14]
    End point description
    This is the maximum concentration measured directly from the whole blood samples (dried blood spot samples) in patients still on study treatment on Day 5 and scheduled to be taken immediately prior to study drug administration on Day 5 and 0.5, 1, 2, 3, 7.5, and 12 hours thereafter. As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg bosentan in all patients. Therefore Cmax was corrected to a dose of 2 mg/kg bosentan (Cmaxc = Cmax / actual dose x 2 mg/kg)
    End point type
    Secondary
    End point timeframe
    Day 5
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: ng/mL
    geometric mean (confidence interval 95%)
        Bosentan
    880 (339.2 to 2282.7)
        Ro 47-8634
    24.9 (9 to 69.1)
        Ro 48-5033
    292.3 (115.8 to 738.1)
        Ro 64-1056
    136 (77.4 to 238.8)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for bosentan on Day 1

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    End point title
    		 Time to maximum whole blood concentration (tmax) for bosentan on Day 1 [15]
    End point description
    tmax was measured directly from the whole blood samples (dried blood spot samples) scheduled to be taken immediately prior to study drug administration and 0.5, 1, 2, 3, 7.5, and 12 hours after first study drug administration on Day 1.
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    10
    Units: hours
        median (full range (min-max))
    12 (7.5 to 12)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for Ro 47-8634 on Day 1

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    End point title
    		 Time to maximum whole blood concentration (tmax) for Ro 47-8634 on Day 1 [16]
    End point description
    tmax was measured directly from the whole blood samples (dried blood spot samples) scheduled to be taken immediately prior to study drug administration and 0.5, 1, 2, 3, 7.5, and 12 hours after first study drug administration on Day 1.
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    5
    Units: hours
        median (full range (min-max))
    12 (7.5 to 12)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for Ro 48-5033 on Day 1

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    End point title
    		 Time to maximum whole blood concentration (tmax) for Ro 48-5033 on Day 1 [17]
    End point description
    tmax was measured directly from the whole blood samples (dried blood spot samples) collected within 12 hours after first study drug administration on Day 1.
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: hours
        median (full range (min-max))
    12 (12 to 12)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for Ro 64-1056 on Day 1

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    End point title
    		 Time to maximum whole blood concentration (tmax) for Ro 64-1056 on Day 1 [18]
    End point description
    Tmax was measured directly from the whole blood samples (dried blood spot samples) scheduled to be taken immediately prior to study drug administration and 0.5, 1, 2, 3, 7.5, and 12 hours after first study drug administration on Day 1.
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    8
    Units: hours
        median (full range (min-max))
    12 (0.5 to 12)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for bosentan on Day 5

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    End point title
    		 Time to maximum whole blood concentration (tmax) for bosentan on Day 5 [19]
    End point description
    tmax was measured directly from the whole blood samples (dried blood spot samples) in patients still on study treatment on Day 5. Samples were scheduled to be taken immediately prior to study drug administration on Day 5 and 0.5, 1, 2, 3, 7.5, and 12 hours thereafter.
    End point type
    Secondary
    End point timeframe
    Day 5
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: hours
        median (full range (min-max))
    7.5 (0.8 to 12)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for Ro 47-8634 on Day 5

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    End point title
    		 Time to maximum whole blood concentration (tmax) for Ro 47-8634 on Day 5 [20]
    End point description
    tmax was measured directly from the whole blood samples (dried blood spot samples) in patients still on study treatment on Day 5. Samples were scheduled to be taken immediately prior to study drug administration on Day 5 and 0.5, 1, 2, 3, 7.5, and 12 hours thereafter.
    End point type
    Secondary
    End point timeframe
    Day 5
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: hours
        median (full range (min-max))
    6.5 (0.8 to 12)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for Ro 48-5033 on Day 5

