GAMES-RP: Can Glyburide Reduce Edema in Severe Stroke?

February 24, 2016

LOS ANGELES — The diabetes drug glyburide, given as an intravenous (IV) infusion within 10 hours of onset of a very severe stroke, did not show an effect on the main primary and secondary endpoints in a phase 2 study but did show some other promising effects that will be studied further in a larger trial.

The drug, which is aimed at preventing edema, a common and devastating consequence of very severe stroke, did not show a significant effect on the incidence of decompressive surgery — a therapeutic option often tried when edema occurs.

However, it was associated with a strong trend toward a reduction in mortality and in the shift analysis of modified Rankin Scale (mRS) scores, as well as neuroimaging and plasma biomarkers of edema.

Glyburide is a generic compound but it is being developed for the indication of prevention of brain edema after stroke by Remedy Pharmaceuticals, which has patented an IV formulation, under the brand name Cirara, for neurologic diseases.

Presenting the study here at the International Stroke Conference (ISC) 2016, Taylor Kimberly, MD, Massachusetts General Hospital, Boston, explained that patients with very severe strokes had few medical options and tissue plasminogen activator (tPA) is generally ineffective.

Dr Taylor Kimberly

"These patients with very large strokes progress to a large amount of edema in the brain, which accumulates over a 2- to 3-day period and is associated with a dramatic clinical deterioration in the patient, and a mortality rate of 30% to 50%.There is a real need for new therapeutic options."

He noted that glyburide represents a novel strategy aimed at blocking specific sodium ion channels in the brain, which open at the time of ischemia, allowing the influx of sodium and fluid and causing edema.

While the main study endpoints were not significant, Dr Kimberley said the trial included a series of intermediate endpoints "to guide interpretation of the clinical results."

"We were very encouraged by some of these findings and we will use these observations to design a phase 3 trial, GAMES-3," he added.

Dr Kimberly said that in hindsight, decompressive surgery probably wasn't the best endpoint to use because there is a large variation between different centers and clinicians as to when to perform such surgery. "All of us have variations in practice. This is a really important point to learn. No one has done this sort of study before and this was one of the goals — to learn and inform for the next phase."

Outside commentators were also cautiously optimistic about the exploratory endpoints in the study.

Bruce Ovbiagele, MD, vice chair of ISC 2016 and chief of neurology at Medical University of South Carolina, Charleston, said, "Although they didn't meet their main endpoints, some of the other exploratory findings accorded with the conceptual issue. They were looking for a reduction in markers of edema and that did occur. That makes so much sense and when you have that you can be confident in moving forward to further studies."

Dr Bruce Ovbiagele

American Heart Association/American Stroke Association spokesperson Philip Gorelick, MD, Hauenstein Neuroscience Center, Grand Rapids, Michigan, added: "It is very interesting to repurpose a diabetes drug to a targeted receptor in this way. The basic science is there. My question is whether targeting this one pathway will be enough or whether we need a more multifaceted approach. But there is certainly potential, keeping in mind this was a relatively small study."

Dr Philip Gorelick

The GAMES-RP study was a multicenter, prospective, randomized, double-blinded study in 83 patients with a large hemispheric stroke (mean National Institutes of Health Stroke Scale score, 20) who were randomly assigned to IV infusion of glyburide or placebo within 10 hours of stroke onset.

Use of IV tPA up to 4.5 hours was permitted, but patients treated with endovascular thrombectomy were excluded. The study drug was given a mean of 9 hours after stroke onset.

The trial did not meet its primary or secondary endpoints. Serious adverse events did not differ between the treatment groups.

Table. GAMES-VR: Main Results

Endpoint Glyburide Placebo P Value
Composite of decompressive surgery or dead by day 14 (primary endpoint) (%) 37 44 .48
Median change in ipsilateral hemispheric swelling (cm3) 68 78 .28
Median lesional swelling at 72 - 96 h (cm3 ) 58 78 .41
Serious adverse events (%) 68 72 .72


However, the study did show a 50% reduction in mortality in the glyburide group (17% vs 36%; P = .06), a 3-fold reduction in neurologic death, and a positive directional trend in functional outcomes on the mRS shift analysis.

There were also a 50% "very significant" reduction in the midline shift, a neuroimaging biomarker of edema (P = .0006); a 40% reduction in matrix metallopeptidase 9, a plasma biomarker of edema (P = .006); and a 10-fold reduction in death from edema (22% to 2%; P = .008).

GAMES-RP was sponsored by Remedy Pharmaceuticals.

International Stroke Conference (ISC) 2016. Abstracts LB6 and LB24. Presented February 19, 2016.


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