ESOC 2024 | Phase III CHARM trial of glibenclamide for large hemispheric infarction
Glibenclamide is a SUR1-TRPM4 channel blocker, shown in preclinical models and early clinical data to reduce cerebral edema following ischemic stroke. W. Taylor Kimberly, MD, PhD, Massachusetts General Hospital, Harvard Medical School, Boston, MA, comments of the results of the Phase III randomized, controlled CHARM study, which randomized patients with large hemispheric infarction to intravenous glibenclamide or placebo. Overall, there was no difference in functional outcomes at three months between the two groups. However, the drug was shown to be safe and a subgroup analysis indicated potential value of glibenclamide in patients with medium-large stroke volumes. Dr Kimberly highlights the importance of these data to inform future trials of the agent. This interview took place at the 10th European Stroke Organisation Conference (ESOC) 2024 in Basel, Switzerland.
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Transcript
So glibenclamide is a drug that inhibits the SUR1-TRPM4 channel and this goes back 15-20 years ago. It was discovered that this drug binds to this channel in the brain and prevents brain swelling or brain edema after brain injury like ischemic stroke. For the last 15 years, together with my colleague Dr Kevin Sheth, we’ve been working on the clinical development of IV glibenclamide in a series of clinical trials, most recently the Phase III CHARM trial...
So glibenclamide is a drug that inhibits the SUR1-TRPM4 channel and this goes back 15-20 years ago. It was discovered that this drug binds to this channel in the brain and prevents brain swelling or brain edema after brain injury like ischemic stroke. For the last 15 years, together with my colleague Dr Kevin Sheth, we’ve been working on the clinical development of IV glibenclamide in a series of clinical trials, most recently the Phase III CHARM trial.
The CHARM trial built upon our prior experience in the Phase II GAMES-RP trial which was solely based in the United States. The CHARM trial was a global trial and it enrolled 535 patients all across the globe. The idea behind the trial was to evaluate the efficacy of IV glibenclamide in improving outcomes in patients with large hemispheric stroke, a subset of ischemic stroke characterized by very large stroke that is associated with lots of brain edema and causes poor outcome. So the idea behind the trial was to test this agent in preventing brain edema and improving outcomes.
Well the overall trial was neutral, as designed. What we found however was, in our pre-specified subgroup analysis which evaluated a variety of subgroups, that the drug had a favorable effect among those who were treated with thrombectomy, those who had been treated with IV tPA, and those with a lower severity of stroke based on the NIH Stroke Scale, and also in the wakeup stroke. So while that is exploratory, it provides a lot of helpful information for the next trial.
In previous investigations we showed evidence that the drug could reduce brain edema and had some preliminary evidence for efficacy. The CHARM trial was designed to try to replicate that patient population but when you go from a single region to a global region you have to sort of balance the practical nature of expanding the number of sites where there are slightly different standards of care or different ways of imaging and evaluating patients. So while we tried to adhere to the study design in the Phase II, there was some necessary changes that we needed to make so what we’ve learned from this is that now we know exactly which patient population in terms of the stroke size and stroke severity to target for the next phase.
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