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    Clinical Trial Results:
    The Effects of Nitric Oxide for Inhalation on the Development of Chronic Lung Disease in Pre-term Infants

    Summary
    EudraCT number
    		 2004-002312-29
    Trial protocol
    		 FI   SE   GB   DE   BE   ES   IT  
    Global end of trial date
    17 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2021
    First version publication date
    03 Feb 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    INOT27
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00551642
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mallinckrodt
    Sponsor organisation address
    1425 State Route 206, Bedminster, NJ, United States, 07921
    Public contact
    Medical Information Call Center, Mallinckrodt, Medinfo@mnk.com
    Scientific contact
    Medical Information Call Center, Mallinckrodt, Medinfo@mnk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and efficacy of inhaled nitric oxide to reduce the risk of chronic lung disease in pre-term infants with respiratory distress and to assess the long term effects of the therapy on the development of these children over 7 years of clinical follow-up.
    Protection of trial subjects
    Trial performed in hospital setting; Follow up assessments made by study doctor to monitor progress of child.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 7 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 155
    Country: Number of subjects enrolled
    Sweden: 44
    Country: Number of subjects enrolled
    United Kingdom: 63
    Country: Number of subjects enrolled
    Belgium: 74
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 231
    Country: Number of subjects enrolled
    Italy: 78
    Country: Number of subjects enrolled
    France: 107
    Country: Number of subjects enrolled
    Netherlands: 40
    Worldwide total number of subjects
    800
    EEA total number of subjects
    800
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    800
    Newborns (0-27 days)
    0
    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
    		 Thirty-five Medical Centers participated and enrolled a total of 800 participants (Intent to treat population).

    Pre-assignment
    Screening details
    		 800 participants were enrolled at 35 medical centers around the world for the Treatment period, and 305 had data at the 7-year Follow-up period

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Double-blind trial also had blinded Carer and Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Inhaled Nitric Oxide (INO)
    Arm description
    		 INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for between 7 and 21 days during the Treatment period, but no intervention during the 7-year Follow-up
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitric oxide
    Investigational medicinal product code
    Other name
    INO max®
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    Nitric Oxide vapour (gas) for inhalation (400 ppm)

    Arm title
    		 Placebo
    Arm description
    		 Placebo gas administered by nasal continuous positive airway pressure, nasal cannula or face mask, for a maximum of 21 days during the Treatment period, but no intervention during the 7-year Follow-up
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo gas for inhalation
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo gas for inhalation for a maximum of 21 days

    Number of subjects in period 1
    		Inhaled Nitric Oxide (INO) Placebo
    Started
    399
    401
    Safety Population
    395
    397
    Completed
    338
    338
    Not completed
    61
    63
         Adverse event, serious fatal
    33
    31
         Delivery device failure
    1
    3
         Inclusion/exclusion criteria
    4
    4
         Consent withdrawn by subject
    2
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    15
    12
         Protocol deviation
    6
    11
    Period 2
    Period 2 title
    7-year Follow-Up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The long-term follow-up analyses included all subjects who received study drug (Safety population), were alive at Week 36 of gestational age (GA), and had 7-year follow-up data (completed a CRF for 7-year follow-up).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Inhaled Nitric Oxide (INO)
    Arm description
    		 INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for 7 to 21 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nitric oxide
    Investigational medicinal product code
    Other name
    INO max®
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    Nitric Oxide vapour (gas) for inhalation (400 ppm)

    Arm title
    		 Placebo
    Arm description
    		 Placebo gas administered by nasal continuous positive airway pressure, nasal cannula or face mask, for a maximum of 21 days during the Treatment period, but no intervention during the 7-year Follow-up
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo gas for inhalation
    Pharmaceutical forms
    Inhalation vapour
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo gas for inhalation for a maximum of 21 days

    Number of subjects in period 2 [1]
    		Inhaled Nitric Oxide (INO) Placebo
    Started
    152
    153
    Completed
    152
    153
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Many patients did not participate in the 7-yearFollow-up

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inhaled Nitric Oxide (INO)
    Reporting group description
    		 INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for between 7 and 21 days during the Treatment period, but no intervention during the 7-year Follow-up

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo gas administered by nasal continuous positive airway pressure, nasal cannula or face mask, for a maximum of 21 days during the Treatment period, but no intervention during the 7-year Follow-up

    Reporting group values
    		 Inhaled Nitric Oxide (INO) Placebo Total
    Number of subjects
    		 399 401 800
    Age categorical
    Units: Subjects
        Preterm newborn infants (gestational age < 37 wks)
    		 399 401 800
    Gender categorical
    Units: Subjects
        Female
    		 192 181 373
        Male
    		 207 220 427

    End points

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    End points reporting groups
    Reporting group title
    Inhaled Nitric Oxide (INO)
    Reporting group description
    		 INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for between 7 and 21 days during the Treatment period, but no intervention during the 7-year Follow-up

