Efficacy and safety of glibenclamide therapy after intracerebral haemorrhage (GATE-ICH): A multicentre, prospective, randomised, controlled, open-label, blinded-endpoint, phase 2 clinical trial

Zhao, Jing; Song, Changgeng; Li, Deshuai; Yang, Xiai; Yu, Liping; Wang, Kangjun; Wu, Jun; Li, Dongsong; Zhang, Bo; Li, Binyong; Guo, Jun; Feng, Weikui; Fu, Feng; Gu, Xinrong; Qian, Ji; Li, Jialong; Yuan, Xiangjun; Liu, Qiuwu; Jiang, Chen; Wang, Xiaocheng; Liu, Yi; Wei, Dong; Shang, L.; Yang, Fang; Jiang, Wen

doi:10.1016/j.eclinm.2022.101666

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…Second, we used a relatively lower dose regimen of glibenclamide compared with that of the GAMES-RP trial and a recent trial of oral glibenclamide therapy for intracerebral hemorrhage (GATE-ICH, 1.25 mg tid). 9 , 26 The dose regimen of SE-GRACE has been found to be well tolerated in patients with acute ischemic stroke in our preliminary study, without an increased risk of hypoglycemia and early neurological deterioration. 13 In addition, our unpublished data has shown that this dose regimen was able to result in average steady-state plasma glibenclamide levels of 19 ng/mL, which was not inferior to the concentrations reached by the effective therapeutic dose in rats (16 ng/mL).…”

Section: Discussionmentioning

confidence: 71%

“… 13 In addition, our unpublished data has shown that this dose regimen was able to result in average steady-state plasma glibenclamide levels of 19 ng/mL, which was not inferior to the concentrations reached by the effective therapeutic dose in rats (16 ng/mL). 27 Unlike diabetics, non-diabetics have a higher risk of hypoglycemia even with lower doses of glibenclamide than diabetes treatment, 9 , 26 which may impair or even counteract the neuroprotective effects of glibenclamide. 28 SE-GRACE did not find an increased risk of hypoglycemia in the glibenclamide group, suggesting that this dosing regimen may be safer.…”

Section: Discussionmentioning

confidence: 99%

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Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): a randomized, double-blind, placebo-controlled trial

Huang,

Zhao,

Zhao

et al. 2023

eClinicalMedicine

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): a randomized, double-blind, placebo-controlled trial

Huang,

Zhao,

Zhao

et al. 2023

eClinicalMedicine

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“…As the search for effective treatment for ICH continues, some investigators are targeting post-ICH secondary brain injury in these patients. 20–25 However, clinical trials have thus far only applied baseline hematoma volume cutoffs as inclusion criteria for enrollment. 24 Given the emergence of automated ICH and PHE segmentation tools, 26 shape features beyond lesion volume (such as PHE sphericity) may also be incorporated in future acute ICH trial triage.…”

Section: Discussionmentioning

confidence: 99%

Peri-hematomal edema shape features related to 3-month outcome in acute supratentorial intracerebral hemorrhage

Dierksen,

Tran,

Zeevi

et al. 2024

European Stroke Journal

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Introduction: Perihematomal edema (PHE) represents secondary brain injury and a potential treatment target in intracerebral hemorrhage (ICH). However, studies differ on optimal PHE volume metrics as prognostic factor(s) after spontaneous, non-traumatic ICH. This study examines associations of baseline and 24-h PHE shape features with 3-month outcomes. Patients and methods: We included 796 patients from a multicentric trial dataset and manually segmented ICH and PHE on baseline and follow-up CTs, extracting 14 shape features. We explored the association of baseline, follow-up, difference (baseline/follow-up) and temporal rate (difference/time gap) of PHE shape changes with 3-month modified Rankin Score (mRS) – using Spearman correlation. Then, using multivariable analysis, we determined if PHE shape features independently predict outcome adjusting for patients’ age, sex, NIH stroke scale (NIHSS), Glasgow Coma Scale (GCS), and hematoma volume. Results: Baseline PHE maximum diameters across various planes, main axes, volume, surface, and sphericity correlated with 3-month mRS adjusting for multiple comparisons. The 24-h difference and temporal change rates of these features had significant association with outcome – but not the 24-h absolute values. In multivariable regression, baseline PHE shape sphericity (OR = 2.04, CI = 1.71–2.43) and volume (OR = 0.99, CI = 0. 98–1.0), alongside admission NIHSS (OR = 0.86, CI = 0.83–0.88), hematoma volume (OR = 0.99, CI = 0. 99–1.0), and age (OR = 0.96, CI = 0.95–0.97) were independent predictors of favorable outcomes. Conclusion: In acute ICH patients, PHE shape sphericity at baseline emerged as an independent prognostic factor, with a less spherical (more irregular) shape associated with worse outcome. The PHE shape features absolute values over the first 24 h provide no added prognostic value to baseline metrics.

