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Impressive Results From Cirara in Phase II Studies
Results from a phase II trial announced at the Neurocritical Care Society meeting in Arizona are creating a buzz.
The GAMES-RP trial was a randomized, double-blind, placebo-controlled, multicenter trial in severe stroke patients who were administered intravenous glyburide (Cirara, Remedy Pharmaceuticals). The trial assessed the impact of a reformulated version of glyburide, which has been used to treat diabetes for decades. Intravenous Cirara is delivered in a three-stage dosing regimen designed to target swelling following a central nervous system injury.
Remedy Pharmaceuticals reported that of the 77 patients in the primary analysis, there were 19 deaths in the first 30-day period: six of 41 in the Cirara group (14%) versus 13 of 36 (36%) in the placebo group (P = 0.03), corresponding to a reduction in mortality of 62%. Within the 90-day follow-up period, there were a total of 20 deaths: Seven of 41 subjects in the Cirara group (17%) versus 13 of 36 (36%) in the placebo group (P = 0.06), a reduction in mortality of 53%.
The modified Rankin Scale (mRS) is a common outcome measure to determine the degree of disability or dependence in the daily activities of people who have suffered a stroke. The scale runs from 0 (perfect health) to 6 (death). Of the Cirara group, 61% had a 90-day mRS of 0–4, versus 47% for the placebo group (p = 0.23). The median mRS in the Cirara group was 4, versus 5 in the placebo arm (P = 0.18). In subjects dosed within eight hours, 63% (5/8) had a 90-day mRS of 0–3, versus 25% (2/8) of more-than-eight-hour placebo subjects.
Brain edema formation is a serious and deadly complication in large strokes. As the affected hemisphere of the brain swells, its space-occupying effect can cause the brain to shift past the midline, pushing into and compressing the other hemisphere of the brain. This shift results in altered consciousness and, when severe, coma. Consistent with Cirara’s mechanism of action, there was a 50% reduction in edema measured by midline shift at 72 to 96 hours, to 4.4 mm for Cirara-treated patients versus 8.8 mm in the placebo group (P = 0.0006)
An unexpected observation from the study was the apparent randomness of decompressive craniotomy (DC), a neurosurgical procedure in which a large part of the skull is removed (and later reattached) to allow the swollen brain room to expand outward, to prevent compressing normal brain and to lower the intracranial pressure. Thirteen Cirara subjects (32%) received a DC, versus eight (22%) placebo subjects (P = 0.35). Variability in the use of DC appeared to be predominantly site-related. Some centers performed no DCs, and at others up to 75% of subjects had a DC. Nevertheless, based on post hoc analysis Cirara patients had improved outcomes regardless of whether they had a DC or not.
As a result of the inconsistent practice of DC, the study missed statistical significance in its primary composite endpoint of improved 90-day mRS of 0–4 and no DC, which was 42% for Cirara subjects versus 39% for placebo subjects (P = 0.77).
About 10% to 15% of the 800,000 Americans who suffer strokes annually suffer from large, ischemic strokes, in which blood clots develop dangerous levels of swelling in the brain. About half of these patients end up dying.
Sources: Remedy Pharmaceuticals, October 9, 2015; Medical Xpress, October 12, 2015.