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    Clinical Trial Results:
    PROPHYLACTIC OROPHARYNGEAL SURFACTANT FOR PRETERM INFANTS: A RANDOMISED TRIAL (THE POPART TRIAL)

    Summary
    EudraCT number
    		 2016-004198-41
    Trial protocol
    		 IE   BE   SE   CZ   PT   NO  
    Global end of trial date
    18 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2022
    First version publication date
    28 Dec 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UCDCRC/16/003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University College Dublin
    Sponsor organisation address
    Nelson Street, Dublin, Ireland, Dublin 7
    Public contact
    Quality & Regulatory Affairs, University College Dublin, 00353 17164593, rabia.hussain@ucd.ie
    Scientific contact
    Quality & Regulatory Affairs, University College Dublin, 00353 17164593, rabia.hussain@ucd.ie
    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
    27 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Our primary objective is to investigate the efficacy of prophylactic oropharyngeal surfactant for reducing the rate of endotracheal intubation, compared to no intervention in infants at risk of RDS.
    Protection of trial subjects
    Ethics approval was obtained prior to commencement of the trial. Ethical approval was obtained from each participating site before site initiation.This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki,in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation (ICH) and in accordance with the ethical principles underlying European Union Directive 2001/20/EC and 2005/28/EC. Written consent for enrolment of the infant in the study was obtained, where applicable, by both parents/guardians prior to any study-related activities, or as per local requirements and as approved by the ethics committee for the site.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 39
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    Ireland: 180
    Worldwide total number of subjects
    252
    EEA total number of subjects
    252
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    252
    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
    		 Names of potential participants’ parents(s)/guardians(s) were obtained from the obstetric team, antenatal wards and clinics. They were approached by a member of the research team or other senior doctor (neonatal consultant or registrar) to inform them of the study.

    Pre-assignment
    Screening details
    		 During the screening period subjects were evaluated for eligibility. Once informed consent was obtained, where preterm delivery prior to 29 weeks gestation ensued, subjects were randomised at the time of delivery.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oropharyngeal Surfactant
    Arm description
    		 Note that originally 127 subjects were allocated to this arm. However, one infant was discontinued early due to meeting exclusion criteria (major congenital anomaly). This infant is excluded from the full analysis set and hence is not included in summary of baseline characteristics or efficacy analysis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CUROSURF (poractant alfa)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Oropharyngeal use
    Dosage and administration details
    Surfactant (Curosurf, Chiesi Farmeceutici, Parma, Italy) is a white suspension. Each mL of suspension contains 80mg poractant alfa (surfactant extract) that includes 76mg of phospholipids and 1mg of protein of which 0.45mg is SP-B and 0.59mg is SP-C. There are two vials of Curosurf: 1.5ml vial (contains 120mg poracant alfa) or 3ml vial (240mg poractant alfa). The 120mg vial was be given to infants <26weeks gestation and a full 240mg vial to infants 26-28 weeks gestation. The surfactant will be warmed by the clinicians prior to being drawn up in a sterile syringe as per manufacturer’s recommendation. This will be done by opening the mouth gently and injecting the surfactant as a single bolus into the oropharynx using a syringe without a needle attached. This will be done as soon as possible after delivery, ideally before the umbilical cord has been clamped.

    Arm title
    		 No Intervention
    Arm description
    		 Infants randomised to the control group will not have anything injected into their oropharynx and will be stabilised on CPAP in the delivery room (DR) as per routine practice.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Oropharyngeal Surfactant No Intervention
    Started
    126
    125
    Completed
    126
    125
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject was enrolled without meeting eligibility criteria and was withdrawn from the trial before any follow up data were collected. This subject is omitted from all statistical analysis, except for safety data analysis.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oropharyngeal Surfactant
    Reporting group description
    		 Note that originally 127 subjects were allocated to this arm. However, one infant was discontinued early due to meeting exclusion criteria (major congenital anomaly). This infant is excluded from the full analysis set and hence is not included in summary of baseline characteristics or efficacy analysis.

    Reporting group title
    No Intervention
    Reporting group description
    		 Infants randomised to the control group will not have anything injected into their oropharynx and will be stabilised on CPAP in the delivery room (DR) as per routine practice.

