Although the participants had all had severe strokes, there were no safety concerns. The team was able to obtain daily MRIs and to look at other outcomes, compared with those of historical controls.
One of the 10 participants died, compared with a much higher percentage among controls with similar-sized strokes, Dr. Kimberly said. Signal intensity from fluid-attenuated inversion recovery (FLAIR) MRI, a marker of vasogenic edema, was significantly lower among those who received IV glyburide. Metalloproteinases (MMP9) in the plasma were also measured, revealing “the suggestion of a dose response,” he said.
This was followed by the GAMES-RP trial, a phase II double blind placebo-controlled trial led by Drs. Kimberly and Sheth that was recently completed. For the 83 patients that were enrolled, the primary efficacy end point was a modified Rankin score (mRS) of 0 to 4 without decompression, and the primary safety end point was hypoglycemia. Remedy Pharmaceuticals said that mortality was reduced by 53% in patients treated with Cirara, compared with placebo, and that 75% of patients dosed in less than eight hours had a 90-day mRS score of 0–3, versus 25% of those in the placebo group.
“This is the first primary prevention trial for brain edema,” Dr. Kimberly noted, adding that open questions remain. “In patients with malignant edema, we still need to determine the appropriate clinical and intermediate end points for further trials.” Another key question is whether edema is a problem for moderately sized strokes.
“Our hypothesis is that malignant edema is the tip of the iceberg,” Dr. Kimberly said, adding that the prospect of “moving from emergent reactive measures that have had only modest effect to potential targets that may be viable for the prevention of brain edema” is exciting.
—Helen Lippman