Erythropoietin and Darbepoetin in Neonatal Encephalopathy Trial (EDEN)

Birth asphyxia related brain injury (hypoxic ischemic encephalopathy; HIE) occurs in 2.6 (95% CI 2.5 to 2.8) per 1000 live births in the UK, and is the most common cause of death and neurodisability in term babies. The economic burden to the treasury on support costs of neuro-disability from HIE is massive.

The only effective treatment for HIE is whole body cooling, with an estimated saving of £100 million per annum to the UK economy, since its introduction as a standard therapy in the NHS in 2007. Cooling therapy has substantially improved the outcomes of babies with HIE in the past decade. However, unacceptably high rate of adverse outcomes are still seen in cooled babies with moderate or severe HIE, and hence better treatments and further optimisation of cooling therapy is required.

A key roadblock in clinical translation of over 15 highly effective neuroprotective treatments in animal models is the long delay between the intervention and outcome assessments in HIE. i.e. the earliest age at which neurodevelopmental outcome can be accurately assessed is 18 months. Hence, despite having over 2 dozen highly effective treatments in animal models, no further neuroprotective drugs in HIE have been introduced into the NHS in the past 10 years.

Erythropoietin (Epo) is a widely used and FDA approved drug for treating anaemia in various age groups, including newborn infants. Over 34 randomised controlled trials recruiting over 3500 premature babies have reported the safety and efficacy of Epo therapy for anaemia of prematurity.

Several recent reviews have highlighted Erythropoietin as one of the most promising therapies to augment hypothermic neuroprotection. Epo has both acute effects (anti-inflammatory, anti-excitotoxic, anti-oxidant, and anti-apoptotic) and regenerative effects (neurogenesis, angiogenesis, and oligodendrogenesis) essential for the repair of injury and normal neurodevelopment in animal models5. Of the long list of highly effective drugs in animal models of HIE and early clinical studies, Epo is the most promising. It is the only drug with a long therapeutic window (at least 24 hours), is widely available, inexpensive, and can be easily administered on a once a day dosing schedule. It has been extensive evaluated in large randomised controlled trials for anaemia of prematurity and has a proven safety profile in newborn infants.

Darbepoetin, a long acting erythropoiesis stimulating agent, has dual erythropoietic and potential neuroprotective effects. It has been extensively evaluated in newborn infants for its erythropoietic effects.

The EDEN trial is a 3 arm randomised control trial and aims to examine the physiological effects of erythropoietin (Epo) and Darbepoetin alfa (Darbe) therapy on proton magnetic resonance spectroscopy thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing cooling therapy.

After informed parental consent, a total of 220 babies with HIE (aged <24 hours) undergoing therapeutic hypothermia will be randomised to one of the following groups

• Arm 1: Erythropoietin (1000 U/kg) IV once a day x 5 doses along with cooling therapy
• Arm 2: Darbepoetin Alpha (10 mcg/kg) IV single dose given less than 24 hours of age along with cooling therapy.
• Arm 3: Cooling only (usual care)

Babies recruited will have electroencephalography (EEG), MR imaging and spectroscopy will be performed at 1 to 2 weeks of age to examine the brain injury. The neurological outcomes will be assessed between 18 to 22 months of age. The trial duration will be 4 years, consisting of a 4 week start up period, 24 month recruitment period, a 18 month follow-up period, and 5 months for data analysis and write up.