Neuroprotective potential of erythropoietin in neonates; design of a randomized trial

BACKGROUND: In 2013, nearly four million babies were born in the U.S., among whom 447,875 were born preterm. Approximately 30,000 of these infants were born before 28 weeks of gestation. These infants, termed Extremely Low Gestational Age Neonates (ELGANs), experience high morbidity and mortality despite modern therapies: approximately 20 % of ELGANs admitted to an NICU die before discharge, 20 % of survivors have severe, and 20 % moderate neurodevelopmental impairment (NDI). New approaches are needed to improve neonatal outcomes. Recombinant erythropoietin (Epo) is a promising neuroprotective agent that is widely available, affordable, and has been used safely in neonates to stimulate erythropoiesis. There are extensive preclinical data to support its use as a neuroprotective intervention: Epo promotes normal brain maturation by increasing neurogenesis, angiogenesis, and by protecting oligodendrocytes. Epo also decreases acute brain injury following hypoxia ischemia by decreasing inflammation, oxidative and excitotoxic injury, resulting in decreased apoptosis. Despite the availability of both preclinical and safety data there has not been a definitive clinical evaluation of the benefit of Epo, and a large phase III trial is necessary to provide evidence to support potential changes in practice guidelines. FINDINGS: We first review the preclinical data motivating further clinical trials, and then describe in detail the design of the PENUT study (Preterm Epo Neuroprotection). PENUT is a phase III study evaluating the effect of neonatal Epo treatment on the combined outcome of death or severe NDI among ELGANS. 940 subjects will be randomized to determine: 1) whether Epo decreases the combined outcome of death or NDI at 22–26 months corrected age; 2) the safety of high dose Epo administration to ELGANs; 3) whether Epo treatment decreases serial measures of circulating inflammatory mediators, and improves biomarkers of brain injury; and 4) whether Epo treatment improves brain structure at 36 weeks postmenstrual age as measured by MRI. CONCLUSIONS: Epo neuroprotection is an exciting new approach to preterm neuroprotection, and if efficacious, will provide a much-needed therapy for this group of vulnerable infants.