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    Clinical Trial Results:
    A RANDOMIZED CONTROLLED STUDY TO EVALUATE THE EFFICACY OF A SUPPLEMENTAL DOSE OF CUROSURF IN PRE-TERM INFANTS ON MECHANICAL VENTILATION FOR RESPIRATORY DISTRESS SYNDROME (RDS) IN PREVENTING EXTUBATION FAILURE.

    Summary
    EudraCT number
    2005-005371-15
    Trial protocol
    IT  
    Global end of trial date
    24 Dec 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Mar 2018
    First version publication date
    16 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DM/PR/5000/004/05
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy, 43126
    Public contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., Chiesi Farmaceutici S.p.A., +39 0521 2791, ClinicalTrials_info@chiesi.com
    Scientific contact
    Clinical Trial Transparency, Chiesi Farmaceutici S.p.A., Chiesi Farmaceutici S.p.A., +39 0521 2791, ClinicalTrials_info@chiesi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jun 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Dec 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Dec 2007
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of a supplemental pre-extubation dose of Curosurf® compared to the standard posology (one or two doses) in pre-term neonates, after extubation from mechanical ventilation (MV).
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice (GCP) guidelines and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 May 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    42
    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
    Number of Patients (planned and analyzed): Planned: approximately 200 evaluable pre-term neonates (100/group). Analyzed: 42 pre-term neonates, 23 in the supplemental Curosurf® group and 19 in the no supplemental Curosurf® group.

    Pre-assignment
    Screening details
    All infants of birth weight (BW) 500–1500 g were screened for eligibility based upon the study selection criteria.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This was an oper label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Supplemental Curosurf
    Arm description
    After randomization, this patient group received a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation. Following extubation, patients were monitored for 48 hours to assess extubation success or failure.
    Arm type
    Experimental

    Investigational medicinal product name
    Curosurf
    Investigational medicinal product code
    Other name
    poractant alfa
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Intratracheal use
    Dosage and administration details
    Curosurf® for intratracheal or intrabronchial administration as prophylactic or rescue treatment for RDS according to manufacturer’s instructions. All patients received treatment with one dose of Curosurf® (100 or 200 mg/kg) and a second dose (100 mg/kg, if needed) according to standard practice. Patients were then randomized in a 1:1 ratio to receive either a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation (Group A) or to receive no supplemental treatment before extubation (Group B). Following extubation, patients were monitored for 48 hours to assess extubation success or failure.

    Arm title
    No supplemental Curosurf
    Arm description
    After randomization this patient group did not receive a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation. Following extubation, patients were monitored for 48 hours to assess extubation success or failure.
    Arm type
    Experimental

    Investigational medicinal product name
    Curosurf
    Investigational medicinal product code
    Other name
    poractant alfa
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Intratracheal use
    Dosage and administration details
    Curosurf® for intratracheal or intrabronchial administration as prophylactic or rescue treatment for RDS according to manufacturer’s instructions. All patients received treatment with one dose of Curosurf® (100 or 200 mg/kg) and a second dose (100 mg/kg, if needed) according to standard practice. Patients were then randomized in a 1:1 ratio to receive either a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation (Group A) or to receive no supplemental treatment before extubation (Group B). Following extubation, patients were monitored for 48 hours to assess extubation success or failure.

    Number of subjects in period 1
    Supplemental Curosurf No supplemental Curosurf
    Started
    23
    19
    Completed
    20
    18
    Not completed
    3
    1
         Adverse event, serious fatal
    1
    -
         Adverse event, non-fatal
    -
    1
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Supplemental Curosurf
    Reporting group description
    After randomization, this patient group received a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation. Following extubation, patients were monitored for 48 hours to assess extubation success or failure.

    Reporting group title
    No supplemental Curosurf
    Reporting group description
    After randomization this patient group did not receive a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation. Following extubation, patients were monitored for 48 hours to assess extubation success or failure.

    Reporting group values
    Supplemental Curosurf No supplemental Curosurf Total
    Number of subjects
    23 19 42
    Age categorical
    Units: Subjects
        Preterm newborn infants (gestational age < 37 wks)
    23 19 42
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    5.6 ± 1.83 5.4 ± 2.04 -
    Gender categorical
    Units: Subjects
        Female
    8 7 15
        Male
    15 12 27
    Subject analysis sets

    Subject analysis set title
    Supplemental Curosurf - Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis population comprised all patients randomized into the study, in which each patient’s treatment was as allocated at randomization.

    Subject analysis set title
    Supplemental Curosurf - Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population comprised all patients randomized into the study, in which each patient’s treatment was as taken on the study.

    Subject analysis set title
    No supplemental Curosurf - Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis population comprised all patients randomized into the study, in which each patient’s treatment was as allocated at randomization.

