Title: Outcome after Selective Early Closure of Ductus Arteriosus in Extremely Preterm Babies (Baby-OSCAR trial)
Funder: Department of Health and Social Care

Abstract: • 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 82 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-Apr 2018: Main trial active recruitment and data collection phase. Nov 2016-Jul 2020: Complete long term follow-up. Aug 2020-Jan 2021: 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.

Lay abstract: The ductus arteriosus is a blood vessel that allows blood pumped from the heart to bypass the fetal lungs. After birth, the ductus arteriosus closes spontaneously and this closure allows blood to pass to the lungs where it is oxygenated. Approximately 7,000 babies each year are born extremely prematurely in the United Kingdom. Extreme prematurity is defined as 12 weeks or more before the expected date of delivery, as calculated from the last menstrual period of the mother. In such premature babies, the ductus arteriosus often fails to close spontaneously. The ductus arteriosus is then known as a patent ductus arteriosus (PDA). A PDA results in extra blood entering the lungs, which places the baby at high risk of death, and having both an increased requirement for artificial breathing support and a higher risk of complications of prematurity, including long-term illness and developmental problems. The increase in requirement for artificial breathing support in turn causes progressive damage to developing lungs, resulting in a complication called bronchopulmonary dysplasia (BPD) - a condition of prolonged oxygen dependency with or without artificial breathing support. A large PDA also has the potential to steal blood from the lower half of the body, including abdominal organs, due to the shunting of blood from the aorta (the major blood vessel supplying blood to the body) to the lungs. This increases the risk of complications of prematurity, in particular necrotising enterocolitis – an infection which includes perforation of the intestines. The complications of prematurity may result in long term health problems or death. The above mentioned complications are all associated with a large increase in healthcare costs. Ibuprofen and indomethacin are two drugs currently used to close a patent ductus arteriosus in premature babies. Ibuprofen has fewer side effects than indomethacin. These drugs have been used in two ways to close a PDA. Firstly, they are used prophylactically, treating all babies early. Since the PDA might close spontaneously, a large proportion of babies are therefore treated unnecessarily. Secondly, an expectant symptomatic approach can be used, waiting until symptoms or signs appear. This approach may result in harm being done by the PDA before treatment is initiated and effective. There is at present no consensus regarding best practice for dealing with a PDA. There is growing uncertainty amongst clinicians as to whether or not to treat a PDA. The option of non treatment, largely because of fear of drug treatment side effects, is untested. The proposed study uses an approach that overcomes the limitations of the two current treatment practices of prophylactic and expectant management. We propose identification of babies with a large PDA, and commencing treatment in such neonates within the first 72 hours before the damage occurs, would reduce the complications of prematurity, improve long term health outcomes and decrease healthcare costs. Babies with a large PDA can be identified using ultrasound scanning of the neonatal heart and associated blood vessels. The study has the potential to test whether using ibuprofen to close the large PDA in this group of neonates can reduce the complications of prematurity and improve outcomes. In addition to improving clinical outcomes it may be possible to demonstrate very substantial savings to the NHS, amounting perhaps to millions of pounds annually. It is proposed that extremely premature babies up to and including 28 weeks of gestation with a large PDA be identified in less than 72 hours using bedside echocardiography (ultrasound of the heart). Using predefined criteria of echocardiography measurements, at risk babies who are unlikely to close the PDA spontaneously would be identified. Parents would be approached so that informed consent for the trial might be obtained. Babies would be randomised to one of two groups. One group would receive ibuprofen intravenously and the other group would receive a matched placebo intravenously. Subsequently any further treatment of a symptomatic PDA would be discouraged and further open label (medical or surgical) treatment limited to those babies meeting predefined criteria. The primary outcomes will be "neonatal death" or "need for oxygen/breathing support at the equivalent of 36 weeks of gestation (BPD)", as calculated from the date of the last menstrual period of the mother. Other outcomes that will be measured will be complications of prematurity, such as duration of respiratory support and side effects of drug treatment. The babies will be followed up initially for a period of 2 years and at that time the health outcomes, including survival without moderate or severe disability and survival without respiratory illnesses, will be assessed. The cost effectiveness of these approaches will also be assessed at this time. It is also intended to further assess the babies at primary school (subject to additional funding). It is intended to carry out the study in 25 neonatal intensive care units across the United Kingdom, following an initial pilot phase of 13 months in four units to allow testing of the components and processes of the study. The clinicians recruiting cases work in established neonatal intensive care units and have much experience in dealing with the ethical issues of consent and clinical management surrounding such studies. The study plans to recruit 730 babies over 3 years and is scheduled to have a duration of 82 months in total. The sample size (total number of babies to be enrolled in the trial) is calculated so that a clinically significant improvement in the primary outcome (reduction in death or BPD from 60% to 48% in the group allocated ibuprofen) can be demonstrated. This equates to a 20% relative risk reduction, which is considered a clinically important reduction by the neonatal community. This calculation includes an assumption that 1% of recruited infants would be potentially lost to follow-up at 36 weeks.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR