Introduction
Background and rationale
Study (Author/Year) | Gestational Age | Weight | Age at enrolment | Respiratory support method | Entry FiO2 requirement or RSS | Findings |
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Minocchieri [9] Level III neonatal unit in Australia, 2019 | 29–33 + 6 | 1560 g (mean) | < 4 h | Bubble CPAP | FiO2 0.22–0.30 | Early AS may reduce the need for intubation in the first 72 h of age for infants > 32 weeks |
Cummings [7] Level III/IV neonatal units in USA, 2019 | 23–41 | 590–4800 g | > 1–< 12 h | Several NIV types | Initially FiO2 0.25–0.40, then removed | AS reduced the need for intubation and intratracheal bolus surfactant by 50%, particularly in infants > 31 weeks |
Jardine [6] Level III neonatal units in Australia, 2021 | 26–30 + 6 | 1170 g (mean) | 15 min—≤ 2 h | nCPAP | Part 1&2: FiO2 < 0.30 Part 2 re-treat: RSS ≥ 2.0 | Non-significant trend toward reduced rates of CPAP failure and need for intratracheal bolus surfactant in AS group |
Dani [5] Level III neonatal units in Europe, 2022 | 28–32 | 1416 g (mean) | > 1–< 12 h | nCPAP | FiO2 0.25–0.40 | AS did not reduce the need for intratracheal bolus surfactant administration in the first 72 h of age compared with CPAP alone |
Aerogen Pharma Phase IIb Level III neonatal units in USA & Canada, 2020 | 26–31 + 6 | ≤ 2000 g | < 24 h | nCPAP or NIV | RSS 1.4–2.0 | Trial underway (clincaltrials.gov trial no: NCT03969992) |
Trial design
Objectives
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To compare the need for repeat intratracheal bolus surfactant dosing between groups
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To compare the need for mechanical ventilation between groups
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To compare the duration of mechanical ventilation, CPAP, high flow nasal cannula (HFNC) and supplementary oxygen between groups
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To compare the rate of adverse events and select comorbidities of prematurity between groups (see Appendix for definitions, included as Supplementary material)
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To compare the incidence of BPD between groups (see Appendix for definitions, included as Supplementary material)
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To compare the incidence of death at any time between groups
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To compare the incidence of death or BPD between groups
Methods
Participants, interventions, and outcomes
Study setting
Eligibility criteria
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Inborn
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Birth weight of 900–1999 g
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27–34 weeks gestational age
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2–24 h of age at time of randomisation
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Persistent fractional inspired oxygen (FiO2) of 0.25–0.35 on nCPAP at 5–7 cmH2O to maintain peripheral oxygen saturation of 90–95%. FiO2 requirement needs to be sustained for at least 15 min.
Note: A best estimate of the gestational age in weeks and days will be recorded for all enrolled infants using the following hierarchy:
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Administration of inotropes and/or intubation prior to enrolment in the delivery room or Neonatal Intensive Care Unit (NICU)
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5-min Apgar score ≤ 5
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Prior instillation of intratracheal bolus surfactant
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Pneumothorax that requires needle thoracentesis or insertion of an intercostal chest drain
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Life-threatening congenital anomaly
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Known or suspected chromosomal abnormality
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Known or suspected congenital infection
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Enrolment in another interventional study with competing outcomes
Interventions
Investigational product
Intervention group
Control group
Failure criteria
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A persistent FiO2 > 0.40 on nCPAP at 5–7cmH2O to maintain peripheral oxygen saturation of 90–95%. FiO2 requirement needs to be sustained for at least 15 min, and/or
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Severe apnoeas defined as two or more apnoeas per hour requiring bag-mask ventilation, or at the treating clinician’s discretion, and/or
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Severe increased work of breathing (at the treating clinician’s discretion) not responding to nCPAP optimization, repositioning of infant or suctioning of secretions.
Concomitant therapy
Outcomes
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Proportion of infants meeting failure criteria in the first 72 h of age in each group
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Proportion of infants receiving multiple doses of intratracheal bolus surfactant in each group
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Number of hours on mechanical ventilation during hospital stay between groups
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Number of days on CPAP and/or HFNC, and supplementary oxygen during hospital stay between groups
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Incidence of adverse events and select comorbidities of prematurity between groups (see Appendix for definitions)
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Incidence of BPD in survivors at 36 weeks’ postmenstrual age between groups (see Appendix for definitions)
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Incidence of BPD or death at 36 weeks’ postmenstrual age between groups
Participant timeline
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Date, time, and age of administration
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Surfactant type, dosing details and method by which it was given (LISA, INSURE, etc.), and
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Respiratory status, including FiO2, oxygen saturation and type of respiratory support, at the time of administration
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Need for oral/nasal suctioning
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Respiratory status including type and level of support, FiO2 requirement and peripheral oxygen saturation
Sample size
Recruitment
Assignment of interventions
Allocation
Blinding
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Objective failure criteria to be eligible for intratracheal bolus surfactant, based on FiO2 requirements. These are collected as a secondary endpoint.
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Consistent policies for use of caffeine between groups at all sites
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Consistent peripheral oxygen saturation targets which drive duration of supplemental oxygen use between groups at all sites
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Consistent criteria for diagnosis of BPD at all sites