Multi-centre, randomised non-inferiority trial of early treatment versus expectant management of patent ductus arteriosus in preterm infants (the BeNeDuctus trial): statistical analysis plan
on behalf of the BeNeDuctus trial study group
(2021) Trials, volume 22, issue 1
(Article)
Abstract
BACKGROUND: Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome.
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In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy. METHODS/DESIGN: The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data. TRIAL REGISTRATION: ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial 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.
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Keywords: Bronchopulmonary dysplasia, Ductal ligation, Expectant management, Ibuprofen, Mortality, Necrotising enterocolitis, Neonatal intensive care unit, Patent ductus arteriosus, Prematurity, Statistical analysis plan, Medicine (miscellaneous), Pharmacology (medical)
ISSN: 1745-6215
Publisher: BioMed Central
Note: Funding Information: We would like to thank the members of the Data Safety Monitor Board of the BeNeDuctus trial: Dr. Anne van Kempen, neonatologist; Dr. Caroline van Baal, biostatistician; and Hans Breur, pediatric cardiologist. We would like to thank Karin Deckers and Wendy Jansen (research coordinators) for their invaluable support. BeNeDuctus trial study group members: Peter H. Dijk, MD, PhD, Department of Neonatology, University Medical Centre Groningen, Beatrix Children’s Hospital, Groningen, The Netherlands; Anton H.L.C. van Kaam, MD, PhD, Emma Children's Hospital Amsterdam University Medical Centers, Department of Neonatology, University of Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Tessa de Baat, MD, Emma Children's Hospital Amsterdam University Medical Centers, Department of Neonatology, University of Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Koen P. Dijkman, MD, Department of Neonatology, Maxima Medical Centre Veldhoven, Veldhoven, The Netherlands; Eduardo Villamor, MD, PhD, Department of Neonatology, Maastricht University Medical Centre, Maastricht, The Netherlands; André A. Kroon, MD, PhD, Department of Neonatology, Erasmus MC Sophia Children’s Hospital, Rotterdam, The Netherlands; Remco Visser, MD, PhD, Department of Neonatology, Leiden University Medical Centre, Willem Alexander Children's Hospital, Leiden, The Netherlands; Susanne M. de Tollenaer, MD, PhD, Department of Neonatology, Isala Women’s and Children’s Hospital Zwolle, Zwolle, The Netherlands; Filip Cools, MD, PhD, Department of Neonatology, UZ Brussel – Vrije Universiteit Brussel, Brussels, Belgium; Marisse Meeus, MD, Department of Neonatology, Antwerp University Hospital, Edegem, Belgium; Anne-Britt Johansson, MD, Department of Neonatology, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles/Brussels, Belgium; Frank Derriks, MD, Department of Neonatology, Cliniques Universitaires de Bruxelles, Hôpital Erasme, Brussels, Belgium; Catheline Hocq, MD, Department of Neonatology, Cliniques Universitaires St Luc, Brussels, Belgium; Alexandra Zecic, MD, Department of Neonatology, Ghent University Hospital, Gent, Belgium; Tine Brink Henriksen, MD, PhD, Neonatal Intensive Care Unit, Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark; Kasper Jacobsen Kyng, MD, PhD, Neonatal Intensive Care Unit, Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark. Funding Information: Ductus arteriosus closure is delayed in prematurity, since it is not yet programmed for prompt postnatal closure []. This is supported by the observation of a high amount of spontaneous closure [] even after ‘failed’ pharmacological treatment []. Since early pharmacological treatment has not been proven to improve outcome, it potentially increases the risk of iatrogenic adverse effect in patients in whom the PDA would have closed spontaneously. These observations have led to an increased interest in expectant PDA management []. Evidence to support expectant PDA management is scarce and conflicting [], due to a high amount of open label treatment in placebo-controlled randomised controlled trials (RCTs) [, ] and a heterogeneous definition of (haemodynamic significant) PDA []. Publisher Copyright: © 2021, The Author(s).
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