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“…Although existing pre-clinical data suggest the need for further pre-clinical research, a recent clinical study from China nonetheless investigated the efficacy of GLC in patients who experienced mild striatal ICH in the Glibenclamide Advantage in Treating Edema after ICH (GATE-ICH) study [ 111 ]. Glibenclamide (1.25 mg) was administered orally, 3 times daily, beginning on average between 22–24 hours after stroke.…”

Section: Discussionmentioning

confidence: 99%

A systematic review and meta-analysis on the efficacy of glibenclamide in animal models of intracerebral hemorrhage

Kung,

Wilkinson,

Liddle

et al. 2023

PLoS ONE

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Intracerebral hemorrhage (ICH) is a devastating stroke with many mechanisms of injury. Edema worsens outcome and can lead to mortality after ICH. Glibenclamide (GLC), a sulfonylurea 1- transient receptor potential melastatin 4 (Sur1-Trpm4) channel blocker, has been shown to attenuate edema in ischemic stroke models, raising the possibility of benefit in ICH. This meta-analysis synthesizes current pre-clinical (rodent) literature regarding the efficacy of post-ICH GLC administration (vs. vehicle controls) on behaviour (i.e., neurological deficit, motor, and memory outcomes), edema, hematoma volume, and injury volume. Six studies (5 in rats and 1 in mice) were included in our meta-analysis (PROSPERO registration = CRD42021283614). GLC significantly improved behaviour (standardized mean difference (SMD) = −0.63, [−1.16, −0.09], n = 70–74) and reduced edema (SMD = −0.91, [−1.64, −0.18], n = 70), but did not affect hematoma volume (SMD = 0.0788, [−0.5631, 0.7207], n = 18–20), or injury volume (SMD = 0.2892, [−0.4950, 1.0734], n = 24). However, these results should be interpreted cautiously. Findings were conflicted with 2 negative and 4 positive reports, and Egger regressions indicated missing negative edema data (p = 0.0001), and possible missing negative behavioural data (p = 0.0766). Experimental quality assessed via the SYRCLE and CAMARADES checklists was concerning, as most studies demonstrated high risks of bias. Studies were generally low-powered (e.g., average n = 14.4 for behaviour), and future studies should employ sample sizes of 41 to detect our observed effect size in behaviour and 33 to detect our observed effect in edema. Overall, missing negative studies, low study quality, high risk of bias, and incomplete attention to key recommendations (e.g., investigating female, aged, and co-morbid animals) suggest that further high-powered confirmatory studies are needed before conclusive statements about GLC’s efficacy in ICH can be made, and before further clinical trials are performed.

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Efficacy and safety of glibenclamide therapy after intracerebral haemorrhage (GATE-ICH): A multicentre, prospective, randomised, controlled, open-label, blinded-endpoint, phase 2 clinical trial

Cited by 8 publications

References 35 publications

Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): a randomized, double-blind, placebo-controlled trial

Safety and efficacy of glibenclamide combined with rtPA in acute cerebral ischemia with occlusion/stenosis of anterior circulation (SE-GRACE): a randomized, double-blind, placebo-controlled trial

Peri-hematomal edema shape features related to 3-month outcome in acute supratentorial intracerebral hemorrhage

A systematic review and meta-analysis on the efficacy of glibenclamide in animal models of intracerebral hemorrhage

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