Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial
Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s1474-4422(12)70225-9
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发表时间：
2012-11-01
期刊：
影响因子：
48
通讯作者：
Tymianski, Michael
中科院分区：
文献类型：
--
作者：
Hill, Michael D.;Martin, Renee H.;Tymianski, Michael
背景：突触后密度-95蛋白的抑制剂NA-1(TAT-NR2B9c)对卒中的灵长类动物模型有神经保护作用。我们评估了NA-1是否可以减少人类的缺血性脑损伤。方法在这项双盲、随机、对照研究中，我们从加拿大和美国的14家医院招募了18岁或18岁以上的患者，他们的颅内动脉瘤破裂或未破裂，适合血管内修复。我们使用计算机生成的随机序列来分配患者在血管内手术结束时接受NA-1或生理盐水对照的静脉输注(1：1；按部位、年龄和动脉瘤状态分层)。患者和调查人员都被蒙面进行治疗分配。主要结果是安全性，主要临床结果是输液后12-95h MRI确定的新的缺血性卒中的数量和体积。我们使用了改良的意向治疗(MITT)分析。这项试验在ClinicalTrials.gov注册，编号NCT00728182。研究发现，在2008年9月16日至2011年3月30日期间，我们随机分配了197名患者接受治疗-12名患者没有接受治疗，因为他们在随机分组后被发现不符合条件，因此Mitt群体由185名患者组成，其中NA-1组92名，安慰剂组93名。两个轻微的不良事件被判定与NA-1有关；没有严重的不良事件可归因于NA-1。无论是弥散加权磁共振成像(调整后p值=0.120)还是液体衰减反转恢复磁共振成像(调整后p值=0.236)，两组间病变体积无差异。根据弥散加权MRI(调整发生率比0.53，95%CI 0.38-0.74)和液体衰减反转恢复MRI(0-59，0.42-0-83)，NA-1组患者比安慰剂组患者遭受的缺血性脑梗塞更少。我们的研究结果表明，在人类缺血性卒中中神经保护是可能的，应该在更大的试验中进行研究。
Background Neuroprotection with NA-1 (Tat-NR2B9c), an inhibitor of postsynaptic density-95 protein, has been shown in a primate model of stroke. We assessed whether NA-1 could reduce ischaemic brain damage in human beings.Methods For this double-blind, randomised, controlled study, we enrolled patients aged 18 years or older who had a ruptured or unruptured intracranial aneurysm amenable to endovascular repair from 14 hospitals in Canada and the USA. We used a computer-generated randomisation sequence to allocate patients to receive an intravenous infusion of either NA-1 or saline control at the end of their endovascular procedure (1:1; stratified by site, age, and aneurysm status). Both patients and investigators were masked to treatment allocation. The primary outcome was safety and primary clinical outcomes were the number and volume of new ischaemic strokes defined by MRI at 12-95 h after infusion. We used a modified intention-to-treat (mITT) analysis. This trial is registered with ClinicalTrials.gov, number NCT00728182.Findings Between Sept 16,2008, and March 30,2011, we randomly allocated 197 patients to treatment-12 individuals did not receive treatment because they were found to be ineligible after randomisation, so the mITT population consisted of 185 individuals, 92 in the NA-1 group and 93 in the placebo group. Two minor adverse events were adjudged to be associated with NA-1; no serious adverse events were attributable to NA-1. We recorded no difference between groups in the volume of lesions by either diffusion-weighted MRI (adjusted p value=0.120) or fluid-attenuated inversion recovery MRI (adjusted p value=0.236). Patients in the NA-1 group sustained fewer ischaemic infarcts than did patients in the placebo group, as gauged by diffusion-weighted MRI (adjusted incidence rate ratio 0.53,95% CI 0.38-0.74) and fluid-attenuated inversion recovery MRI (0-59,0.42-0-83).Interpretation Our findings suggest that neuroprotection in human ischaemic stroke is possible and that it should be investigated in larger trials.