UCSF Pediatric Focus

Can High-Dose Epo “HEAL” Infant Brains?

A multisite, nationwide study seeks to confirm that high-dose erythropoietin (Epo) can safely protect and, perhaps, heal the brains of infants with neonatal encephalopathy.

As head and whole body cooling has become standard of care, the percentage of newborns with asphyxia or hypoxic-ischemic encephalopathy (HIE) who experience neurodevelopmental problems or early death has dropped from nearly 70 percent to about 40 percent.

“But that’s still way too high,” says neonatologist Fernando Gonzalez, MD, of the UCSF Neuro-Intensive Care Nursery (NICN). “Based on two small studies that have been conducted over the last few years, we’re hoping that adding a few doses of Epo during the baby’s first week of life will significantly reduce those numbers.”

That hope underlies a large phase III study (High-dose Erythropoietin for Asphyxia and Encephalopathy, or HEAL) led by UCSF child neurologist Yvonne Wu, MD, MPH, who was the principal investigator for the two prior studies, and University of Washington neonatologist Sandra Juul, MD, PhD. The HEAL trial is currently enrolling patients at its more than 20 participating hospitals nationwide.

Racing to Find Solutions

Concerned by the long-term suffering inflicted by neonatal encephalopathies, researchers around the world are testing numerous neuroprotective agents, including Epo, melatonin and cannabinoid derivatives. “But from our perspective, Epo has shown the greatest potential for reducing injury and helping stem cells grow and develop more neurons,” says Wu. “And because Epo is already in use to treat infants with anemia, it’s cleared a lot of regulatory hurdles.”

Gonzalez’ own research program has long focused on exploring the hormone’s potential to protect and repair infant brains. Testing in rats with early brain injury led to the discovery that a series of higher-than-normal doses over a one-week period appeared to help reduce brain injury and enhance repair – resulting in long-term motor and cognitive improvement. “Behavioral studies in rats after they reached adulthood demonstrated enhanced behavioral function without raising the red blood cell count or causing any other adverse effects,” says Gonzalez.

Those findings led to Wu’s phase I and phase II trials, known as NEAT and NEATO, for Neonatal Erythropoietin And Therapeutic Hypothermia [Outcomes] in Newborn Brain Injury. Combined, these early trials suggested that administering five doses over the baby’s first week of life, at 1,000 units per kilogram, was safe and possibly effective in a small sample size of 50 infants. The placebo-controlled NEATO trial used an MRI of the neonate’s brain and one-year behavioral outcomes to document its results.

The findings convinced the National Institutes of Health (NIH) to fund HEAL to enroll 500 infants in its multisite effort. The study will again use MRI to observe the effects on early brain injury and add neurodevelopmental assessments over the children’s first two years. Wu hopes they will eventually secure funding to follow the infants through 8 years of age.

Any infant with suspected HIE who undergoes cooling – including passive cooling – within six hours of birth may be eligible for the study. Families will need to consent and have their infant admitted to a participating hospital for treatment with Epo or placebo within 24 hours of birth.

“Our NEATO findings were exciting, but some centers have already begun to use high-dose Epo to treat HIE, and that’s troublesome until we can clearly show it to be safe and effective,” says Wu. “We need to know if we found a true effect, and the sooner we can enroll patients and complete this study, the sooner we can know if our approach is valid.”

Questions about the study? Please email the study coordinators at: HEAL@ucsf.edu

Questions about a potential patient? Please contact the UCSF Access Center at 877-822-4453 to discuss them with an attending neonatologist.