Brain swelling resulting from a large, acute stroke event causes further damage and can lead to major disability and death, and there are few effect treatment options. Existing drug regimens do not improve survival or functional outcome. Decompressive craniectomy, a surgical procedure to remove part of the skull, allowing the brain to swell without being squeezed, improves outcomes in some patients but increases survival with major disability in others.
Future treatments are likely to target pathways involved in brain swelling, and several potential candidates have been identified. One of these key mediators is a suphonylurea receptor pathway triggered by ischaemia and hypoxia, that can be inhibited by glyburide, a drug given orally to people with diabetes to control their blood sugar levels. In rodent models of stroke, glyburide, delivered by continuous intravenous infusion, reduces brain swelling. A pilot study involving 10 stroke patients showed the drug is well tolerated, but its efficacy in humans remains unclear.
Holly Hinson, M.D., M.C.R., assistant professor in the Department of Neurology at OHSU, co-authored a paper published on Aug. 23, 2016, in The Lancet Neurology entitled “Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial.” The clinical trial involved 77 patients; 41 participants received intravenous glyburide, and 36 received placebo. Outcomes were measured using the modified Rankin Scale from 0-6 where 0 represents no symptoms at all, and 6 represents death. The percentage of people with a score of 0-4 (healthy to moderate disability) at 90 days was not significantly different between the glyburide and placebo groups, and mortality was not significantly reduced overall. However, function outcome measured by the Rankin Scale was improved in patients treated with the active drug.
Though the primary end point was negative, the results are consistent with the preclinical and pilot studies showing the sulphonylurea receptor pathway plays an important role in the formation of brain swelling, and treatment with intravenous glyburide is well tolerated in acute ischemia stroke patients. The study was cut short due to funding issues, resulting in too small a sample size to provide statistically significant data on efficacy. But the results are encouraging enough to warrant further investigation. A larger phase 3 trial is planned for early 2017.
This research was funded by Remedy Pharmaceuticals, Inc., and was conducted in collaboration with researchers from Yale University School of Medicine, Medical University of South Carolina, University of Pittsburgh, Massachusetts General Hospital, University of Washington, and University of Maryland.