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 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.

Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) Score

“…16.5% of participants did not have fully documented neurologic exams—in these cases only listed findings were scored. While our use of the composite outcome of death or DHC has precedent, 15 it could introduce bias as practitioners may have different thresholds for surgical intervention. Practice variability is arguably less at a single institution, it may nevertheless limit the score's generalizability.…”

Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial: Rationale and Design

“…In order to translate these findings into clinical practice, we completed GAMES-Pilot, a phase IIa open label study of 10 subjects with large anterior circulation ischemic stroke at high risk of malignant edema and poor outcome [13,14]. Drug administration was safe and well tolerated, and compared to historical controls, mortality and functional outcomes were improved [13,14].…”

“…Drug administration was safe and well tolerated, and compared to historical controls, mortality and functional outcomes were improved [13,14]. We now describe the design of a phase II clinical trial, underline the rationale, and present the primary components of the statistical plan.…”

Human Data Supporting Glyburide in Ischemic Stroke

“…In addition, there were no PH1/PH2 hemorrhages, despite 9/10 patients receiving IV rtPA. Neurological outcome at three months, overall mortality, need for DC, and hemorrhagic transformation were all improved compared to historical, matched patients 19,20 . GAMES-Pilot was a non-randomized, unblinded study with a small sample size; however, safety at the target dose of 3 mg/day and preliminary signals of efficacy provided the motivation for a randomized, double-blind phase IIb study.…”

“…The Glyburide Advantage in Malignant Edema and Stroke (GAMES) Pilot study 19,20 (ClinicalTrials.gov identifier: NCT01268683) evaluated the safety and feasibility of administering a 3 mg dose of RP-1127 in patients with severe stroke at high risk for swelling. The primary objective of this prospective, open-label, phase IIa study was to assess the feasibility of enrolling, evaluating, and treating with RP-1127 (bolus followed by 72 hour infusion at 3 mg/day dose) patients with severe ischemic stroke, whether or not they were treated with IV rtPA.…”