TREOCAPA: Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen. Statistical analysis plan for the randomized phase III group sequential trial

Abstract

Background Persistent patency of the ductus arteriosus (PDA) has challenged neonatologists for more than 40 years. Controversies persist about the management of PDA in extremely preterm infants. PDA is associated with morbidities but no therapeutic strategy has resulted in an improved neonatal outcome. Acetaminophen appears to be a promising alternative with possibly fewer adverse effects. The primary objective is to determine whether a prophylactic pharmacological intervention with acetaminophen, may increase the survival without severe morbidity at postmenstrual age of 36 weeks. Methods and analysis TREOCAPA Phase III is a randomized, multicenter, double-blind, stratified, placebo-controlled superiority trial, two arms in a 1:1 ratio performed in 43 NICUs of 14 European countries and evaluating whether the intervention increases the survival without severe morbidity by 10 percent until the age of 36 postmenstrual weeks. Patients eligible for inclusion are preterm infants with a gestational age between 23 and 28 weeks. In acetaminophen group, 20 mg/kg loading dose within 12 hours after birth, followed by 7.5 mg/kg quarter in die (QID) for 5 days will be administered to the 27–28 weeks gestational age group, and 25 mg/kg loading dose then 10 mg/kg QID to the 23–26 weeks gestational age group. The severe morbidities include severe bronchopulmonary dysplasia (BPD Grade 3) according to NIH consensus, necrotizing enterocolitis (NEC) of Bell's stage II or III, intraventricular hemorrhage (IVH) grade III-IV according to Papille classification or cystic leukomalacia. Discussion Whatever the results, the conclusions of this study should be informative for the neonatal scientific community: Secondary effects of aceminotophen or not? Prophylactic treatment of PDA useful or not? Ethics and dissemination Ethical approval of the trial has been performed in each of the 14 countries after approval, at the European level, by the Voluntary Harmonization Procedure committee on 04/07/2020. Results will be disseminated through articles in peer-reviewed journals. Trial registration European Clinical Trials Database: EudraCT Number: 2019-004297-26