    Subject analysis set title
    No supplemental Curosurf - Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population comprised all patients randomized into the study, in which each patient’s treatment was as taken on the study.

    Subject analysis sets values
    Supplemental Curosurf - Full Analysis Population Supplemental Curosurf - Safety Population No supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Safety Population
    Number of subjects
    23
    23
    19
    19
    Age categorical
    Units: Subjects
        Preterm newborn infants (gestational age < 37 wks)
    23
    23
    19
    19
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    5.6 ± 1.83
    5.6 ± 1.83
    5.4 ± 2.04
    5.4 ± 2.04
    Gender categorical
    Units: Subjects
        Female
    8
    8
    7
    7
        Male
    15
    15
    12
    12

    End points

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    End points reporting groups
    Reporting group title
    Supplemental Curosurf
    Reporting group description
    After randomization, this patient group received a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation. Following extubation, patients were monitored for 48 hours to assess extubation success or failure.

    Reporting group title
    No supplemental Curosurf
    Reporting group description
    After randomization this patient group did not receive a supplemental dose of Curosurf® (100 mg/kg) 1–6 hours before extubation. Following extubation, patients were monitored for 48 hours to assess extubation success or failure.

    Subject analysis set title
    Supplemental Curosurf - Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis population comprised all patients randomized into the study, in which each patient’s treatment was as allocated at randomization.

    Subject analysis set title
    Supplemental Curosurf - Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population comprised all patients randomized into the study, in which each patient’s treatment was as taken on the study.

    Subject analysis set title
    No supplemental Curosurf - Full Analysis Population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis population comprised all patients randomized into the study, in which each patient’s treatment was as allocated at randomization.

    Subject analysis set title
    No supplemental Curosurf - Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population comprised all patients randomized into the study, in which each patient’s treatment was as taken on the study.

    Primary: Extubation failure overall at 48 h

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    End point title
    Extubation failure overall at 48 h
    End point description
    Assessment begins at time of extubation, at least every hour between extubation and 48 hours post-extubation
    End point type
    Primary
    End point timeframe
    48 h post-extubation +/-15 min
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    23
    19
    Units: number of failures
    5
    4
    Statistical analysis title
    Supplemental Curosurf vs no Supplemental Curosurf
    Comparison groups
    Supplemental Curosurf - Full Analysis Population v No supplemental Curosurf - Full Analysis Population
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    5
    Notes
    [1] - The proportion of pre-term patients who experienced extubation failures was compared between the two treatment groups by logistic regression, with treatment group, and BW group as covariates.

    Primary: Indices of respiratory failure - Blood pH

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    End point title
    Indices of respiratory failure - Blood pH [2]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    22
    17
    Units: pH
        arithmetic mean (standard deviation)
    7.2777 ± 0.05536
    7.2914 ± 0.06285
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - PaO2

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    End point title
    Indices of respiratory failure - PaO2 [3]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    19
    14
    Units: mmHg
        arithmetic mean (standard deviation)
    44.639 ± 14.0930
    49.560 ± 17.1049
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - PaCO2

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    End point title
    Indices of respiratory failure - PaCO2 [4]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    22
    17
    Units: mmHg
        arithmetic mean (standard deviation)
    47.911 ± 8.5708
    46.702 ± 11.1231
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - Blood base excess

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    End point title
    Indices of respiratory failure - Blood base excess [5]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    22
    17
    Units: mEg
        arithmetic mean (standard deviation)
    -4.463 ± 2.6424
    -4.021 ± 4.3291
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - FiO2

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    End point title
    Indices of respiratory failure - FiO2 [6]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    23
    19
    Units: percentage
        arithmetic mean (standard deviation)
    28.82 ± 7.585
    25.48 ± 5.657
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - SaO2

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    End point title
    Indices of respiratory failure - SaO2 [7]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    23
    19
    Units: percentage
        arithmetic mean (standard deviation)
    94.59 ± 1.812
    95.74 ± 2.359
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - Oxygenation index

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    End point title
    Indices of respiratory failure - Oxygenation index [8]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    18
    10
    Units: number
        arithmetic mean (standard deviation)
    3.6062 ± 1.50953
    2.9788 ± 1.94566
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - Ventilatory index

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    End point title
    Indices of respiratory failure - Ventilatory index [9]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    7
    3
    Units: number
        arithmetic mean (standard deviation)
    19.273 ± 16.8912
    19.939 ± 23.8648
    No statistical analyses for this end point

