Abstract
The next phase of clinical trials in neonatal encephalopathy (NE) focuses on hypothermia adjuvant therapies targeting alternative recovery mechanisms during the process of hypoxic brain injury. Identifying infants eligible for neuroprotective therapies begins with the clinical detection of brain injury and classification of severity. Combining a variety of biomarkers (serum, clinical exam, EEG, movement patterns) with innovative clinical trial design and analyses will help target infants with the most appropriate and timely treatments. The timing of magnetic resonance imaging (MRI) and MR spectroscopy after NE both assists in identifying the acute perinatal nature of the injury (days 3–7) and evaluates the full extent and evolution of the injury (days 10–21). Early, intermediate outcome of neuroprotective interventions may be best defined by the 21-day neuroimaging, with recognition that the full neurodevelopmental trajectory is not yet defined. An initial evaluation of each new therapy at this time point may allow higher-throughput selection of promising therapies for more extensive investigation. Functional recovery can be assessed using a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action. As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow safe, efficient, and targeted therapeutics.
Impact
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As precision medicine revolutionizes healthcare, it should also include the redesign of NE clinical trials to allow faster development of safe, effective, and targeted therapeutics.
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This article provides a multidisciplinary perspective on the future of clinical trials in NE; novel trial design; study management and oversight; biostatistical methods; and a combination of serum, imaging, and neurodevelopmental biomarkers can advance the field and improve outcomes for infants affected by NE.
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Innovative clinical trial designs, new intermediate trial end points, and a trajectory of neurodevelopmental evaluations targeted to a prespecified and mechanistically derived hypothesis of drug action can help address common challenges in NE clinical trials and allow for faster selection and validation of promising therapies for more extensive investigation.
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Acknowledgements
Thank you to Kenji M. Cunnion and Neel K. Krishna for hosting the 2019 HIE Symposium: Developing the Future. The symposium was made possible through support from ReAlta Life Sciences, Children’s Specialty Group, Eastern Virginia Medical School, and the Children’s Hospital of The King’s Daughters. This work was supported by 1R01HD081120-01A1 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to N.L.M. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding organizations.
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K.L.B., T.E.I., A.M.G., and N.L.M. participated in the conception and design, drafted the initial manuscript, revised the manuscript critically for important intellectual content, and approved the final version for publication. C.M.C., D.R.N., T.A.S., and J.C.S. participated in the conception and design, revised the manuscript critically for important intellectual content, and approved the final version for publication.
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Benninger, K.L., Inder, T.E., Goodman, A.M. et al. Perspectives from the Society for Pediatric Research. Neonatal encephalopathy clinical trials: developing the future. Pediatr Res 89, 74–84 (2021). https://doi.org/10.1038/s41390-020-0859-9
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DOI: https://doi.org/10.1038/s41390-020-0859-9
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