Abstract 211: GAMES (Glyburide Advantage in Malignant Edema and Stroke) Pilot Study

Abstract

Introduction: Malignant infarction is characterized by the formation of cerebral edema, and decompressive craniectomy (DC) is the only proven therapy. The NC (Ca-ATP) channel, regulated by the SUR1 receptor, is blocked by the sulfonylurea drug glyburide, which attenuates brain water content in preclinical models of large stroke. A phase I study has been safely completed. We assessed the hypothesis that a pilot study of RP-1127 (Glyburide for Injection) in patients at high risk for malignant infarction was safe and feasible. Methods: The objective of this four-center prospective, open label, phase IIa trial was to assess the safety and feasibility of treating severe anterior circulation ischemic stroke patients with RP-1127, whether or not treated with IV rtPA. The study enrolled patients with a baseline MRI DWI lesion between 82 cm3 and 210 cm3, age 18-80 years, and time from symptom onset to drug infusion of ≤ 10 hours. Patients received a RP-1127 bolus followed by continuous infusion for 72 hours. Results: Recruitment of 10 patients was completed within 9.6 months. The mean initial DWI lesion volume was 102 ± 23 cm3. There were no serious adverse events related to the drug. The incidence of malignant edema was 20%, compared to 88% in a prospective observational study with DWI ≥82 cm3. Further, 8/10 patients did not require any bolus osmotherapy or DC. The mean increase in ipsilateral hemisphere volume was 50±33 cm3 compared to historical controls of 71.5±27 cm3. The proportion of 30 day mRS ≤ 4 was 90% compared to 23.8% (at 12 months) in control patients from a pooled analysis of DC trials. Conclusions: These findings suggest that a Phase II trial for patients at risk of malignant infarction is feasible and will provide important insights into the safety and potential efficacy of RP-1127.