Outcome after Selective Early Closure of Ductus Arteriosus in Extremely Preterm Babies (Baby-OSCAR trial)

• Trial design: Multicentre, masked, randomised, placebo-controlled parallel group trial to determine if the treatment of a large PDA with ibuprofen in extremely preterm babies (23+0 to 28+6 weeks of gestation) improves short and long term health and economic outcomes. • Participants: Babies will be considered eligible for inclusion into the trial if they are: (a) Born at 23+0 to 28+6 weeks of gestation; (b) Less than 72 hours old; (c) Confirmed by echocardiography as having a large PDA which: (i) Is at least 1.5 mm in diameter (determined by gain optimised colour Doppler) AND (ii) Has unrestrictive pulsatile left to right flow (Ratio of flow velocity in PDA Maximum (Vmax) to Minimum (Vmin) > 2:1) In addition: (d) The responsible clinician is uncertain about whether this baby might benefit from treatment to close the PDA (e) Written informed consent has been obtained from the parent(s). Exclusion criteria: Babies will be excluded from participation in the trial if they have: (a) No realistic prospect of survival; (b) Severe congenital anomaly; (c) Structural heart disease requiring treatment; (d) Other conditions that would contraindicate the use of ibuprofen (clinically significantly intracranial or gastrointestinal haemorrhage, coagulopathy, thrombocytopenia (platelet count <50,000), renal failure, pulmonary hypertension, known or suspected necrotising enterocolitis); (e) Antenatal exposure to cyclo-oxygenase inhibitors; (f) Indomethacin, ibuprofen, paracetamol administration after birth. • Setting: The trial will be conducted in 25 level 3 tertiary neonatal units across the UK (4 units will be involved in the internal pilot phase). Only units that are in equipoise in the way that they manage PDA and are able and agree to perform echocardiograms within 72 hours of birth to confirm the presence of a large PDA and are part of a Local Clinical Research Network (LCRN) will be selected. • Randomisation: Treatment allocation of ibuprofen to placebo will be in a ratio of 1:1 and masked such that the allocation will not be known by clinicians, the baby’s family or the trial outcome assessors. Randomisation will be managed via a secure web-based randomisation facility hosted by the NPEU CTU with telephone back-up available at all times (24/7, 365 days a year). In order to randomise an eligible baby into the trial, details of the baby’s gestational age, time of birth, care status in terms of respiratory support, inotrope requirements and echocardiogram parameters that confirmed a large PDA will be needed. The randomisation program will use a minimisation algorithm to ensure balance between the groups with respect to the size of the PDA, gestational age at birth, age at randomisation, sex, trial site, multiple births, mode of respiratory support at randomisation (1) invasive ventilation, (2) non-invasive ventilation through CPAP or HHFNC (humidified high flow nasal cannula) or (3) no support (in room air) and receiving inotropes or not at the time of randomisation. • Health technology being assessed: the intervention group will receive a loading dose of i.v. ibuprofen lysine 10 mg/kg, the control group a matching placebo (0.9% normal saline), given at initiation of treatment, followed by 2 further doses of i.v. ibuprofen lysine 5mg/kg (or placebo; 0.9% normal saline) given at 24 hour intervals. Any rescue treatments will be strictly guided by pre-defined criteria. • The primary outcome is defined as a composite outcome of death or bronchopulmonary dysplasia (BPD) at 36 weeks post menstrual age (PMA). BPD will be defined by the need for respiratory support or oxygen supplementation at 36 weeks' PMA [Ehrenkranz 2005]. • Secondary outcomes are divided into short and long term outcomes. Short term outcomes: Death before discharge; Incidence and/or duration of the following up to discharge: Severe IVH (grade 3/4 with ventricular dilation or intraparenchymal bleeding), cystic PVL, moderate or severe BPD, ROP requiring treatment, pulmonary haemorrhage, NEC definitive and/or complicated (Bell stage II and above) confirmed by radiology or histopathology, NEC requiring surgery, gastrointestinal bleeding within 7 days of the first dose of trial drug administration, spontaneous intestinal perforation, PDA closure at 3 weeks of age (or hospital discharge, if discharged before this age), medical rescue treatment with a COX inhibitor/surgical treatment of a symptomatic PDA, administration and duration of inotropic support, duration of mechanical ventilation, total duration of respiratory support, ventilation + nasal Continuous