    Reporting group values
    		 Oropharyngeal Surfactant No Intervention Total
    Number of subjects
    		 126 125 251
    Age categorical
    Best Estimate of Gestational Age (completed weeks). All estimates were determined by early dating ultrasound (<20 weeks), with the exception of two infants in the No Intervention arm whose Gestational Age was recorded as the best clinical estimate
    Units: Subjects
        <26 weeks
    		 48 44 92
        26-28 weeks
    		 78 81 159
    Age continuous
    Reported for the Full Analysis Set
    Units: weeks
        median (inter-quartile range (Q1-Q3))
    		 26 (25 to 27) 26 (25 to 27) -
    Gender categorical
    Full analysis set.
    Units: Subjects
        Female
    		 57 62 119
        Male
    		 69 63 132
    Maternal ethnicity
    Units: Subjects
        Caucasian
    		 110 112 222
        Asian
    		 9 5 14
        African
    		 6 6 12
        Other
    		 1 2 3
    Administration of antenatal steroids
    Units: Subjects
        Yes
    		 126 125 251
        No
    		 0 0 0
    Spontaneous labour
    Units: Subjects
        Yes
    		 62 61 123
        No
    		 64 64 128
    Evidence of preterm premature rupture of membrane?
    Units: Subjects
        Yes
    		 55 51 106
        No
    		 71 74 145
    Mode of delivery
    Units: Subjects
        Vaginal vertex
    		 35 32 67
        Vaginal breach
    		 7 13 20
        Forceps
    		 0 2 2
        Vacuum
    		 0 0 0
        Caesarean section in labour
    		 22 15 37
        Caesarean section not in labour
    		 62 63 125
    Administration of regional anaesthesia (e.g. spinal, epidural)
    In women undergoing caesarean delivery
    Units: Subjects
        Yes
    		 70 70 140
        No
    		 13 8 21
        Missing
    		 1 0 1
        N/A
    		 42 47 89
    General Anaesthesia
    In women undergoing caesarean section
    Units: Subjects
        Yes
    		 16 8 24
        No
    		 67 66 133
        Missing
    		 1 4 5
        N/A
    		 42 47 89
    Birth multiplicity
    Units: Subjects
        One
    		 82 80 162
        Two
    		 34 36 70
        Three
    		 10 9 19
    Maternal age
    Units: Years
        arithmetic mean (standard deviation)
    		 32.9 ( 5.5 ) 32 ( 5.3 ) -
    Total number of doses of antenatal corticosteroids
    Maternal baseline characteristic
    Units: Number of doses
        median (inter-quartile range (Q1-Q3))
    		 2 (2 to 2) 2 (2 to 2) -
    Duration of premature membrane rupture
    This is reported only for the 106 mothers with evidence of PROM (55 in the Oropharyngeal Surfactant arm and 51 in the No Intervention arm)
    Units: Hours before birth
        median (inter-quartile range (Q1-Q3))
    		 123 (48.5 to 411.5) 62 (25 to 173) -
    Birth weight
    Units: grams
        median (inter-quartile range (Q1-Q3))
    		 857.5 (671.2 to 1035) 829 (640 to 1025) -
    Apgar score (1 min)
    6 infants in the Oropharyngeal Surfactant arm and 4 in the No Intervention arm were missing data Apgar score at 1 minute post birth.
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 6 (4 to 7) 5 (4 to 7) -
    Apgar score (5 min)
    6 infants in the Oropharyngeal Surfactant arm and 4 in the No Intervention arm were missing data Apgar score at 5 minutes post birth.
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 8 (7 to 9) 8 (6 to 9) -
    Apgar score (10 min)
    56 infants in the Oropharyngeal Surfactant arm and 51 in the No Intervention arm were missing data Apgar score at 10 minutes post birth.
    Units: Points
        median (inter-quartile range (Q1-Q3))
    		 8 (8 to 9) 8 (7 to 9) -

    End points

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    End points reporting groups
    Reporting group title
    Oropharyngeal Surfactant
    Reporting group description
    		 Note that originally 127 subjects were allocated to this arm. However, one infant was discontinued early due to meeting exclusion criteria (major congenital anomaly). This infant is excluded from the full analysis set and hence is not included in summary of baseline characteristics or efficacy analysis.

    Reporting group title
    No Intervention
    Reporting group description
    		 Infants randomised to the control group will not have anything injected into their oropharynx and will be stabilised on CPAP in the delivery room (DR) as per routine practice.

