# High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) CCC

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $3,533,187

## Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) refers to brain injury resulting from reduced blood and
oxygen flow to a baby's brain near the time of birth. HIE affects up to 12,000 newborns each year in the U.S.
Half of affected infants have a bad outcome including death, cerebral palsy and cognitive impairment despite
receiving hypothermia, the only available treatment. Cerebral palsy is the most common long term
neurodevelopmental impairment in survivors of HIE. Each year in the U.S., new cases of HIE resulting in
cerebral palsy impose an estimated economic burden of $1.7 billion in lifetime costs. Erythropoietin (Epo) is a
cytokine with remarkable neuroprotective and neuroregenerative effects demonstrated in animal models of
neonatal brain injury. Epo reduces apoptotic, inflammatory and oxidative brain injury following hypoxia-
ischemia, and enhances neurogenesis and oligodendrocyte survival, promoting brain regeneration and
improved function. In non-human primates, Epo reduces the rate of cerebral palsy and improves neurologic
function in animals undergoing hypothermia for HIE. Small human trials suggest that infants with HIE treated
with Epo have better neurologic outcomes. In our phase I trial of Epo + hypothermia, we found that Epo 1000
U/Kg/dose best reproduced the pharmacokinetics of neuroprotective dosing in animal models. Long term
outcomes were better than expected based on entry criteria and MRI findings. Our phase II trial compared 50
cooled infants randomized to receive Epo or placebo. Infants treated with hypothermia + Epo had less brain
injury on early MRI, and better 6-month developmental outcome based on a standardized parental
questionnaire. Epo is commercially available, relatively inexpensive, and safe in neonates. We hypothesize
that Epo given to cooled infants with moderate/severe HIE will reduce the combined primary outcome of death
or neurodevelopmental impairment from 49 to 33%. To test this hypothesis, we propose a randomized, double-
blind, placebo-controlled trial of Epo therapy in 500 infants with HIE undergoing hypothermia. Our specific aims
are 1) To determine if 5 doses of Epo 1000 U/kg IV reduces the rate of death, motor or cognitive deficits at 2
years; 2) To assess safety of Epo by evaluating clinical toxicity; and 3) To determine whether Epo decreases
the severity of neonatal brain injury as evidenced by early MRI and circulating biomarkers of brain injury. Motor
outcome will be determined by a standardized neurologic exam and by the Gross Motor Function Classification
System. Cognitive outcome will be determined by Bayley III exam. In secondary analyses, we will examine the
effect of Epo on cerebral palsy, severity of motor impairment, Bayley III cognitive and language scores,
epilepsy and behavioral abnormalities. We anticipate that Epo will confer improved 2-year neurodevelopmental
outcome, will be safe, and will decrease brain injury severity as determined by early biomarkers. The CCC will
initiate and m...

## Key facts

- **NIH application ID:** 9989901
- **Project number:** 5U01NS092764-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sandra E Juul
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,533,187
- **Award type:** 5
- **Project period:** 2016-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989901

## Citation

> US National Institutes of Health, RePORTER application 9989901, High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) CCC (5U01NS092764-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989901. Licensed CC0.

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