PAEAN Trial Information

Erythropoietin for hypoxic ischaemic encephalopathy in newborns

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Objective

A lack of oxygen (hypoxia) or low blood supply (ischaemia) before or during birth can destroy cells in a newborn baby's brain. The damage caused by the lack of oxygen continues for some time afterwards. One way to try to reduce this damage is to induce hypothermia cooling the baby or just the baby's head for hours to days. Erythropoietin (Epo) given in the first week after birth shows promise as a treatment that may also help. The objective of this study is to determine whether Epo plus induced hypothermia (cooling) of near-term newborn babies who have suffered from low blood or oxygen supply to the brain at birth reduces death and disability in survivors at two years of age.

Study Design

This is a double blind, placebo controlled, parallel, 2 arm randomised, phase III multicentre trial, stratified by study site and by severity of encephalopathy at study entry.

Study Population

The target population is 300 newborn term or near term infants (greater than or equal to 35+0 weeks gestation) with hypoxic ischaemic encephalopathy who are receiving, or planned to receive hypothermia and who are able to be recruited in time to allow study treatment to commence before 24 hours of age.

Intervention

The treatment group of 150 infants will receive human recombinant Epo, 1000 IU/kg IV (capped at 4000 IU daily) on days 1, 2, 3, 5 & 7 of life. The control group will receive 0.9% sodium chloride as a placebo on days 1, 2, 3, 5 & 7 of life.

Outcome Measures

Primary outcome: Composite of death or moderate/severe disability using  disability assessments such as paediatric review (Any CP), GMFCS score (greater than or equal to 1) and Bayley Scale of Infant Development III (less than or equal to 80),every 6 months until 2 years of age.

Data/Power Analysis

The sample size of 150 per treatment group is large enough to detect a 19% absolute risk reduction in the combined endpoint of death or severe/moderate motor/cognitive deficit assuming a control event rate of 46%, (decrease from 46% to 27%) and allowing for a 10% non-compliance/lost to follow-up rate with 90% power and a two-sided Type I error of 0.05. Three hundred infants will be recruited. Each infant will be followed for 24 months to assess the primary and secondary outcomes.

Analyses of the primary and secondary outcomes will adhere to the Intention to Treat (ITT) principle, where all neonates randomised will be included. Analysis of safety endpoints will be according to treatment received, including only neonates who received at least one dose of treatment. All p-values will be two tailed without adjustment. A nominal significance level of 0.05 will be applied.

The proportion of neonates who have death or severe/moderate motor/cognitive deficit at 2 years will be compared using a chi-squared test. Continuous outcomes will be compared using t-tests where appropriate. Time-to-event outcomes will be displayed using Kaplan-Meier curves and comparisons where appropriate using the log-rank test.

Multivariable comparisons using regression methods will be used to explore the impact of key prognostic variables on outcomes.

Commencement Date

November 2014

Investigators and Primary Contacts

Chief Investigator: Associate Professor Helen Liley, Mater Health Services, Aubigny, 1 Raymond Terrace, South Brisbane Qld 4101

Contact: PAEAN Trial Coordinator, NHMRC Clinical Trials Centre, Locked Bag 77 Camperdown NSW 2050, paean@ctc.usyd.edu.au

Australia New Zealand Clinical Trials Registry (ANZCTR) Trial Registry Number

ACTRN12614000669695