    Primary: Intubation for respiratory failure

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    End point title
    		 Intubation for respiratory failure
    End point description
    The primary endpoint is endotracheal intubation for respiratory failure within 120 hours of birth. Enrolled infants were intubated for persistent apnoea and/or bradycardia in the DR, or for respiratory failure in the NICU defined as ≥ 2 of: • Clinical signs – worsening tachypnoea; grunting; subcostal, intercostal and/or sternal recession • Acidosis – pH < 7.2 on 2 blood gases (arterial or capillary) ≥ 30 minutes apart • O2 –FiO2 >0.4 to keep SpO2 ≥90% for >30 minutes • PCO2 > 9.0 kPa on 2 blood gases (arterial or capillary) ≥ 30 minutes apart • Apnoea – recurrent apnoea treated with mask ventilation The frequency of blood gas monitoring is based on the clinical decision of the treating physician, as per routine practice.
    End point type
    Primary
    End point timeframe
    120 hours of life
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    80
    81
        No
    46
    44
    Statistical analysis title
    		 Primary analysis of the primary endpoint
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9327
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9798
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8124
         upper limit
    		 1.1811
    Statistical analysis title
    		 Sensitivity analysis adjusting for covariates
    Statistical analysis description
    A generalized estimating equation (GEE) model was fitted to the primary endpoint, intubation for respiratory failure within 120 hours of birth, to estimate the effect of treatment on this endpoint while adjusting for relevant covariates, including gestational age category, center, gender, doses of antenatal steroids, mode of delivery and birth weight. Within center correlation was allowed for using an exchangable correlation structure. The model was fit with a logit link.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78614
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.651
         upper limit
    		 1.476
    Statistical analysis title
    		 Sensitivity analysis - protocol criteria
    Statistical analysis description
    This sensitivity analysis assumes that infants who were intubated without strictly meeting the protocol defined criteria would not have met the primary endpoint (11 in the intervention arm and 9 in the control arm). In the intervention arm, 69 (54.8%) of subjects were intubated after meeting the protocol-defined criteria for respiratory depression within 120 hours of life, compared with 72 (57.6%) of the control arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7445
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9507
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7623
         upper limit
    		 1.1841
    Statistical analysis title
    		 Sensitivity analysis - Per protocol analysis
    Statistical analysis description
    Per protocol analysis of the primary endpoint excludes two subjects who were included in the intention-to-treat set but who did not meet trial eligibility criteria - both were allocated to the standard-of-care (control) arm. Therefore 249 subjects were included in this analysis.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.933
    Method
    		 Z test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9885
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.19
    Statistical analysis title
    		 Sensitivity analysis - competing risks
    Statistical analysis description
    This sensitivity analysis accounts for competing risks in estimation of treatment effect on the primary endpoint. To evaluate sensitivity of results to the reason for intubation (meeting pre- defined criteria or not), a competing risks analysis was carried out using the cmprsk package in R.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.378 [1]
    Method
    		 Grey's test (Chi Square)
    Confidence interval
    Notes
    [1] - Grey's test for between-group difference in CIF functions (for event of intubation meeting protocol-defined criteria for primary endpoint), in the presence of the competing risk of intubation before meeting protocol-defined criteria
    Statistical analysis title
    		 Subgroup analysis - gestational age <26w
    Statistical analysis description
    Relative risk of the primary endpoint for gestational age <26 weeks for oropharyngeal surfactant vs standard-of-care (CPAP). In this age category there were 48 subjects in the oropharyngeal surfactant (intervention) arm 44 subjects in the standard-of-care (control) arm.
    Comparison groups
    No Intervention v Oropharyngeal Surfactant
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0748
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.888
         upper limit
    		 1.2986
    Statistical analysis title
    		 Subgroup analysis - gestational age 26-28w
    Statistical analysis description
    Relative risk of the primary endpoint for gestational age 26-28 weeks for oropharyngeal surfactant vs standard-of-care (CPAP). In this age category there were 78 subjects in the oropharyngeal surfactant (intervention) arm of whom 50% met the primary endpoint and 81 subjects in the standard-of-care (control) arm of whom 56.8% met the primary endpoint.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.657
         upper limit
    		 1.179
    Statistical analysis title
    		 Subgroup analysis - center- NMH, Dublin
    Statistical analysis description
    Relative risk of the primary endpoint for subjects enrolled at NMH, Dublin for oropharyngeal surfactant vs standard-of-care (CPAP). In this center there were 65 subjects in the oropharyngeal surfactant (intervention) arm and 66 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.704
         upper limit
    		 1.31
    Statistical analysis title
    		 Subgroup analysis - center - Coombe, Dublin
    Statistical analysis description
    Relative risk of the primary endpoint for subjects enrolled at Coombe, Dublin for oropharyngeal surfactant vs standard-of-care (CPAP). In this center there were 23 subjects in the oropharyngeal surfactant (intervention) arm and 25 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.815
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.165
    Statistical analysis title
    		 Subgroup analysis - Norwegian centers
    Statistical analysis description
    Relative risk of the primary endpoint for subjects enrolled in the two Norwegian centers for oropharyngeal surfactant vs standard-of-care (CPAP). In this centre there were 21 subjects in the oropharyngeal surfactant (intervention) arm and 18 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.286
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.888
         upper limit
    		 1.862
    Statistical analysis title
    		 Subgroup analysis - Other centres
    Statistical analysis description
    Relative risk of the primary endpoint for subjects enrolled in Other centers (centers not including Ireland or Norway) for oropharyngeal surfactant vs standard-of-care (CPAP). In these centers there were 17 subjects in the oropharyngeal surfactant (intervention) arm and 16 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.941
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.429

