Exploratory analysis of glyburide as a novel therapy for preventing brain swelling

Kevin N. Sheth, W. Taylor Kimberly, Jordan J. Elm, Thomas A. Kent, Albert J. Yoo, Götz Thomalla, Bruce Campbell, Geoffrey A. Donnan, Stephen M. Davis, Gregory W. Albers, Sven Jacobson, Gregory Del Zoppo, J. Marc Simard, Barney J. Stern, Pitchaiah Mandava

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Malignant infarction is characterized by the formation of cerebral edema, and medical treatment is limited. Preclinical data suggest that glyburide, an inhibitor of SUR1-TRPM4, is effective in preventing edema. We previously reported feasibility of the GAMES-Pilot study, a two-center prospective, open label, phase IIa trial of 10 subjects at high risk for malignant infarction based on diffusion weighted imaging (DWI) threshold of 82 cm3 treated with RP-1127 (glyburide for injection). In this secondary analysis, we tested the hypothesis that RP-1127 may be efficacious in preventing poor outcome when compared to controls. Methods: Controls suffering large hemispheric infarction were obtained from the EPITHET and MMI-MRI studies. We first screened subjects for controls with the same DWI threshold used for enrollment into GAMES-Pilot, 82 cm3. Next, to address imbalances, we applied a weighted Euclidean matching. Ninety day mRS 0-4, rate of decompressive craniectomy, and mortality were the primary clinical outcomes of interest. Results: The mean age of the GAMES cohort was 51 years and initial DWI volume was 102 ± 23 cm3. After Euclidean matching, GAMES subjects showed similar NIHSS, higher DWI volume, younger age and had mRS 0-4 - 90 % versus 50 % in controls p = 0.049; with a similar trend in mRS 0-3 (40 vs. 25 %; p = 0.43) and trend toward lower mortality (10 vs. 35 %; p = 0.21). Conclusions: In this pilot study, RP-1127-treated subjects showed better clinical outcomes when compared to historical controls. An adequately powered and randomized phase II trial of patients at risk for malignant infarction is needed to evaluate the potential efficacy of RP-1127.

Original languageEnglish (US)
Pages (from-to)43-51
Number of pages9
JournalNeurocritical care
Volume21
Issue number1
DOIs
StatePublished - Aug 2014
Externally publishedYes

Keywords

  • Brain swelling
  • Cerebral edema
  • Clinical trial
  • Decompressive craniectomy
  • Hemorrhage
  • Hemorrhagic transformation
  • Malignant edema
  • Stroke

ASJC Scopus subject areas

  • Clinical Neurology
  • Critical Care and Intensive Care Medicine

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