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A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage

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An Invited Commentary to this article was published on 09 December 2021

Abstract

Background

Epoxyeicosatrienoates (EETs) are endogenous regulators of neuroinflammation and cerebral blood flow. Their metabolism to dihydroxyeicosatrienoates (DHETs) is catalyzed by soluble epoxide hydrolase (sEH). After subarachnoid hemorrhage (SAH), EETs’ pathway amplification may be a therapeutic target for the prevention of delayed cerebral ischemia (DCI). We conducted a double-blind, placebo-controlled, phase Ib randomized trial of GSK2256294, a pharmacologic inhibitor of sEH, to evaluate the safety profile and to assess biomarkers of neurovascular inflammation in patients with aneurysmal SAH.

Methods

Patients were randomly assigned to receive 10 mg of GSK2256294 or a placebo treatment once daily for 10 days, beginning within 72 hours after aneurysm rupture. The primary study end point was safety. Secondary end points included serum and cerebrospinal fluid (CSF) EETs-to-DHETs ratio, cytokine levels, and serum endothelial injury biomarkers, measured at day 7 and day 10 after SAH. Tertiary end points included neurologic status, disposition, length of stay, incidence of DCI, and mortality; these were assessed at hospital discharge and at 90 days.

Results

Ten patients received GSK2256294 and nine patients received a placebo. There were no adverse events related to the study drug. GSK2256294 administration resulted in a significant increase in the EET/DHET ratio at day 7 and day 10 in serum, but not in the CSF. There was a trend for decreased CSF inflammatory cytokines following GSK2256294 administration, but this did not reach statistical significance.

Conclusions

GSK2256294 administration was safe and well tolerated in critically ill patients with SAH, producing an increase in serum EETs and the EET-to-DHET ratio. Our findings support future studies in a larger population to evaluate the role of sEH inhibition in the prevention of DCI after SAH and other forms of brain injury and inflammatory conditions.

Clinical trial registration

ClinicalTrials.gov: NCT03318783.

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Funding

This study was supported by a Mentored Research Training Grant from the Foundation for Anesthesia Education and Research to R. Martini. GlaxoSmithKline provided the study drug free of charge.

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Authors and Affiliations

  1. Oregon Anesthesiology Group, Portland, OR, USA

    Ross P Martini

  2. Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA

    Ross P Martini, Nabil J. Alkayed & Elyse Allen

  3. Department of Neurosurgery, Oregon Health and Science University, Portland, OR, USA

    Dominic Siler & Justin Cetas

  4. Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA

    Nabil J. Alkayed & Elyse Allen

  5. Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, TMP3, New Haven, CT, 06510, USA

    Miriam M Treggiari

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  1. Ross P Martini
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  4. Nabil J. Alkayed
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Contributions

RPM contributed to the conception and design, data analysis, interpretation of the data, drafting of the work, giving final approval of the version to be published, and obtaining funding. DS, JC, NJA contributed to the conception, interpretation of the data, revising the work for critically for important intellectual content, giving final approval of the version to be published. EA contributed to developing and performing the Luminex assay and biomarkers analyses, giving final approval of the version to be published. MMT contributed to the conception and design, data analysis, interpretation of the data, revising the work for critically for important intellectual content, giving final approval of the version to be published, and obtaining funding.

Corresponding author

Correspondence to Miriam M Treggiari.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Martini, R.P., Siler, D., Cetas, J. et al. A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 36, 905–915 (2022). https://doi.org/10.1007/s12028-021-01398-8

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  • DOI: https://doi.org/10.1007/s12028-021-01398-8

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