    Secondary: Death before hospital discharge

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    End point title
    		 Death before hospital discharge
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    23
    22
        No
    103
    103
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0372
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6142
         upper limit
    		 1.7528
    Statistical analysis title
    		 Cox proportional hazard regression model
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.7
    Statistical analysis title
    		 Subgroup analysis - <26 weeks gestational age
    Statistical analysis description
    Relative risk of death before hospital discharge for gestational age <26 weeks for oropharyngeal surfactant vs standard-of-care (CPAP). In this age category there were 48 subjects in the oropharyngeal surfactant (intervention) arm 44 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.974
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.564
         upper limit
    		 1.682
    Statistical analysis title
    		 Subgroup analysis - gestational age 26-28w
    Statistical analysis description
    Relative risk of death before hospital discharge for gestational age 26-28 weeks for oropharyngeal surfactant vs standard-of-care (CPAP). In this age category there were 78 subjects in the oropharyngeal surfactant (intervention) arm of whom 50% met the primary endpoint and 81 subjects in the standard-of-care (control) arm of whom 56.8% met the primary endpoint.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3498
         upper limit
    		 3.083
    Statistical analysis title
    		 Subgroup analysis - center- NMH, Dublin
    Statistical analysis description
    Relative risk of death before hospital discharge for subjects enrolled at NMH, Dublin for oropharyngeal surfactant vs standard-of-care (CPAP). In this center there were 65 subjects in the oropharyngeal surfactant (intervention) arm and 66 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.624
         upper limit
    		 2.794
    Statistical analysis title
    		 Subgroup analysis - centre - Coombe, Dublin
    Statistical analysis description
    Relative risk of death before hospital discharge for subjects enrolled at Coombe, Dublin for oropharyngeal surfactant vs standard-of-care (CPAP). In this center there were 23 subjects in the oropharyngeal surfactant (intervention) arm and 25 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.725
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.234
         upper limit
    		 2.246
    Statistical analysis title
    		 Subgroup analysis - Norwegian centers
    Statistical analysis description
    Relative risk of death before hospital discharge for subjects enrolled in the two Norwegian centers for oropharyngeal surfactant vs standard-of-care (CPAP). In this centre there were 21 subjects in the oropharyngeal surfactant (intervention) arm and 18 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.143
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.471
         upper limit
    		 9.741
    Statistical analysis title
    		 Subgroup analysis - Other centres
    Statistical analysis description
    Relative risk of death before hospital discharge for subjects enrolled in Other centers (centers not including Ireland or Norway) for oropharyngeal surfactant vs standard-of-care (CPAP). In these centers there were 17 subjects in the oropharyngeal surfactant (intervention) arm and 16 subjects in the standard-of-care (control) arm.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.235
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.029
         upper limit
    		 1.888

    Secondary: Intubation in the delivery room

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    End point title
    		 Intubation in the delivery room
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery room discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    28
    38
        No
    98
    87
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1841
    Method
    		 Two-sample Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.731
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4796
         upper limit
    		 1.1079