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo gas administered by nasal continuous positive airway pressure, nasal cannula or face mask, for a maximum of 21 days during the Treatment period, but no intervention during the 7-year Follow-up
    Reporting group title
    Inhaled Nitric Oxide (INO)
    Reporting group description
    		 INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for 7 to 21 days

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo gas administered by nasal continuous positive airway pressure, nasal cannula or face mask, for a maximum of 21 days during the Treatment period, but no intervention during the 7-year Follow-up

    Primary: Survival Without Bronchopulmonary Dysplasia (BPD) in Preterm Infants With Respiratory Distress

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    End point title
    		 Survival Without Bronchopulmonary Dysplasia (BPD) in Preterm Infants With Respiratory Distress
    End point description
    The primary outcome was determined by assessment of survival and incidence of BPD, which was defined by the need for supplemental oxygen at 36 weeks gestational age (GA); an infant who was alive without BPD at 36 weeks GA was counted as success; an infant who died or had BPD at 36 weeks GA was counted as a failure.
    End point type
    Primary
    End point timeframe
    36 weeks gestational age
    End point values
    		 Inhaled Nitric Oxide (INO) Placebo
    Number of subjects analysed
    395 [1]
    400 [2]
    Units: patients
    258
    262
    Notes
    [1] - Patients with efficacy data
    [2] - Patients with efficacy data
    Statistical analysis title
    		 Arm Comparison
    Statistical analysis description
    Comparison
    Comparison groups
    Inhaled Nitric Oxide (INO) v Placebo
    Number of subjects included in analysis
    795
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.734
    Method
    		 Wald Chi-square
    Confidence interval

    Other pre-specified: Mortality at 7-year Follow-up

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    End point title
    		 Mortality at 7-year Follow-up
    End point description
    Number of participants who died between 2 years and the 7-year Follow-up
    End point type
    Other pre-specified
    End point timeframe
    at 7 year follow-up
    End point values
    		 Inhaled Nitric Oxide (INO) Placebo
    Number of subjects analysed
    152 [3]
    153 [4]
    Units: patients
    0
    0
    Notes
    [3] - Patients who completed 7-year follow-up
    [4] - Patients who completed 7-year follow-up
    No statistical analyses for this end point

    Other pre-specified: Strengths and Difficulties Questionnaire Results for Subjects With 7-Year Follow-Up Data

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    End point title
    		 Strengths and Difficulties Questionnaire Results for Subjects With 7-Year Follow-Up Data
    End point description
    The Strengths and Difficulties Questionnaire contained 25 questions that were used to create 5 scales (ranging from 10=most normal to 0=most abnormal) for emotional symptoms, conduct problems, hyperactivity, peer problems, and (10=most abnormal, 0=most normal) for prosocial.
    End point type
    Other pre-specified
    End point timeframe
    at 7-year follow-up
    End point values
    		 Inhaled Nitric Oxide (INO) Placebo
    Number of subjects analysed
    147 [5]
    147 [6]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Emotional (0=most normal, 10=most abnormal)
    1.9 ( 1.79 )
    2.1 ( 1.96 )
        Conduct (0=most normal, 10=most abnormal)
    1.4 ( 1.55 )
    1.4 ( 1.58 )
        Hyperactivity (0=most normal, 10=most abnormal)
    3.8 ( 2.64 )
    3.4 ( 2.66 )
        Peer problems (0=most normal, 10=most abnormal)
    1.2 ( 1.41 )
    1.5 ( 1.74 )
        Prosocial (10=most abnormal, 0=most normal)
    8.6 ( 1.73 )
    8.4 ( 1.81 )
    Notes
    [5] - Patients with questionnaire data at 7-Year Follow-up
    [6] - Patients with questionnaire data at 7-Year Follow-up
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (including clinically significant changes in vital signs, oxygen saturation, and laboratory values) were collected in the safety population throughout screening and treatment for a maximum of 21 days (not during follow-up).
    Adverse event reporting additional description
    All serious adverse events are listed. Non-serious treatment-emergent adverse events (TEAEs) are listed if 5% or more participants in any arm experienced any form of that preferred term. For example, the term "Sepsis" includes Bacterial Sepsis, Candida Sepsis, Catheter Sepsis, Enterobacter Sepsis, Enterococcal Sepsis, Escherichia Sepsis, etc.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Inhaled Nitric Oxide (INO)
    Reporting group description
    		 Safety population receiving INO administered by nasal continuous positive airway pressure, nasal cannula or face mask at 5 parts per million (ppm) for 7 to 21 days during the Treatment period, but no intervention during the 7-year Follow-up

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo gas administered by nasal continuous positive airway pressure (nasal cannula or face mask) for a maximum of 21 days during the Treatment period, but no intervention during the 7-year Follow-up

