Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial
Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial
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DOI：
10.1016/s1474-4422(16)30196-x
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发表时间：
2016-10-01
期刊：
影响因子：
48
通讯作者：
Kimberly, W. Taylor
中科院分区：
文献类型：
--
作者：
Sheth, Kevin N.;Elm, Jordan J.;Kimberly, W. Taylor
脑卒中的临床模型表明，静脉注射格列本脲可减少脑肿胀，提高生存率。我们评估了静脉注射格列本脲（RP-1127；格列本脲）是否可以安全地减少脑肿胀，减少对减压颅骨切除术的需求，并改善大面积半球梗死患者的临床结果。方法：在这项双盲、随机、安慰剂对照的2期试验中，我们招募了美国18家医院的患者（年龄18-80岁），临床诊断为大前循环半球梗死时间小于10小时，MRI弥散加权基线图像病变体积为82-300 cm(3)。我们使用基于网络的随机化（1:1）将患者分配到安慰剂组或静脉注射格列本脲组。前2分钟静脉注射格列本脲0.13 mg，随后前6小时静脉注射0.16 mg/h，其余66小时静脉注射0.11 mg/h。主要疗效指标是在90天未进行减压开颅手术的情况下达到改良兰金量表（mRS） 0-4分的患者比例。分析是按每个方案进行的。安全性分析包括所有随机分配的接受研究药物的患者。该试验已在ClinicalTrials.gov注册，编号NCT01794182。在2013年5月3日至2015年4月30日期间，86名患者被随机分配，但由于资金原因而停止入组。出资人、主要研究者、现场研究者、患者、成像核心和结局人员对治疗进行匿名。按方案研究人群为41名接受静脉注射格列本脲的参与者和36名接受安慰剂的参与者。静脉注射格列本胺组17例（41%）患者和安慰剂组14例（39%）患者在不进行减压颅骨切除术的90天mRS评分为0-4（校正优势比0.87,95% CI 0.32-2.32; p=0.77）。静脉注射格列本脲组44名参与者中有10名（23%）和安慰剂组39名参与者中有10名（26%）发生心脏事件（p=0.76）， 20名参与者中有4名发生严重不良事件（静脉注射格列本脲组2名，安慰剂组2名，p=1.00）。每组均发生1例心源性死亡（p=1.00）。解释静脉注射格列本脲对有脑水肿危险的大半球脑卒中患者耐受性良好。综合主要结局无差异。需要进一步的研究来评估静脉注射格列本脲减少肿胀的潜在临床益处。
Background Predinical models of stroke have shown that intravenous glyburide reduces brain swelling and improves survival. We assessed whether intravenous glyburide (RP-1127; glibenclamide) would safely reduce brain swelling, decrease the need for decompressive craniectomy, and improve clinical outcomes in patients presenting with a large hemispheric infarction.Methods For this double-blind, randomised, placebo-controlled phase 2 trial, we enrolled patients (aged 18-80 years) with a clinical diagnosis of large anterior circulation hemispheric infarction for less than 10 h and baseline diffusion weighted MRI image lesion volume of 82-300 cm(3) on MRI at 18 hospitals in the USA. We used web-based randomisation (1:1) to allocate patients to the placebo or intravenous glyburide group. Intravenous glyburide was given as a 0.13 mg bolus intravenous injection for the first 2 min, followed by an infusion of 0.16 mg/h for the first 6 h and then 0.11 mg/h for the remaining 66 h. The primary efficacy outcome was the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-4 at 90 days without undergoing decompressive craniectomy. Analysis was by per protocol. Safety analysis included all randomly assigned patients who received the study drug. This trial is registered with ClinicalTrials.gov, number NCT01794182.Findings Between May 3, 2013, and April 30, 2015, 86 patients were randomly assigned but enrolment was stopped because of funding reasons. The funder, principal investigators, site investigators, patients, imaging core, and outcomes personnel were masked to treatment. The per-protocol study population was 41 participants who received intravenous glyburide and 36 participants who received placebo. 17 (41%) patients in the intravenous glyburide group and 14 (39%) in the placebo group had an mRS score of 0-4 at 90 days without decompressive craniectomy (adjusted odds ratio 0.87, 95% CI 0.32-2.32; p=0.77). Ten (23%) of 44 participants in the intravenous glyburide group and ten (26%) of 39 participants in the placebo group had cardiac events (p=0.76), and four of 20 had serious adverse events (two in the intravenous glyburide group and two in the placebo group, p=1.00). One cardiac death occurred in each group (p=1.00).Interpretation Intravenous glyburide was well tolerated in patients with large hemispheric stroke at risk for cerebral oedema. There was no difference in the composite primary outcome. Further study is warranted to assess the potential clinical benefit of a reduction in swelling by intravenous glyburide.