Positive Airway Pressure (nCPAP)/high flow oxygen therapy), discharge home on oxygen, duration of initial hospitalisation (birth to neonatal unit discharge home), postnatal steroid use, number of doses of trial drug received during intervention period. Secondary long term clinical outcomes assessed at 2 years of age corrected for prematurity: Survival without moderate or severe neurodevelopmental disability, individual components of survival without moderate or severe neurodevelopmental disability (in the four domains of motor, cognitive, hearing and visual function). Cognitive disability will be assessed by determining the Parent Report Composite score obtained through the Parent Report of Cognitive Abilities-Revised (PARCA-R) assessment. The PARCA-R assessment will be adapted to include questions to assess hearing and visual function. Motor function will be assessed using the Gross Motor Function Classification System. Respiratory morbidity. Respiratory morbidity will be assessed by the need for oxygen or respiratory support; presence of persistent cough and/or wheeze; need for regular treatment for respiratory illness; unscheduled attendances at hospital/GP; number of re-hospitalisation episodes and duration. • Economic analysis: Health economic outcomes will take the form of a cost-effectiveness analysis of deaths avoided and reduction of any BPD at 36 weeks postmenstrual age as well as analysis of the cost implications of secondary outcomes. Analysis will be from the perspective of the NHS so only direct NHS costs will be collected. • Project milestones and timeline: Total duration is estimated to be 97 months. An internal pilot phase (13 months) will be carried out to allow an assessment of whether the procedures for recruitment and retention work effectively and efficiently. Apr 2014-Jul 2014: Internal pilot study set-up in 4 sites; obtain R&D approvals and train local personnel in trial procedures. Aug 2014-Apr 2015: Recruitment in 4 pilot sites. Obtain R&D approvals and set-up the trial in remaining 21 recruiting sites; train local personnel in trial procedures. May 2015: Submit report on pilot study to TSC/HTA for gaining permissions to roll out recruitment to remaining 21 sites; following approval. May 2015-Dec 2020: Main trial active recruitment and data collection phase. May 2019-Mar 2023: Complete long term follow-up. Jan 2021-Aug 2023: Analysis, reporting and dissemination phase. • Sample size: To demonstrate a clinically significant improvement i.e. a reduction in the primary outcome of death or BPD at 36 weeks PMA from 60% to 48% in the group allocated ibuprofen, using a two-sided significance level of 5% with 90% power, ~730 infants would be required in total (365 per trial arm). This equates to a 20% relative risk reduction (RRR), which is considered a clinically important difference by the neonatology community. This calculation is based on the assumption that 1% of recruited infants will potentially be lost to follow up until 36 weeks PMA. With long term outcome data expected to be available on a total sample of ~600, the trial will have about 80% power to detect an increase in survival without moderate or severe neurodevelopmental disability of 11% from 55% (control group event rate) to 66%, and 90% power to detect an increase of 13%, from 55% to 68%. • Feasibility of recruitment: There are ~2,000 babies born before and up to 28 completed weeks and admitted to the level 3 neonatal units that have expressed an interest in participation in this study. As about 46% (Stoll 2010) of these infants will have a large PDA, ~900 infants each year would be eligible for inclusion in this study. Assuming a 20-30% enrolment rate, ~250 infants per year (12-15% of all babies born before and up to 28 completed weeks of gestation admitted to level 3 units) would need to be enrolled to recruit a total sample size of up to 730 infants in 3 years. This enrolment rate is deliberately conservative, partly due to the requirement of echocardiography confirmation of a large PDA within 72 hours of birth and the challenge of obtaining consent during the immediate postnatal period while extreme premature babies are receiving intensive care. • Statistical analysis: Babies will be analysed in the groups to which they are randomly assigned, comparing the outcome of all babies allocated to ibuprofen with all those allocated to placebo, regardless of deviation from the protocol or treatment received (referred to as the Intention to Treat (ITT) population). • Independent Data Monitoring Committee (DMC): A DMC will be established to ensure the wellbeing of trial patients and to advise the Trial Steering Committee.