title: Exploratory analysis of glyburide as a novel therapy for preventing brain swelling.
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 cm(3) 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 cm(3). 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 cm(3). 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.
authors.affiliation: Departments of Neurology and Neurosurgery, Yale University School of Medicine, 15 York Street, LCI 710A, New Haven, CT, 06520, USA, kevin.sheth@yale.edu.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Sheth
authors.forename: W Taylor
authors.initials: WT
authors.lastname: Kimberly
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Elm
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kent
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Yoo
authors.forename: Götz
authors.initials: G
authors.lastname: Thomalla
authors.forename: Bruce
authors.initials: B
authors.lastname: Campbell
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Donnan
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Davis
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Albers
authors.forename: Sven
authors.initials: S
authors.lastname: Jacobson
authors.forename: Gregory
authors.initials: G
authors.lastname: del Zoppo
authors.forename: J Marc
authors.initials: JM
authors.lastname: Simard
authors.forename: Barney J
authors.initials: BJ
authors.lastname: Stern
authors.forename: Pitchaiah
authors.initials: P
authors.lastname: Mandava
mesh_terms: D000328:Adult; D000368:Aged; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control*; D020520:Brain Infarction / Q000150:complications / Q000473:pathology*; D017322:Clinical Trials, Phase II as Topic; D038524:Diffusion Magnetic Resonance Imaging; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D010865:Pilot Projects; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D005905:Glyburide