Neurology Today Conference Reporter: AAN Annual Meeting

Access daily, concise peer-reviewed reports from the AAN Annual Meeting selected by the Neurology Today editors.

Monday, April 18, 2016

IV Glyburide Shows Promise in Reducing Edema After Ischemic Stroke


VANCOUVER—Administering an intravenous (IV) version of the oral diabetes drug glyburide within 10 hours of a severe ischemic stroke may safely reduce brain edema, according to findings from a phase 2 clinical trial presented here on Saturday at the AAN Annual Meeting.

The double-blind, randomized, placebo-controlled study — referred to as GAMES (Glyburide Advantage in Malignant Edema and Stroke) — was conducted at 18 stroke centers and included 88 patients between the ages of 18 and 80, with baseline stroke lesion volumes of between 82 and 300 cm3.  Glyburide IV was administered to 44 patients, while 38 others were given a placebo bolus followed by a continuous 72-hour infusion within a target of 10 hours.

 The investigators reported that the study did not meet its composite primary outcome — a modified Rankin Scale (mRS) of 0-4 without decompressive craniectomy (DC) at 90 days — but there was trend toward a reduction in mortality and improved functional outcome on shift analysis of mRS scores. The data showed that IV glyburide RP-1127 reduced midline shift and matrix metalloproteinase 9 (MMP-9) levels, both neuroimaging markers of brain edema.

Treated patients who did not undergo decompressive craniectomy had a greater decrease in midline shift at 72 to 96 hours (4.4 ± 3.6 mm compared with 8.8 ± 4.9 mm in the placebo group), the researchers found. Hemispheric swelling was 49 mL in the treatment arm versus 77 mL in subjects given placebo, while swelling volume was 41 mL versus 75mL, respectively. MMP-9 levels were also lower in patients who received glyburide IV at 211 ng/mL, compared with 345 ng/mL in the placebo group.

The researchers found no difference in the frequency and severity of adverse events between treated and placebo groups — 68 percent versus 72 percent, respectively. An analysis of outcomes at six months in subjects 70 years of age or younger showed a three-fold reduction in overall mortality, as well as a ten-fold decrease in death resulting from brain swelling.

The absolute mortality rate for treated patients was about 50 to 60 percent lower in the treatment arm compared with the placebo group, the researchers reported.

 "There is currently no therapy available for reducing brain edema, but I think that the findings are provocative enough for further study, and we hope to begin a larger phase 3 trial by the end of this year," the principal investigator Kevin N. Sheth, MD, FAAN, associate professor of neurology and neurosurgery and division chief of neurocritical care and emergency neurology at Yale University School of Medicine in New Haven, CT, told the Neurology Today Conference Reporter.

Although the study failed to meet efficacy endpoints, its positive findings, together with its safety profile, should encourage further study in a larger group of patients, Dr. Sheth said, adding: "We also observed that younger patients seem to be at greater risk from edema after an ischemic stroke, and we hope to include more patients under the age of 70 in the phase 3 study."

Commenting on the study, Edward M. Manno, MD, FAAN, a professor of neurosurgery and neurology at Cleveland Clinic and chief of neurocritical care at Cleveland Clinic's Cerebrovascular Center, said: "I think the researchers picked the wrong primary endpoint using modified Rankin Scale (mRS) scores without decompressive craniectomy. They used decompressive craniectomy as an endpoint, and when these were performed it was not standardized so the application of this procedure was not controlled. Reduction in midline shift would have made a better endpoint."

Dr. Manno also noted that in preclinical studies as well as in the phase 1 GAMES trial, the researchers were able to use one-tenth of the dose of glyburide, a water channel aquaporin inhibitor, and while glyburide appears to be safe in most patients, it would be contraindicated in patients with sulfonamide allergies.

"I don't think that it is surprising that the researchers failed to achieve a modified Rankin Scale at 90 days," said Michael James, MD, an associate professor of anesthesiology and neurology at Duke University Medical Center in Durham, NC. "The problem is that unless you have data for a longer period, the results are iffy. The findings are significant but still borderline, especially with regard to midline shift where not everyone responds the same," he said.​