    Secondary: Number of attempts to successfully intubate in the delivery room

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    End point title
    		 Number of attempts to successfully intubate in the delivery room
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery room discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    1.0 (1.0 to 2.0)
    1.0 (1.0 to 2.0)
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Analysed for infants intubated in the delivery room only (28 in the intervention arm and 38 in the control arm). There was one missing data value in the control arm and complete case analysis was performed.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3959
    Method
    		 Mann-Whitney U
    Parameter type
    		 Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7613
         upper limit
    		 1.2429
    Statistical analysis title
    		 Best-worst case sensitivity analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.303
    Method
    		 Two-sided Z-test
    Parameter type
    		 Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.674
         upper limit
    		 1.2982
    Notes
    [2] - Best-worst case analysis
    Statistical analysis title
    		 Worst-best case sensitivity analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4472
    Method
    		 Two-sided Z-test
    Parameter type
    		 Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.718
         upper limit
    		 1.1116

    Secondary: Chest compressions in the delivery room

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    End point title
    		 Chest compressions in the delivery room
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery room discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    5
    3
        No
    121
    122
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7279
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.6534
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4459
         upper limit
    		 6.1636

    Secondary: Adrenaline administration in the delivery room

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    End point title
    		 Adrenaline administration in the delivery room
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to delivery room discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    1
    0
        No
    125
    125
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Confidence interval

    Secondary: Rectal temperature on admission to the NICU

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    End point title
    		 Rectal temperature on admission to the NICU
    End point description
    Analysed for rectal temperature on admission to NICU only with 67 in the intervention arm and 61 in the control arm. There were 59 missing data values in the intervention arm and 61 missing data value in the control arm.
    End point type
    Secondary
    End point timeframe
    Admission to NICU
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    36.3 (35.9 to 36.7)
    36.5 (35.9 to 36.9)
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Frequence of missing data for this variable was greater than 40% and hence, in accordance with the statistical analysis plan, only complete case analysis is performed. Results should be interpreted with caution.
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1022
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (net)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.552
         upper limit
    		 0.09

    Secondary: NICU intubation-first intubation occurring in the NICU

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    End point title
    		 NICU intubation-first intubation occurring in the NICU
    End point description
    End point type
    Secondary
    End point timeframe
    120 hours of life
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    55
    49
        No
    71
    76
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5568
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1135
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8299
         upper limit
    		 1.4983

    Secondary: Intra-tracheal surfactant received post-intervention

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    End point title
    		 Intra-tracheal surfactant received post-intervention
    End point description
    End point type
    Secondary
    End point timeframe
    Post intervention to death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    75
    78
        No
    51
    47
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7357
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9539
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7804
         upper limit
    		 1.1643

    Secondary: Number of doses of post-intervention surfactant

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    End point title
    		 Number of doses of post-intervention surfactant
    End point description
    Analysed for infants who received post-intervention intra-tracheal surfactant before death or hospital discharge only (75 in the intervention arm and 78 in the control arm).
    End point type
    Secondary
    End point timeframe
    Post intervention to death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    2.0 (1.0 to 2.0)
    1.0 (1.0 to 2.0)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1902
    Method
    		 Two-sided Z-test
    Parameter type
    		 Median difference (net)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4446
         upper limit
    		 2.5726

    Secondary: Respiratory distress syndrome

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    End point title
    		 Respiratory distress syndrome
    End point description
    Clinical evidence of respiratory distress with radiological evidence (ground glass appearance on CXR)
    End point type
    Secondary
    End point timeframe
    Randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    54
    53
        No
    72
    72
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0108
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7583
         upper limit
    		 1.3479

    Secondary: Incidence of pneumothorax

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    End point title
    		 Incidence of pneumothorax
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    21
    8
        No
    105
    117
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0189
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    2.6042
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2299
         upper limit
    		 5.5874

    Secondary: Incidence of pulmonary haemorrhage

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    End point title
    		 Incidence of pulmonary haemorrhage
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    6
    5
        No
    120
    120
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1905
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3951
         upper limit
    		 3.5948

    Secondary: Mechanical ventilation

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    End point title
    		 Mechanical ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    78
    84
        No
    48
    41
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4563
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9212
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7638
         upper limit
    		 1.1077

    Secondary: Days of mechanical ventilation

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    End point title
    		 Days of mechanical ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    1.0 (0.0 to 7.0)
    2.0 (0.0 to 7.0)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4678
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7173
         upper limit
    		 -0.0576