    Serious adverse events
    		 Inhaled Nitric Oxide (INO) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    170 / 395 (43.04%)
    177 / 397 (44.58%)
         number of deaths (all causes)
    56
    48
         number of deaths resulting from adverse events
    43
    39
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic haemangioma rupture
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 395 (1.01%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Infarction
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Chest tube insertion
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter related complication
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Foreign body aspiration
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 397 (0.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Laryngeal oedema
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal respiratory failure
         subjects affected / exposed
    3 / 395 (0.76%)
    3 / 397 (0.76%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    1 / 3
    0 / 2
    Pneumomediastinum
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    12 / 395 (3.04%)
    13 / 397 (3.27%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 15
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    12 / 395 (3.04%)
    14 / 397 (3.53%)
         occurrences causally related to treatment / all
    3 / 12
    7 / 14
         deaths causally related to treatment / all
    2 / 3
    3 / 4
    Pulmonary hypertension
         subjects affected / exposed
    3 / 395 (0.76%)
    3 / 397 (0.76%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary interstitial emphysema syndrome
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Bacterial test positive
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood cortisol decreased
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood growth hormone decreased
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain scan abnormal
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Coarctation of the aorta
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patent ductus arteriosus
         subjects affected / exposed
    62 / 395 (15.70%)
    54 / 397 (13.60%)
         occurrences causally related to treatment / all
    13 / 62
    11 / 54
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Persistent foetal circulation
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitello-intestinal duct remnant
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bradycardia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 395 (0.51%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest neonatal
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiomyopathy
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intracardiac thrombus
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Central nervous system lesion
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ventricle dilatation
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    50 / 395 (12.66%)
    42 / 397 (10.58%)
         occurrences causally related to treatment / all
    17 / 52
    14 / 42
         deaths causally related to treatment / all
    6 / 16
    4 / 11
    Hydrocephalus
         subjects affected / exposed
    4 / 395 (1.01%)
    4 / 397 (1.01%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periventricular leukomalacia
         subjects affected / exposed
    7 / 395 (1.77%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinopathy of prematurity
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    2 / 395 (0.51%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    17 / 395 (4.30%)
    14 / 397 (3.53%)
         occurrences causally related to treatment / all
    2 / 17
    0 / 14
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Intussusception
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meconium ileus
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meconium plug syndrome
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising enterocolitis neonatal
         subjects affected / exposed
    16 / 395 (4.05%)
    9 / 397 (2.27%)
         occurrences causally related to treatment / all
    1 / 16
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Oesophageal perforation
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder perforation
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 395 (0.00%)
    4 / 397 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter related infection
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    34 / 395 (8.61%)
    35 / 397 (8.82%)
         occurrences causally related to treatment / all
    0 / 35
    1 / 39
         deaths causally related to treatment / all
    0 / 7
    1 / 9
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (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
    Acidosis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Inhaled Nitric Oxide (INO) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    358 / 395 (90.63%)
    334 / 397 (84.13%)
    Congenital, familial and genetic disorders
    Patent ductus arteriosus
         subjects affected / exposed
    183 / 395 (46.33%)
    158 / 397 (39.80%)
         occurrences all number
    187
    163
    Vascular disorders
    Hypotension
         subjects affected / exposed
    55 / 395 (13.92%)
    50 / 397 (12.59%)
         occurrences all number
    57
    54
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    73 / 395 (18.48%)
    55 / 397 (13.85%)
         occurrences all number
    81
    58
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    189 / 395 (47.85%)
    168 / 397 (42.32%)
         occurrences all number
    253
    226
    Thrombocytopenia
         subjects affected / exposed
    29 / 395 (7.34%)
    28 / 397 (7.05%)
         occurrences all number
    29
    31
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    122 / 395 (30.89%)
    120 / 397 (30.23%)
         occurrences all number
    138
    130
    Jaundice
         subjects affected / exposed
    98 / 395 (24.81%)
    89 / 397 (22.42%)
         occurrences all number
    107
    97
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    73 / 395 (18.48%)
    78 / 397 (19.65%)
         occurrences all number
    78
    79
    Infections and infestations
    Sepsis
         subjects affected / exposed
    68 / 395 (17.22%)
    60 / 397 (15.11%)
         occurrences all number
    75
    66
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    90 / 395 (22.78%)
    68 / 397 (17.13%)
         occurrences all number
    100
    75
    Hyponatraemia
         subjects affected / exposed
    21 / 395 (5.32%)
    19 / 397 (4.79%)
         occurrences all number
    22
    21
    Metabolic acidosis
         subjects affected / exposed
    49 / 395 (12.41%)
    52 / 397 (13.10%)
         occurrences all number
    53
    62

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2004
    Amendment changes that impacted the 7-year data (being reported in this full data set (after the summary results previously prepared and attached) were included in Amendment 1 and Amendment 7. Amendment 1: Deleted "Health related quality of life (child and caregiver) at one year, two years, and seven years corrected age.”
    04 Jan 2012
    Amendment 7: 1) Deletion of pulmonary function test assessment at the 7-year long term follow-up. 2) Two endpoints were revised (where applicable) throughout the protocol: - Incidence of death after 36 weeks of GA to 7 years actual postnatal age, stratified by gestational age at birth - Long-term neuro-developmental outcome assessed by a validated, age appropriate developmental assessment at 2 years corrected age and 7 years actual postnatal age

    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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