Journal Article

Early treatment versus expectative management of patent ductus arteriosus in preterm infants: a multicentre, randomised, non-inferiority trial in Europe (BeNeDuctus trial)

Donders, Rogier, de Boode, Willem P., van Kaam, Anton H. L. C., Johansson, Anne-Britt, Hundscheid, Tim, Dijk, Peter, Hocq, Catheline, Onland, Wes, Kooi, Elisabeth M. W., Cools, Filip, van Overmeire, Bart, de Tollenaer, Susanne M., Zecic, Alexandra, van Laere, David, Dijkman, Koen P., Visser, Remco, Adang, Eddy, Vijlbrief, Daniel C., Kroon, André A., van Heijst, Arno F. J., Villamor, Eduardo, de Vries, Willem

2018

Overview

Background Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. Methods This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. Discussion As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. Trial registration This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017–001376-28 .

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Age / Analgesics / Analysis / Annual reports / Bronchopulmonary dysplasia / Budgets / Care and treatment / Clinical trials / Congenital diseases / Coronary vessels / Cost-Benefit Analysis / Cyclooxygenase Inhibitors - therapeutic use / Diagnosis / Ductal ligation / Ductus Arteriosus, Patent - complications / Ductus Arteriosus, Patent - drug therapy / Ductus Arteriosus, Patent - mortality / Ductus Arteriosus, Patent - surgery / Enterocolitis, Necrotizing - etiology / Equivalence Trials as Topic / Evidence-based medicine / Expectative management / Health aspects / Health economics / Humans / Ibuprofen / Ibuprofen - therapeutic use / Infant, Extremely Premature / Infant, Newborn / Infant, Premature, Diseases - drug therapy / Infant, Premature, Diseases - mortality / Infants / Intensive care / Internal Medicine / Ligation / Medicine / Medicine & Public Health / Mortality / Multicenter Studies as Topic / Necrotizing enterocolitis / Neonatal intensive care unit / Neonatology / Newborn babies / Nonsteroidal anti-inflammatory drugs / Patent ductus arteriosus / Pediatrics / Premature babies / Prematurity / Research Design / Risk factors / Study Protocol / Systematic review / Time-to-Treatment / Watchful Waiting - economics