    Primary: Indices of respiratory failure - Aa oxygen gradient

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    End point title
    Indices of respiratory failure - Aa oxygen gradient [10]
    End point description
    Pre- versus post-extubation overall mean values for Supplemental Curosurf and No Supplemental Curosurf groups (Full Analysis Population) are reported.
    End point type
    Primary
    End point timeframe
    For the indices of respiratory failure, within-group differences between overall pre- and post-extubation mean values were compared using a paired t-test.
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No between-group statistical analysis was performed.
    End point values
    Supplemental Curosurf - Full Analysis Population No supplemental Curosurf - Full Analysis Population
    Number of subjects analysed
    19
    14
    Units: mmHg
        arithmetic mean (standard deviation)
    99.81 ± 66.905
    82.89 ± 42.539
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE were assessed: - 1-6 hours pre-extubation; - at 0 hour extubation; - 48 hours post-extubation (+/-15 min); - after 28 days +/- 1 day (follow-up); - after 36 weeks +/- 3 days (follow-up).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    8.1
    Reporting groups
    Reporting group title
    Supplemental Curosurf - Safety Population
    Reporting group description
    The safety population comprised all patients randomized into the study, in which each patient’s treatment was as taken on the study.

    Reporting group title
    No supplemental Curosurf - Safety population
    Reporting group description
    The safety population comprised all patients randomized into the study, in which each patient’s treatment was as taken on the study.

    Serious adverse events
    Supplemental Curosurf - Safety Population No supplemental Curosurf - Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 19 (5.26%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    Pyloric stenosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal perforation
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (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: 4.3%
    Non-serious adverse events
    Supplemental Curosurf - Safety Population No supplemental Curosurf - Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 23 (100.00%)
    17 / 19 (89.47%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Hypotension
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 19 (0.00%)
         occurrences all number
    6
    0
    Investigations
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Cardiac murmur
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Culture positive
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Echocardiogram abnormal
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Oxygen consumption increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 19 (15.79%)
         occurrences all number
    3
    7
    Platelet count increased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Protein C decreased
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    5
    Ventricular hypertrophy
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Patent ductus arteriosus
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 19 (0.00%)
         occurrences all number
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 23 (26.09%)
    6 / 19 (31.58%)
         occurrences all number
    6
    10
    Neutropenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Neutrophilia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    8 / 23 (34.78%)
    5 / 19 (26.32%)
         occurrences all number
    11
    7
    Bronchial dysplasia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Bronchopulmonary dysplasia
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Bronchospasm
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 19 (10.53%)
         occurrences all number
    5
    2
    Hypercapnia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Neonatal respiratory distress syndrome
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Respiratory disorder
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Nervous system disorders
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 19 (15.79%)
         occurrences all number
    3
    3
    Lenticular opacities
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Retinopathy of prematurity
         subjects affected / exposed
    8 / 23 (34.78%)
    6 / 19 (31.58%)
         occurrences all number
    8
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Enterocolitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastric disorder
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 19 (10.53%)
         occurrences all number
    2
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    0
    3
    Fluid retention
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    1 / 19 (5.26%)
         occurrences all number
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Hypochloraemia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    Hyponatraemia
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 19 (10.53%)
         occurrences all number
    3
    2
    Hypovitaminosis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Metabolic acidosis
         subjects affected / exposed
    4 / 23 (17.39%)
    5 / 19 (26.32%)
         occurrences all number
    4
    5
    Infections and infestations
    Enterobacter infection
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Enterococcal infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 19 (10.53%)
         occurrences all number
    2
    4
    Klebsiella infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Pseudomonas infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Sepsis
         subjects affected / exposed
    5 / 23 (21.74%)
    4 / 19 (21.05%)
         occurrences all number
    7
    5
    Staphylococcal infection
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2006
    The original protocol was dated 21 November 2005. There was one protocol amendment dated 14 February 2006. The amendment introduced the following changes to the study: · The planned start date of the study was delayed from January 2006 to March 2006. · The number of centers and investigators was increased from 16 to 19. · The secondary endpoint “Death before discharge” was changed to “Death before 36 weeks PCA” to ensure all patients would be followed until the same time point. · The procedure “physical examination” was removed from the protocol as study patients would not be undergoing “typical” physical examinations during the study. · To ensure more accurate terminology was used, the phrase “critical events” was replaced by “major clinical diagnoses” (MCDs) and these were defined. The event “asphyxia” was added to the list of MCDs. The sensitivity analysis was not performed. · To correct inconsistencies, the schedule of events was updated to reflect the frequency of procedures outlined in Section 7.5. · It was clarified that AEs would not be recorded as such if they occurred before randomization. · The protocol was updated to say that ventilator parameters would be monitored at the follow-up assessments. This was an error in the protocol; if ventilation was still required at follow-up, its parameters are of interest and must be recorded. · The procedures for reporting and recording AEs were updated to comply with the sponsor’s Standard Operating Procedures. · Other administrative changes (see protocol amendment included in Section 13.1.1). All modifications were considered to be medically and ethically relevant and the patients’ risk was not increased by the amendment.

    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.
    There are no limitations nor caveats applicable to this summary of results.
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