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

Jingjing Zhao, Changgeng Song, Deshuai Li, Xiai Yang, Liping Yu, Kangjun Wang, Jun Wu, Xiaofeng Wang, Dongsong Li, Bo Zhang, Binyong Li, Jun Guo, Weikui Feng, Feng Fu, Xinrong Gu, Jian Qian, Jialong Li, Xiangjun Yuan, Qiuwu Liu, Jiang Chen, Xiaocheng Wang, Yi Liu, Dong Wei, Ling Wang, Lei Shang, Fang Yang, Wen Jiang, GATE-ICH Study Group, Jingjing Zhao, Changgeng Song, Deshuai Li, Xiai Yang, Liping Yu, Kangjun Wang, Jun Wu, Xiaofeng Wang, Dongsong Li, Bo Zhang, Binyong Li, Jun Guo, Weikui Feng, Feng Fu, Xinrong Gu, Jian Qian, Jialong Li, Xiangjun Yuan, Qiuwu Liu, Jiang Chen, Xiaocheng Wang, Yi Liu, Dong Wei, Ling Wang, Lei Shang, Fang Yang, Wen Jiang, GATE-ICH Study Group

Abstract

Background: Glibenclamide is a promising agent for treating brain oedema, but whether it improves clinical outcomes in patients with intracerebral haemorrhage (ICH) remains unclear. In this study, we aimed to explore the efficacy and safety of glibenclamide treatment in patients with acute ICH.

Methods: The Glibenclamide Advantage in Treating Oedema after Intracerebral Haemorrhage (GATE-ICH) study was a randomised controlled phase 2 clinical trial conducted in 26 hospitals in the northwest of China, recruiting patients with acute ganglia ICH no more than 72 h after onset from Dec 12, 2018 to Sept 23, 2020. During the first 7 days after enrolment, patients randomly assigned to the glibenclamide group were given glibenclamide orally (1.25 mg, 3/day) and standard care, while patients randomly assigned to the control group were given standard care alone. The computer-generated randomisation sequence was prepared by a statistician not involved in the rest of the study. Randomisation was computer-generated with a block size of four. The allocation results were unblinded to participants and investigators. The primary outcome was the percentage of patients with poor outcome (defined as modified Rankin Scale [mRS] score of ≥3) at day 90. The trial was registered at ClinicalTrials.gov (NCT03741530).

Findings: 220 participants were randomised and 200 participants (mean [standard deviation] age, 56 [11] years; sex, 128 [64.0%] male and 72 [36.0%] female) were included in the final analysis, with 101 participants randomly assigned to the control group and 99 to the glibenclamide group. The incidence of poor outcome at day 90 was 20/99 (20.2%) in glibenclamide group and 30/101 (29.7%) in control group (absolute difference, 9.5%; 95% confidence interval [CI], -3.2%-21.8%; P = 0.121) with adjusted odds ratios of 0.54 (95% CI, 0.24-1.20; P = 0.129). No significant difference was found in the overall rates of adverse events or serious adverse events between groups. However, the incidence of asymptomatic hypoglycaemia was significantly higher in glibenclamide group than control group (15/99 [15.2%] vs 0/101 [0.0%]; absolute difference, 15.2%; 95% CI, 7.5%-24.1%; P < 0.001).

Interpretation: Our study provides no evidence that glibenclamide (1.25 mg, 3/day) significantly reduces the proportion of poor outcome at day 90 after ICH. In addition, glibenclamide could result in higher incidence of hypoglycaemia. Larger trials of glibenclamide with optimised medication regimen are warranted.

Funding: Shaanxi Province Key Research and Development Project (2017DCXL-SF-02-02) and Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation (tzjhjw).

Keywords: Glibenclamide; ICH, Intracerebral haemorrhage; Intracerebral haemorrhage; PHE, Perihemaetomal oedema; Perihemaetomal oedema; Prognosis.

Conflict of interest statement

JZ reports grants from the Xijing Hospital Clinical Research Program (XJZT18ML15) outside the submitted work. FY reports grants from the Shaanxi Province Key Research and Development Project (2020SF-306) outside the submitted work. WJ reports grants from the National Natural Science Foundation of China (81771406 and 81974204) outside the submitted work, the Shaanxi Province Key Research and Development Project (2017DCXL-SF-02-02) and Shaanxi Province Special Support Program for Leading Talents in Scientific and Technological Innovation (tzjhjw) for this study. All other authors declare no competing interests.

© 2022 The Author(s).

Figures

Figure 1
Figure 1
CONSORT Diagram.
Figure 2
Figure 2
Blood glucose during the intervention period. Median blood glucose over the 7-day trial period, expressed in mmol/L (mean difference: glibenclamide group vs. control group, -0.641 [-1.027− -0.256], P = 0.001. Time, 0.034 [0.022-0.046], P < 0.001). The dashed vertical line indicates 2 h after enrolment, and error bars indicate interquartile range.
Figure 3
Figure 3
Outcomes at day 90 according to the Scores on mRS. Distribution of 90-day scores on mRS for mITT population and PP population. 200 patients in the mITT analysis, including 101 patients in control group and 99 patients in glibenclamide group. 193 patients in the PP analysis, including 98 patients in control group and 95 patients in glibenclamide group. Abbreviations: mITT, modified intention-to-treat; mRS, modified Rankin Scale; PP, per-protocol.

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Source: PubMed

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