Long term Follow-up of the TREOCAPA (Prophylactic TREatment Of the duCtus Arteriosus in Preterm infants by Acetaminophen) Study (TREOCAPA-LT): protocol and statistical analysis plan

Introduction

The TREOCAPA (Prophylactic TREatment Of the duCtus Arteriosus in Preterm infants by Acetaminophen) trial was a pan-European, multi-centre, phase II/III trial investigating the impact of prophylactic paracetamol (also known as acetaminophen) given during the first 5 days of life for children born before 29 weeks’ gestational age (GA) on survival to 36 weeks’ post-menstrual age without severe neonatal morbidities. However, due to time restrictions, long-term follow-up was not planned as part of the initial trial despite recommendations for neonatal trials to include endpoints measuring efficacy after discharge from the neonatal unit and on-going debate about the long-term effects of paracetamol in the neonatal period. This protocol describes a study to follow-up participants in the TREOCAPA trial at 2 years corrected age initiated after the trial’s onset.

Methods and analysis

The TREOCAPA Long Term (TREOCAPA-LT) study population consists of all children included in the TREOCAPA phase III trial in centres in countries participating in the follow-up study who are aged between 23.5 and 27.5 months corrected age during the study period. Families are contacted by the clinical teams and a parent or guardian is invited to complete an internet-based (online) questionnaire. The primary outcome is cognition, as measured by the non-verbal Cognitive Scale standard score from the Parent Report of Children’s Abilities-Revised (PARCA-R) questionnaire. Secondary outcomes are moderate to severe neurodevelopment, health service use and costs. Data will be analysed according to the study groups to which children were randomised in the original TREOCAPA RCT.

Ethics and Dissemination

The TREOCAPA-LT protocol was first approved by ethics’ committees in France (the study’s sponsor) and subsequently by all participating countries. Results from TREOCAPA-LT will be published in open access journals in accordance with the funder’s regulations.

Registration

https://clinicaltrials.gov/study/NCT06064825

Strengths and limitations

• This follow-up study of a large multi-country randomised controlled trial of paracetamol use in preterm children born below 29 weeks of gestation is the first to examine long term effects of paracetamol without the influence of potential confounding factors in this vulnerable population.

• The study builds on an existing questionnaire in multiple European languages to assess cognition at 2 years of corrected age (PARCA-R) using newly developed questions to permit assessment of overall neurodevelopmental abilities as well as health economic analyses.

• Support in designing the study by the Global Foundation for Care of Newborn Infants (GFCNI) ensures that the study is relevant to patients and their families, and promotes knowledge sharing and public understanding of innovative research in neonatal care and preterm health.

• Despite differing regulatory and ethical requirements for participation between countries which caused some delays in study initiation, the number of eligible children is on target to achieve >80% power to detect a difference of 4.5 IQ points on a standardised scale – below the threshold of 6 which is considered clinically important.