Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial

Gupta, Samir; Juszczak, Edmund; Hardy, Pollyanna; Subhedar, Nimish; Wyllie, Jonathan; Kelsall, Wilf; Sinha, Sunil; Johnson, Sam; Roberts, Tracy; Hutchison, Elisabeth; Pepperell, Justine; Linsell, Louise; Bell, Jennifer L.; Stanbury, Kayleigh; Laube, Marketa; Edwards, Clare; Field, David; on behalf of the �The Baby-OSCAR Collaborative Group

Abstract

Background
The question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks’ gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic.

Methods
This is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0–28+ 6 weeks’ gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0–28+ 6 weeks’ gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks’ postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age.

Discussion
Prophylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done.

Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks’ postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age.

Citation

Gupta, S., Juszczak, E., Hardy, P., Subhedar, N., Wyllie, J., Kelsall, W., Sinha, S., Johnson, S., Roberts, T., Hutchison, E., Pepperell, J., Linsell, L., Bell, J. L., Stanbury, K., Laube, M., Edwards, C., Field, D., & on behalf of the ‘The Baby-OSCAR Collaborative Group. (2021). Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial. BMC Pediatrics, 21, Article 100. https://doi.org/10.1186/s12887-021-02558-7

• Journal Article Type: Article
• Acceptance Date: Feb 15, 2021
• Online Publication Date: Feb 26, 2021
• Publication Date: Feb 26, 2021
• Deposit Date: Mar 15, 2021
• Publicly Available Date: Mar 16, 2021
• Journal: BMC Pediatrics
• Electronic ISSN: 1471-2431
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Article Number: 100
• DOI: https://doi.org/10.1186/s12887-021-02558-7
• Keywords: Pediatrics, Perinatology, and Child Health
• Public URL: https://nottingham-repository.worktribe.com/output/5396319
• Publisher URL: https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-021-02558-7
• Additional Information: Baby-OSCAR received approval from the MHRA, the NHS Health Research Authority, and East Midlands – Nottingham 2 Research Ethics Committee: ExternalRef removed on 16 December 2014 (REC ref.: CitationRef removed/EM/0172). Trust Confirmation of Capacity and Capability was obtained at each site. The Chief Investigator or delegate will submit an Annual Progress Report, End of Study Notification, and Final Report to the Funder; NIHR HTA, MHRA, REC, HRA, host organisation and Sponsor.Where necessary, approvals are obtained from the above parties for all substantial amendments to the original approved documents and disseminated by NPEU CTU to relevant parties.Parents of eligible babies are provided with both verbal and written information in the form of a Parent Information Leaflet (Additional file InternalRef removed), by their clinical team. Parent(s) with legal parental responsibility of eligible babies are approached to discuss the trial further, answer any questions they may have, and to request consent. Parent(s) have as much time as they need to consider the information, and the opportunity to question the research team, or other independent parties to decide whether they wish to participate in the study. Informed consent for the study must obtained by a suitably qualified member of the study team. A parent must personally sign and date the latest approved version of the Informed Consent form (Additional file InternalRef removed) before any study specific procedures are performed. Parent(s) who do not speak English will only be approached if an adult interpreter is available.; : Not applicable.; : SG is member of steering committee of ESPR NPE (Neonatologist performed echocardiography). EJ was a member of the NIHR HTA General Board from 2016 to 2017 and the NIHR HTA Commissioning Board from 2013 to 2016. PH is currently a member of the NIHR HTA Commissioning Board. EJ, LL, NS and PH report receipt of funding from NIHR, outside the submitted work. NS receives fees for educational activities from Recordati Group.