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  • Clinical Research Article
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On target dosing: erythropoietin exposure in neonates with hypoxic-ischemic encephalopathy in the HEAL trial

Pediatric Research volume 98, pages 218–223 (2025)Cite this article

Abstract

Background

The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia demonstrated no neurodevelopmental benefit but was associated with a higher rate of serious adverse events (SAEs). Understanding if targeted Epo plasma exposures were achieved in the HEAL trial and if SAEs were associated with higher exposures would help future therapeutic programs of Epo as a candidate neuroprotective treatment.

Methods

Ancillary study of a subset of HEAL neonates who received Epo (1000 U/kg IV on days 1, 2, 3, 4, and 7) and had plasma drug concentrations measured. Within a Bayesian pharmacokinetic framework, the area under the curve during the first 48 h (AUC48h) and 7 days (AUC7d) of treatment was estimated. The % of neonates who achieved animal model neuroprotective targets of AUC48h >140,000 mU*h/ml and AUC7d >420,000 mU*h/ml was calculated. The relationship between AUC7d and SAEs after study drug was evaluated using logistic regression.

Results

Among n = 89 neonates, variation in Epo exposure was low, and over 95% of neonates achieved the target AUC48h and AUC7d. No meaningful relationship was seen between AUC7d and risk of SAE.

Conclusions

The Epo dosing strategy in the HEAL trial consistently achieved target plasma exposures. Higher exposures were not associated with SAEs.

Impact

  • In the HEAL randomized, placebo-controlled trial of high-dose erythropoietin (Epo) for neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia, the Epo dosing strategy achieved animal model neuroprotective plasma exposure targets in >95% of neonates.

  • This understanding further strengthens the HEAL trial’s primary conclusion that Epo provides no additional benefit in neonates with HIE also receiving therapeutic hypothermia.

  • While Epo treatment was associated with a higher rate of serious adverse events (SAEs) compared to placebo in the primary HEAL trial, higher plasma exposures of Epo were not associated with the risk of SAEs.

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Fig. 1: Epo concentrations in a subset of neonates with HIE who received Epo (n = 89) in the HEAL study.
Fig. 2: Epo exposure in a subset of neonates with HIE who received Epo (n = 89) in the HEAL study.
Fig. 3: Relationship between quartile of Epo exposure as measured by the area under the curve during the first 7 days (AUC7d) of treatment and rate of at least one serious adverse event (SAE).

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Data availability

We will prepare and share a final research data set that the accepted primary pragmatic trial publication is based upon. The final data set will be structured to maximize future scientific value while protecting patient and health system privacy. The UW DCC will remove or de-identify all 18 HIPAA-specified direct identifiers. The aim of our data sharing policy is to strive for the least restrictive plan possible while providing appropriate protection for participant privacy, health system privacy, and scientific integrity. Within 9 months of the end of the final year of funding, a final study data set will be accessible via a supervised private data enclave managed by the National Institute of Neurological Disorder and Stroke (NINDS) at: https://www.ninds.nih.gov/ Current-Research/Research-Funded-NINDS/Clinical-Research/Archived-Clinical-Research- Datasets. The shared data set will contain all data collected under both the HEAL Trial protocol and HEAL ancillary studies. Access will be limited to registered users who submit proposed specific questions or analysis plans and sign a data use agreement according to NINDS guidelines. “Supervised” indicates that individual requests are reviewed to protect the intellectual property rights of the project investigative team by restricting external development of manuscripts using the study data that substantially overlap with those that are already in development by study investigators.

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Funding

The study was supported in part by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award numbers U01NS092764 and U01NS092553.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Stanford University, Palo Alto, CA, USA

    Adam Frymoyer

  2. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Ana Gabriela Vasconcelos, Bryan A. Comstock & Patrick J. Heagerty

  3. Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

    Sandra E. Juul

  4. Departments of Neurology, University of California, San Francisco, CA, USA

    Yvonne W. Wu

  5. Departments of Pediatrics, University of California, San Francisco, CA, USA

    Yvonne W. Wu

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  2. Ana Gabriela Vasconcelos
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  6. Yvonne W. Wu
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Contributions

All authors made substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; drafted the article or revised it critically for important intellectual content; and gave final approval of the version to be published.

Corresponding author

Correspondence to Adam Frymoyer.

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Competing interests

A.F. is a scientific advisor and holds a financial interest in Halo Biosciences unrelated to the current work. The other authors have no conflicts of interest relevant to this article to disclose.

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Informed consent was obtained from parents of all neonates in the current study.

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Frymoyer, A., Vasconcelos, A.G., Juul, S.E. et al. On target dosing: erythropoietin exposure in neonates with hypoxic-ischemic encephalopathy in the HEAL trial. Pediatr Res 98, 218–223 (2025). https://doi.org/10.1038/s41390-024-03709-z

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