    Secondary: Use of postnatal corticosteroids for ventilator dependence

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    End point title
    		 Use of postnatal corticosteroids for ventilator dependence
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    29
    30
        No
    97
    95
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9721
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.959
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6152
         upper limit
    		 1.4942

    Secondary: Days of duration of respiratory support

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    End point title
    		 Days of duration of respiratory support
    End point description
    There was no missing data value in the intervention arm and 1 missing value in the control arm. Primary analysis was by complete case analysis with sensitivity analysis with imputation of missing data
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    53 (27.2 to 73.0)
    50 (25.5 to 70.2)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8274
    Method
    		 Two-sided Z-test
    Parameter type
    		 Median difference (net)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4718
         upper limit
    		 14.7284
    Statistical analysis title
    		 Best-worst case sensitivity analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7444
    Method
    		 Two-sided Z-test
    Parameter type
    		 Median difference (net)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3298
         upper limit
    		 15.1468
    Statistical analysis title
    		 Worst-best case sensitivity analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.914
    Method
    		 Two-sided Z-test
    Parameter type
    		 Median difference (net)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.7387
         upper limit
    		 14.5366

    Secondary: Bronchopulmonary dysplasia-supplemental O2 at 28 days of life

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    End point title
    		 Bronchopulmonary dysplasia-supplemental O2 at 28 days of life
    End point description
    Analysed for infants who were alive at 28 days of life only (105 in the intervention arm and 107 in the control arm). There were two missing data values in the intervention arm and one missing data value control arm. Primary analysis was by complete case analysis, with sensitivity analysis with missing data imputation
    End point type
    Secondary
    End point timeframe
    At 28 days of life
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    107
    108
    Units: Subjects
        Yes
    73
    74
        No
    32
    33
        Missing
    2
    1
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Complete case analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8376
         upper limit
    		 1.206
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9634
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9824
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8176
         upper limit
    		 1.179
    Statistical analysis title
    		 Worse-best case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9184
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.023
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8539
         upper limit
    		 1.2266

    Secondary: Chronic lung disease of prematurity-supplemental O2 at 36 week

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    End point title
    		 Chronic lung disease of prematurity-supplemental O2 at 36 week
    End point description
    Analysed for infants who were alive at 36 weeks of life only (103 in the intervention arm and 102 in the control arm). There were no missing data values in the intervention arm and one missing data value control arm. Primary analysis was by complete case analysis with sensitivity analysis with imputation of missing data
    End point type
    Secondary
    End point timeframe
    36 weeks of life
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    103
    103
    Units: Subjects
        Yes
    28
    30
        No
    75
    72
        Missing
    0
    1
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Complete case analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8423
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9243
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5982
         upper limit
    		 1.4258
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7579
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5868
         upper limit
    		 1.3869
    Statistical analysis title
    		 Worse-best case analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8769
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9333
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6038
         upper limit
    		 1.4403

    Secondary: Medical treatment for patent ductus arteriosus

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    End point title
    		 Medical treatment for patent ductus arteriosus
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    27
    37
        No
    99
    88
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1801
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.7239
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4707
         upper limit
    		 1.107

    Secondary: Surgical treatment for patent ductus arteriosus

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    End point title
    		 Surgical treatment for patent ductus arteriosus
    End point description
    There were two missing data points per arm. Primary analysis is by complete case analysis, with best-worst case and worst-best case imputation for sensitivity analysis.
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    2
    2
        No
    122
    121
        Missing
    2
    2
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9919
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1771
         upper limit
    		 5.5562
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6722
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.496
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1075
         upper limit
    		 2.2747
    Statistical analysis title
    		 Worse-best case analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6867
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.9841
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4327
         upper limit
    		 9.1559

    Secondary: Proven necrotising enterocolitis

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    End point title
    		 Proven necrotising enterocolitis
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    10
    15
        No
    116
    110
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    No Intervention v Oropharyngeal Surfactant
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3875
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.6614
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3134
         upper limit
    		 1.3878

