An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo.
Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models.
Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo).
In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia.
In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies.
Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo).
There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.
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HEAL Trial Data-sharing plan. 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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The authors would like to thank Dr Taeun Chang (1971–2022) for her tireless contributions to this work, site investigators Drs John Flibotte and Lori Billinghurst, as well as the Clinical Research Coordinators at each study site.
The study was funded by NIH/NINDS R01NS104322, U01NS092764, and U01NS092553. A.L.N. received grant support during the study period from NINDS K23NS105918.
The authors declare no competing interests.
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Glass, H.C., Wusthoff, C.J., Comstock, B.A. et al. Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-02398-w