Feasibility of neurodevelopmental outcome assessments after early and extended erythropoietin monotherapy for neonatal encephalopathy in low- and middle-income countries: an external pilot randomised controlled trial

Objective To assess the feasibility of a randomised controlled trial of early erythropoietin (Epo) therapy with neurodevelopmental follow-up. Design Multicentre, double-blind, external pilot randomised controlled trial. Setting Eight tertiary neonatal units in India and Bangladesh that were part of the Consortium for Time-Critical Neuroprotection Trials in Neonatal Encephalopathy (CONNECTIONS). Patients 50 infants (≥36 weeks) with moderate or severe hypoxic-ischaemic encephalopathy (HIE). Interventions Infants were randomised to Epo 500 U/kg/day for nine doses (n=26) or sham (n=24) within 6 hours of birth. Therapeutic hypothermia was not allowed. Main outcome measures Feasibility of recruitment, protocol adherence, timing of intervention delivery, MRI acquisition and completion of assessment at 18–22 months using the Bayley Scales of Infant and Toddler Development, fourth edition, scales of infant and toddler development. Results Among 50 infants, 45 (90%) had moderate HIE and 5 (10%) had severe HIE, and the trial intervention was given at a mean (SD) age of 4.4 (1.2) hours. Adherence to the trial protocol was excellent. All 33 infants who survived beyond a week had MRI scans which were abnormal in 30 (91%). Overall, 16 (32%) died before hospital discharge, 21 (42%) before 18 to 22 months; 29 (58%) met the composite outcome of death or moderate to severe disability with a 100% follow-up. All four infants discharged against medical advice subsequently died. Conclusions Robust research governance, early erythropoietin administration in infants with HIE, MRI acquisition and complete neurodevelopmental follow-up can be achieved in South Asian neonatal units. CONNECTIONS provides a platform for high-quality multicountry randomised controlled trials. Trial registration number NCT05395195.