    Secondary: Incidence of intraventricular haemorrhage

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    End point title
    		 Incidence of intraventricular haemorrhage
    End point description
    There were five missing data values in the intervention arm and one missing data value control arm. Primary analysis was by complete case analysis with best-worst case and worst-best case imputation for sensitivity analysis.
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    16
    18
        No
    105
    106
        Missing
    5
    1
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Complete case analysis
    Comparison groups
    No Intervention v Oropharyngeal Surfactant
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9141
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9109
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4915
         upper limit
    		 1.6848
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6967
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.8354
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.454
         upper limit
    		 1.5333
    Statistical analysis title
    		 Worse-best case analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7479
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.1574
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6542
         upper limit
    		 2.0528

    Secondary: Incidence of severe intraventricular haemorrhage

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    End point title
    		 Incidence of severe intraventricular haemorrhage
    End point description
    There were five missing data values in the intervention arm and one missing data value control arm. Primary analysis was by complete case analysis with best-worst case and worst-best case imputation for sensitivity analysis.
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    7
    9
        No
    114
    115
        Missing
    5
    1
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Complete case analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8353
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.7971
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3162
         upper limit
    		 2.0018
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6035
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.6944
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.249
         upper limit
    		 1.9259
    Statistical analysis title
    		 Worst-best case analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6622
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.3228
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5917
         upper limit
    		 2.9687

    Secondary: Incidence of cystic periventricular leukomalacia

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    End point title
    		 Incidence of cystic periventricular leukomalacia
    End point description
    There were five missing data values in the intervention arm and one missing data value control arm. Primary analysis was by complete case analysis with best-worst case and worst-best case imputation for sensitivity analysis.
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    4
    5
        No
    117
    119
        Missing
    5
    1
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Complete case analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.8198
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.243
         upper limit
    		 2.7587
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7372
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.6614
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2043
         upper limit
    		 2.1313
    Statistical analysis title
    		 Worst-best case analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4181
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.7857
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6463
         upper limit
    		 4.9691

    Secondary: Retinopathy of prematurity treated with laser photocoagulation

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    End point title
    		 Retinopathy of prematurity treated with laser photocoagulation
    End point description
    There were 24 missing data values in the intervention arm and 23 missing data value in the control arm. Primary analysis used multiple imputation by chained equations to impute missing data.
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    14
    10
        No
    88
    92
        Missing
    24
    23
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Multiple imputation for this endpoint using Gestational age, Treatment group allocation, Birth weight, and Use of postnatal steroids, carried out using the mice package in R. Results shown are pooled results from logistic regression
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4642
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.605
         upper limit
    		 3.012

    Secondary: Survival without BPD at hospital discharge

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    End point title
    		 Survival without BPD at hospital discharge
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    31
    30
        No
    95
    95
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.0251
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6642
         upper limit
    		 1.5832

    Secondary: Survival without CLD at hospital discharge

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    End point title
    		 Survival without CLD at hospital discharge
    End point description
    There was one missing data value in the control arm and complete case analysis was performed.
    End point type
    Secondary
    End point timeframe
    From randomisation to hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    71
    72
        No
    55
    52
        Missing
    0
    1
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Complete case analysis
    Comparison groups
    No Intervention v Oropharyngeal Surfactant
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8838
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9705
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7816
         upper limit
    		 1.2043
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8408
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9649
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7778
         upper limit
    		 1.1958
    Statistical analysis title
    		 Worst-best case analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9421
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9783
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7875
         upper limit
    		 1.2147

    Secondary: Duration of hospitalisation

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    End point title
    		 Duration of hospitalisation
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation until death or hospital discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        median (inter-quartile range (Q1-Q3))
    74 (53.5 to 92.8)
    76 (53.0 to 89.0)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.865
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2209
         upper limit
    		 3.6004

    Secondary: Use of home oxygen therapy

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    End point title
    		 Use of home oxygen therapy
    End point description
    There were three missing data value in the control arm and complete case analysis was performed for the primary analysis. Sensitivity analysis carried out imputation of missing data.
    End point type
    Secondary
    End point timeframe
    Discharged home on oxygen therapy, measured at discharge
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: Subjects
        Yes
    5
    10
        No
    21
    112
        Missing
    0
    3
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    Complete case analysis
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2584
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.4841
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1771
         upper limit
    		 1.3126
    Statistical analysis title
    		 Best-worst case analysis
    Statistical analysis description
    Best-worst case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0836
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.3816
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1449
         upper limit
    		 0.9934
    Statistical analysis title
    		 Worst-best case analysis
    Statistical analysis description
    Worst-best case imputation of missing data
    Comparison groups
    Oropharyngeal Surfactant v No Intervention
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2797
    Method
    		 Two-sided Z-test
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.496
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1814
         upper limit
    		 1.3451