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    End point title
    		 Time to maximum whole blood concentration (tmax) for Ro 48-5033 on Day 5 [21]
    End point description
    tmax was measured directly from the whole blood samples (dried blood spot samples) in patients still on study treatment on Day 5. Samples were scheduled to be taken immediately prior to study drug administration on Day 5 and 0.5, 1, 2, 3, 7.5, and 12 hours thereafter.
    End point type
    Secondary
    End point timeframe
    Day 5
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: hours
        median (full range (min-max))
    7.5 (0.8 to 12)
    No statistical analyses for this end point

    Secondary: Time to maximum whole blood concentration (tmax) for Ro 64-1056 on Day 5

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    End point title
    		 Time to maximum whole blood concentration (tmax) for Ro 64-1056 on Day 5 [22]
    End point description
    tmax was measured directly from the whole blood samples (dried blood spot samples) in patients still on study treatment on Day 5. Samples were scheduled to be taken immediately prior to study drug administration on Day 5 and 0.5, 1, 2, 3, 7.5, and 12 hours thereafter.
    End point type
    Secondary
    End point timeframe
    Day 5
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: hours
        median (full range (min-max))
    12 (7.5 to 12)
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve over one dosing interval [AUC(0-12)] on Day 1 for bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056)

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    End point title
    		 Area under the concentration-time curve over one dosing interval [AUC(0-12)] on Day 1 for bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056) [23]
    End point description
    AUC(0-12) on Day 1 was calculated according to the trapezoidal rule using the measured concentration-time values above the limit of quantification (LOQ). AUC(0-12) was determined on the basis of scheduled blood sampling time points (prior to study drug administration and 0.5, 1, 2, 3, 7.5, and 12 hours after first study drug administration on Day 1).
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    11
    Units: h*ng/mL
    geometric mean (confidence interval 95%)
        Bosentan
    163.9 (9.6 to 2795.4)
        Ro 47-8634
    0.1 (0 to 3.7)
        Ro 48-5033
    1.4 (0 to 69.9)
        Ro 64-1056
    2.2 (0.1 to 64.1)
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve over a dosing interval at steady state (AUCtau)on Day 5 for Bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056)

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    End point title
    		 Area under the concentration-time curve over a dosing interval at steady state (AUCtau)on Day 5 for Bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056) [24]
    End point description
    AUCtau on Day 5 was calculated according to the trapezoidal rule using the measured concentration-time values above the limit of quantification. AUCtau was determined on the basis of scheduled blood sampling time points (prior to study drug administration on Day 5 and 0.5, 1, 2, 3, 7.5, and 12 hours thereafter) in patients still on study treatment on Day 5.
    End point type
    Secondary
    End point timeframe
    Day 5
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: h*ng/mL
    geometric mean (confidence interval 95%)
        Bosentan
    6165.4 (2429.6 to 15645.3)
        Ro 47-8634
    217.3 (75.3 to 626.8)
        Ro 48-5033
    2839.5 (1155.2 to 6979.2)
        Ro 64-1056
    1321.7 (729.5 to 2395)
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve over a period of 24 h [AUC(0-24c)] on Day 1 for Bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056)

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    End point title
    		 Area under the concentration-time curve over a period of 24 h [AUC(0-24c)] on Day 1 for Bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056) [25]
    End point description
    AUC(0-24c) on Day 1 was calculated as a multiple of AUC0-12 (2 × AUC0-12 for 2 times daily dosing) and corrected to 2 mg/kg (target dose). AUC(0-24c) was determined on the basis of scheduled blood sampling time points (prior to study drug administration and 0.5, 1, 2, 3, 7.5, and 12 hours after first study drug administration on Day 1).
    End point type
    Secondary
    End point timeframe
    Day 1
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    11
    Units: h*ng/mL
    geometric mean (confidence interval 95%)
        Bosentan
    287.5 (15 to 5504.7)
        Ro 47-8634
    0.1 (0 to 6.1)
        Ro 48-5033
    2 (0 to 125.8)
        Ro 64-1056
    3.4 (0.1 to 120.8)
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve over a period of 24 h [AUC(0-24hc)] on Day 5 for Bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056)

