Abstract
Objective: To describe the rationale and design of CHARM, a Phase III study evaluating whether intravenous (IV) glibenclamide (BIIB093) improves functional outcomes in participants with large hemispheric infarction (LHI) at 90 days compared with placebo.
Background: LHI is a life-threatening type of ischemic stroke with high morbidity and mortality. Severe cerebral edema is a frequent complication of LHI. IV glibenclamide inhibits the SUR1/TRPM4 cation channel and may reduce cerebral edema due to LHI.
Design/Methods: CHARM is a global, randomized, multi-center, double blind, placebo-controlled, Phase III trial (NCT02864953). Part 1 will evaluate functional outcomes at 90 days. Part 2 will examine longer term disability at 6 and 12 months. Eligible participants will be 18–85 years old, have a clinical diagnosis of acute ischemic stroke of the middle cerebral artery with a baseline infarct volume between 80 cm3 and 300 cm3 assessed by diffusion-weighted magnetic resonance imaging (MRI) or computed tomography (CT) perfusion or an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) between 1–5 with at least 2 M regions, and be treatable with IV glibenclamide infusion within 10 hours of the time of last known normal. Participants will be randomly assigned in a 1:1 randomization to either a 72 hours continuous infusion of IV glibenclamide or placebo and may receive standard of care therapy including alteplase and endovascular therapy. Participants will undergo imaging at baseline for eligibility and at 72–96 hours for midline shift assessment. The primary endpoint is the modified Rankin Scale (mRS) at 90 days in participants ≤70 years of age analyzed as a shift analysis using a 5-category ordinal scale (0/1 and 5/6 collapsed).
Results: CHARM began enrollment in September 2018.
Conclusions: CHARM will include ~680 participants across ~22 countries.
Disclosure: Dr. Sheth has received royalty, license fees, or contractual rights payments from Alva Health. Dr. Sheth has received research support from Biogen, Novartis, Bard, and Hyperfine. Dr. Kimberley has received research support from Biogen. Dr. Albers has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with iSchemaView, Medtronic, Biogen. Dr. Albers has received royalty, license fees, or contractual rights payments from RAPID software. Dr. Albers holds stock and/or stock options in iSchemaView. Dr. Hinson has received research support from Biogen. Dr. Molyneaux has nothing to disclose. Dr. Nogueira has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Stryker Neurovascular, Medtronic, Cerenovus/Neuravi, Phenox, Anaconda, Genentech, Biogen, Prolong Pharmaceuticals, Viz.ai, Coriundu. Dr. Nogueira holds stock and/or stock options in Viz.ai, Coriundus. Dr. Saver has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, MedAvante, and BrainsGate. Dr. Steiner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Bayer, Boehringer, BMS, Pfizer, and Daiichi Sankyo. Dr. Toyoda has nothing to disclose. Dr. Wintermark has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with MoreHealth, Magnetic Insight, Subtle Medical, Nines, icometrix, Biogen. Dr. Elkins has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Elkins holds stock and/or stock options in Biogen which sponsored research in which Dr. Elkins was involved as an investigator. Dr. Deykin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Deykin holds stock and/or stock options in Biogen. Dr. Wald has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Wald holds stock and/or stock options in Biogen, which sponsored research in which Dr. Wald was involved as an investigator. Dr. Wald holds stock and/or stock options in Amgen, Medtronic, and AbbVie. Dr. Landen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen.
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