    Secondary: Total dose of surfactant administered

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    End point title
    		 Total dose of surfactant administered
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to death or hospital discharge.
    End point values
    		 Oropharyngeal Surfactant No Intervention
    Number of subjects analysed
    126
    125
    Units: mg
        median (inter-quartile range (Q1-Q3))
    240 (240 to 433.1)
    120 (0 to 492)
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    No Intervention v Oropharyngeal Surfactant
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (net)
    Point estimate
    120
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 84
         upper limit
    		 240

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were recorded from randomisation to end of study (discontinuation, completion or death) for each subject.
    Adverse event reporting additional description
    Only AEs which were not directly associated with the underlying condition of extreme prematurity were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1-22
    Reporting groups
    Reporting group title
    Oropharyngeal Surfactant
    Reporting group description
    		 Note that one infant who was randomised into this arm was discontinued early due to meeting exclusion criteria (major congenital anomaly). This infant is excluded from the full analysis set

    Reporting group title
    No Intervention
    Reporting group description
    		 Infants randomised to the control group will not have anything injected into their oropharynx and will be stabilised on CPAP in the delivery room (DR) as per routine practice.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: The number of non-serious adverse events recorded was low (24 in total, 13 in the intervention arm and 11 in the control arm). None of these occurred with more than 5% frequency per treatment arm and so are not reported here. The most frequently occurring was sepsis, occurring in 4 cases (2 in each treatment arm).
    Serious adverse events
    		 Oropharyngeal Surfactant No Intervention
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 127 (19.69%)
    23 / 125 (18.40%)
         number of deaths (all causes)
    23
    22
         number of deaths resulting from adverse events
    22
    22
    Congenital, familial and genetic disorders
    Pulmonary hypoplasia
    Additional description: 10037407 Pulmonary hypoplasia (Preferred term)
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest neonatal
    Additional description: 10007618 Cardio-respiratory arrest neonatal
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary valve stenosis
    Additional description: 10037450 Pulmonary valve stenosis (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
    Additional description: 10008111 Cerebral haemorrhage (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage intracranial
    Additional description: 10018985 Haemorrhage intracranial (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Periventricular leukomalacia
    Additional description: 10052594 Periventricular leukomalacia (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
    Additional description: 10070511 Hypoxic-ischaemic encephalopathy (Preferred Term)
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pregnancy, puerperium and perinatal conditions
    Premature baby
    Additional description: 10036590 Premature baby (Preferred Term)
         subjects affected / exposed
    4 / 127 (3.15%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 4
    0 / 1
    General disorders and administration site conditions
    Death
    Additional description: 10011906 Death (Preferred Term)
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Neonatal multi-organ failure
    Additional description: 10050401 Neonatal multi-organ failure (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Eye disorders
    Retinopathy
    Additional description: 10038923 Retinopathy (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Necrotising colitis
    Additional description: 10051606 Necrotising colitis (Preferred term)
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Necrotising enterocolitis neonatal
    Additional description: 10055667 Necrotising enterocolitis neonatal (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neonatal intestinal perforation
    Additional description: 10074160 Neonatal intestinal perforation (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary dysplasia
    Additional description: 10006475 Bronchopulmonary dysplasia (Preferred Term)
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neonatal respiratory distress syndrome
    Additional description: 10028974 Neonatal respiratory distress syndrome (Preferred Term)
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary haemorrhage
    Additional description: 10037394 Pulmonary haemorrhage (Preferred Term)
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
    Additional description: 10038695 Respiratory failure (Preferred Term)
         subjects affected / exposed
    6 / 127 (4.72%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    Pulmonary haemorrhage neonatal
    Additional description: 10082194 Pulmonary haemorrhage neonatal (Preferred Term)
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Pneumonia escherichia
    Additional description: 10035699 Pneumonia escherichia (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis neonatal
    Additional description: 10040049 Sepsis neonatal (Preferred Term)
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    Candida sepsis
    Additional description: 10053166 Candida sepsis (Preferred Term)
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bacterial sepsis
    Additional description: 10053840 Bacterial sepsis (Preferred Term)
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oropharyngeal Surfactant No Intervention
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 127 (0.00%)
    0 / 125 (0.00%)

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

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

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