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    End point title
    		 Area under the concentration-time curve over a period of 24 h [AUC(0-24hc)] on Day 5 for Bosentan and Its Metabolites (Ro 47-8634, Ro 48-5033, and Ro 64-1056) [26]
    End point description
    AUC(0-24c) on Day 5 was calculated as a multiple of AUCtau, (2 × AUCtau for 2 times daily dosing) corrected to 2 mg/kg (target dose). [AUC(0-24c)] was determined on the basis of scheduled blood sampling time points (prior to study drug administration on Day 5 and 0.5, 1, 2, 3, 7.5, and 12 hours thereafter) in patients still on study treatment on Day 5.
    End point type
    Secondary
    End point timeframe
    Day 5
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: h*ng/mL
    geometric mean (confidence interval 95%)
        Bosentan
    11530.2 (4507 to 29497.5)
        Ro 47-8634
    406.3 (139.8 to 1180.9)
        Ro 48-5033
    5310.3 (2184.4 to 12908.9)
        Ro 64-1056
    2471.9 (1386.1 to 4408)
    No statistical analyses for this end point

    Secondary: Accumulation index (AI) for Bosentan

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    End point title
    		 Accumulation index (AI) for Bosentan [27]
    End point description
    AI was calculated as the ratio AUCtau / AUC(0-12) for the subjects having PK samples collected on both Day 1 and Day 5 and with AUC0-12 > 0 ng.h/mL.
    End point type
    Secondary
    End point timeframe
    5 days
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Exploratory endpoint with only descriptive summary statistics provided
    End point values
    		 Bosentan
    Number of subjects analysed
    7
    Units: accumulation index
        geometric mean (confidence interval 95%)
    61.6 (0.5 to 7813.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Events with onset up to 7 days after end of treatment
    Adverse event reporting additional description
    For serious adverse events, a 60-day post-treatment safety follow-up was conducted by phone. During this follow-up period, hepatitis was reported in one bosentan-treated patient (8 days after study drug stop) and resolved within the 60-days follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 This arm includes neonates who received matching placebo on top of iNO for a minimum of 2.5 days to a maximum duration of 6.5 days (i.e., until 24 hours after complete weaning from iNO) (median duration = 4.0 days).

    Reporting group title
    Bosentan
    Reporting group description
    		 This arm includes neonates who received bosentan on top of iNO at least once to a maximum duration of 10 days (i.e., up to treatment failure or until 24 hours after complete weaning from iNO) (median duration = 4.5 days).

    Serious adverse events
    		 Placebo Bosentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 13 (15.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    CIRCULATORY COLLAPSE
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATITIS
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    HYPERCAPNIA
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    SEPSIS
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    METABOLIC ACIDOSIS
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Bosentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    9 / 13 (69.23%)
    Investigations
    BILIRUBIN CONJUGATED INCREASED
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    BODY TEMPERATURE INCREASED
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    ENDOTRACHEAL INTUBATION COMPLICATION
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    PROCEDURAL COMPLICATION
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Cardiac disorders
    MITRAL VALVE INCOMPETENCE
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 13 (23.08%)
         occurrences all number
    1
    3
    COAGULOPATHY
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    METHAEMOGLOBINAEMIA
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    GENERALISED OEDEMA
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    VOMITING
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    DYSPHONIA
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    PNEUMOMEDIASTINUM
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Infections and infestations
    INFECTIOUS DISEASE CARRIER
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    METABOLIC ACIDOSIS
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2012
    Changes in the inclusion criteria Classification of objectives and endpoints into primary and secondary criteria
    17 Dec 2012
    Due to the slow recruitment, the eligibility criteria were adjusted to be less stringent, allowing inclusion of patients with less severe persistent pulmonary hypertension of the newborn (PPHN) and who were still in need of continuous inhaled nitric oxide (iNO) therapy and could benefit from additional therapy with bosentan

    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.
    Overall, the disease was more severe in the bosentan group than in the placebo group (higher oxygen index at baseline), which may have introduced a bias into the treatment comparison of the outcome "time to iNO weaning"
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