title: Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial.
abstract: BACKGROUND
  Preclinical models of stroke have shown that intravenous glyburide reduces brain swelling and improves survival. We assessed whether intravenous glyburide (RP-1127; glibenclamide) would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction.
  
  
  METHODS
  For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18-80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion-weighted MRI image lesion volume of 82-300 cm(3) on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous glyburide group. Intravenous glyburide was given as a 0·13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0·16 mg/h for the first 6 h and then 0·11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov, number NCT01794182.
  
  
  RESULTS
  Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous glyburide group and 14 (39%) in the placebo group had an mRS score of 0-4 at 90 days without decompressive craniectomy (adjusted odds ratio 0·87, 95% CI 0·32-2·32; p=0·77). Ten (23%) of 44 participants in the intravenous glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0·76), and four of 20 had serious adverse events (two in the intravenous glyburide group and two in the placebo group, p=1·00). One cardiac death occurred in each group (p=1·00).
  
  
  CONCLUSIONS
  Intravenous glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous glyburide.
  
  
  BACKGROUND
  Remedy Pharmaceuticals.
authors: Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: kevin.sheth@yale.edu.
authors: Kevin N
authors: KN
authors: Sheth
authors: Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
authors: Jordan J
authors: JJ
authors: Elm
authors: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Bradley J
authors: BJ
authors: Molyneaux
authors: Department of Neurology, Oregon Health Sciences University, Portland, OR, USA.
authors: Holly
authors: H
authors: Hinson
authors: Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Yale University School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
authors: Lauren A
authors: LA
authors: Beslow
authors: Department of Radiology, Yale University School of Medicine, New Haven, CT, USA.
authors: Gordon K
authors: GK
authors: Sze
authors: Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors: Ann-Christin
authors: AC
authors: Ostwaldt
authors: Division of Hematology, Department of Medicine, and Department of Neurology, University of Washington, Seattle, WA, USA.
authors: Gregory J
authors: GJ
authors: Del Zoppo
authors: Department of Neurosurgery, University of Maryland, Baltimore, MD, USA.
authors: J Marc
authors: JM
authors: Simard
authors: Remedy Pharmaceuticals, New York, NY, USA.
authors: Sven
authors: S
authors: Jacobson
authors: Department of Neurology, Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Boston, MA, USA. Electronic address: wtkimberly@mgh.harvard.edu.
authors: W Taylor
authors: WT
authors: Kimberly
mesh_terms: D061605:Administration, Intravenous; D000368:Aged; D001929:Brain Edema / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D002544:Cerebral Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care
chemical_list: D007004:Hypoglycemic Agents; D005905:Glyburide