Results of a preliminary study presented at the International Stroke Conference suggest that IV glyburide may aid patients with stroke at high risk for excessive cerebral edema.
The GAMES-RP trial tested the safety and preliminary efficacy of IV glyburide (RP-1127, Remedy Pharmaceuticals) for critically ill patients with acute ischemic stroke at high risk for cerebral edema.
The randomized, double blind, placebo-controlled, phase 2 study was conducted at 18 U.S. centers. Patients were randomly assigned to receive an IV bolus (31 mL/hour) and then continuous 72-hour infusion (21 mL/hour) of glyburide (n = 44) or placebo (n = 39) within 10 hours of stroke onset. All patients were followed for 6 months.
Eligible patients presented with a baseline lesion between 82 cm3 and 300 cm3 and were aged 18 to 80 years. Patients treated with endovascular thrombectomy were excluded.
The outcomes of interest included: a composite of modified Rankin scale score of 0-4 and avoidance of decompressive craniectomy; a composite of decompressive craniectomy and mortality by day 14; change in ipsilateral hemispheric swelling; lesional swelling at 72 to 96 hours; and serious adverse events.
The trial did not meet its primary or secondary endpoints, according to data presented. The researchers observed no difference in the composite outcome of modified Rankin scale score of 0-4 and avoidance of decompressive craniectomy at 90 days (P = .77). However, there was a trend toward an effect in all-cause mortality, in shift analysis of the modified Rankin scale, and a potential reduction in neurological causes of death. The researchers reported a significant decrease in all-cause mortality (17% vs. 36%; P = .06) and in mortality due to neurological causes (7% vs. 25%; P = .03) in the glyburide group. The frequency of severe adverse events was 68% in the glyburide group vs. 72% in the placebo group.
According to W. Taylor Kimberly, MD, PhD, associate director, neuroscience intensive care unit, Massachusetts General Hospital, the investigators knew at the start of the trial that “this was a new therapeutic direction for the field and for this group of patients.” Kimberly said decompressive craniectomy was a challenging endpoint rates of decompressive craniectomy varied across the 18 centers in this study. For this reason, the investigators included intermediate endpoints to help guide the interpretation of the clinical endpoints, Kimberly said.
In a secondary analysis presented at ISC 2016, the researchers evaluated the effect of IV glyburide on midline shift and total matrix metalloproteinase-9 (MMP-9) levels during drug infusion. Higher MMP-9 levels were associated with malignant brain edema in this study, Kimberly reported. Patients in the glyburide group exhibited a 50% decrease in midline shift at 72 to 96 hours (4.6 3.6 mm vs. 8.4 4.9 mm; P = .0006) and a 40% reduction in MMP-9 (211 ng/mL vs. 345 ng/mL; P = .006) compared with placebo.
According to the researchers, these data provide a better understanding of the safety and efficacy of IV glyburide in this patient population as they move into a phase 3 trial.
“We are very enthusiastic about moving on to GAMES 3, where we intend to answer the question of whether this drug can improve clinical outcomes in this patient population,” Kimberly said. – by Tracey Romero
Kimberly WT, et al. LB 24. Presented at: International Stroke Conference; Feb. 16-19, 2016; Los Angeles.
isclosure: The trial was funded by Remedy Pharmaceuticals. Kimberly reports receiving funding from the American Heart Association/American Stroke Association, National Institutes of Neurological Disorders and Stroke, and Remedy Pharmaceuticals.