Positive outcomes from phase II trial of Cirara (glibenclamide for injection) in stroke patients- Remedy Pharmaceuticals

Remedy Pharmaceuticals announced preliminary results from GAMES-RP, an exploratory Phase II randomized double blind, placebo-controlled, multi-center trial in severe stroke patients administered Cirara (glibenclamide for injection). The 90-day follow up finds that mortality in the Cirara group was reduced by 53% vs. placebo. There were also no deaths in patients treated with Cirara less than 8 hours from onset of stroke. In contrast, half the placebo subjects treated in less than 8 hours died and 29% more Cirara-treated subjects had 0–4 modified Rankin Scale (mRS) – which runs from 0 to 6, 0 being perfect health, to 6 indicating death – vs. placebo patients. In subjects dosed for less than 8 hours, 75% of Cirara patients had 90-day mRS of 0–4 and 63% had a 90-day mRS of 0–3, vs. 25% for both mRS of 0–3 and 0–4 in the placebo group. Midline shift, a key indicator of brain swelling, was also halved in the Cirara group vs. placebo. There were no safety issues reported.

Of the 77 patients in the primary analysis, there were 19 deaths within the first 30-day period, 6 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, 7 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%.

An unexpected observation from the study was the apparent randomness of decompressive craniotomy (DC), a neurosurgical procedure to prevent compressing normal brain and to lower the intracranial pressure. Thirteen subjects, or 32% of Cirara subjects received a DC, versus 8, or 22% of placebo subjects (p=0.35). There was no correlation with either growth in diffusion weighted image lesion volume or midline shift, two key selection criteria commonly used for determining whether a patient should undergo DC. Variability in the use of DC appeared to be predominantly site related. Some centres 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 this inconsistent practice of DC, the study showed no difference in its primary composite endpoint of improved 90-day modified Rankin Score (mRS) of 0-4 AND no DC, which was 42% for Cirara subjects versus 39% for placebo subjects (p=0.77).