Recent findings from a phase 3 study revealed improvements in independent ambulation and overall functional outcomes in patients with large hemispheric infarction treated with intravenous glibenclamide.
Sven Jacobson
(Credit: The Org)
According to new data from the phase 3 CHARM trial (NCT02864953), findings revealed significant improvement in the ability to ambulate independently following administration of intravenous (IV) glibenclamide (CIRARA; Remedy Pharmaceuticals), specifically when used in combination with endovascular thrombectomy (EVT), among patients with large hemispheric infarction (LHI).1
In the new post hoc analyses, patients with a lesion volume under 125 mL (n = 118) who were treated with CIRARA reported an odds ratio (OR) of 4.1 to achieve modified Rankin Scale (mRS) scores of 0-3 following treatment (P <.01). Overall, researchers reported an OR of 18.5 to achieve a better functional outcome, particularly in the ability to ambulate independently (P = .03), among patients in the modified intent-to-treat population with a lesion volume of less than 125 mL (n = 34) who received CIRARA with EVT.
"These new findings are incredibly encouraging and provide strong evidence that CIRARA could be a game-changer in the treatment of large hemispheric infarction," Sven Jacobson, CEO of Remedy Pharmaceuticals, said in a statement.1 "The significant improvements in functional outcomes, and particularly the increased rates of independent ambulation, highlight the potential of CIRARA to revolutionize stroke care and offer new hope to patients and their families."
CHARM was a multicenter, multinational, double-blind, randomized, placebo-controlled phase 3 study that consisted of patients aged 18-85 with LHI who presented later than 10 hours after they were last known well. In the trial, investigators enrolled a total of 535 patients, including 431 patients aged 18-70 that were used for the efficacy analysis population, and 81 patients aged 71-85. The company noted that the study was terminated early by Cambridge-based Biogen following a strategic realignment of resources, which led to the return of the program to it.
Despite neutral top-line results, post-hoc data from the phase 3 CHARM trial announced in May showed that treatment with CIRARA resulted in meaningful improvements in functional outcomes among subgroups of patients with LHI.2 Furthermore, a pre-specified analysis of patients who received recombinant tissue plasminogen activator (rtPA) and underwent EVT highlighted the treatment benefits of CIRARA over placebo.
In a subgroup of patients with National Institute of Health Stroke Scale (NIHSS) less than 20 (n = 274), findings showed statistically significant improvements in functional outcomes on the mRS, indicated by OR of 1.66 (P = .03). With EVT therapy increasingly used in LHI, investigators observed an OR of 1.75 favoring CIRARA in combination with the treatment. While not statistically significant, the study authors noted these findings were particularly encouraging.
"These findings are very promising and suggest that CIRARA is complementary to current standard of care, such as tPA and endovascular therapy, and could be the next big advancement in the treatment of large hemispheric infarctions," principal investigator Taylor Kimberly, MD, PhD, chief of the Division of Neurocritical Care at Massachusetts General Hospital, and associate professor of neurology at Harvard Medical School, said in a statement at the time of the announced data.2
Currently, there are not any medications available to specifically reduce brain swelling caused by LHI. Among those in the mITT population with computed tomography perfusion (CTP)/MRI lesion volume less than 125 mL (n = 118), results showed an OR of 2.15 in favor of CIRARA (P = .04) for ambulate independently. Mortality was numerically decreased from 22% in the placebo group to 14% in the CIRARA group without an increase in severe disability. In addition, the proportion of patients with an mRS between 0-3 was 36% in the CIRARA group vs 19% for those on placebo, otherwise representing a 89% increase.
"Mortality and long-term disability remain stubbornly high, especially in cases of severe stroke,” Kevin Sheth, MD, a professor of neurology and director of the Yale Center for Brain & Mind Health, and co-principal investigator on the CHARM study, said in a statement.2 "CIRARA could help the tens of thousands of patients who fall victim to LHI each year have a fighting chance to live and enjoy productive lives."
A subgroup of patients in the mITT who underwent EVT and had CTP/MRI lesion volume less than 125 mL (n = 34) experienced even greater benefit from CIRARA. All told, this group had an OR of 7.13 favoring active treatment (P = .01) on mRS, with 62% having scores between 0-3 vs 31% of those on placebo. In addition, mortality was numerically decreased from 31% in the placebo group to 6% in the CIRARA group without an increase in severe disability.
