Background and Purpose—EG-1962 is a sustained release formulation of nimodipine administered via external ventricular drain in patients with aneurysmal subarachnoid hemorrhage. A randomized, open-label, phase 1/2a, dose-escalation study provided impetus for this study to evaluate efficacy and safety of a single intraventricular 600 mg dose of EG-1962 to patients with aneurysmal subarachnoid hemorrhage, compared with standard of care oral nimodipine.Methods—Subjects were World Federation of Neurological Surgeons grades 2–4, modified Fisher grades 2–4 and had an external ventricular drain inserted as part of standard of care. The primary end point was the proportion of subjects with favorable outcome at day 90 after aneurysmal subarachnoid hemorrhage (extended Glasgow outcome scale 6–8). The proportion of subjects with favorable outcome at day 90 on the Montreal cognitive assessment, as well as the incidence of delayed cerebral ischemia and infarction, use of rescue therapy and safety were evaluated.Results—The study was halted by the independent data monitoring board after planned interim analysis of 210 subjects (289 randomized) with day 90 outcome found the study was unlikely to achieve its primary end point. After day 90 follow-up of all subjects, the proportion with favorable outcome on the extended Glasgow outcome scale was 45% (65/144) in the EG-1962 and 42% (62/145) in the placebo group (risk ratio, 1.01 [95% CI, 0.83–1.22], P=0.95). Consistent with its mechanism of action, EG-1962 significantly reduced vasospasm (50% [69/138] EG-1962 versus 63% [91/144], P=0.025) and hypotension (7% [9/138] versus 10% [14/144]). Analysis of prespecified subject strata suggested potential efficacy in World Federation of Neurological Surgeons 3–4 subjects (46% [32/69] EG-1962 versus 32% [24/75] placebo, odds ratio, 1.22 [95% CI, 0.94–1.58], P=0.13). No safety concerns were identified that halted the study or that preclude further development.Conclusions—There was no significant increase in favorable outcome for EG-1962 compared with standard of care in the overall study population. The safety profile was acceptable.Registration—URL: https://www.clinicaltrials.gov; Unique identifier: NCT02790632.

中文翻译：

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单剂量脑室内尼莫地平微粒与口服尼莫地平治疗动脉瘤性蛛网膜下腔出血的关系。

背景与目的-EG-1962是尼莫地平的缓释制剂，通过动脉外蛛网膜下腔出血患者通过外部心室引流给药。一项随机，开放标签，1 / 2a期剂量递增研究为该研究提供了动力，以评估单剂量脑室内600 mg剂量EG-1962对动脉瘤性蛛网膜下腔出血患者的疗效和安全性（与口服护理标准相比）尼莫地平。方法—受试者为2–4级世界神经外科医师联合会，2–4级改良的Fisher受试者，并插入外部心室引流作为护理标准的一部分。主要终点是在动脉瘤性蛛网膜下腔出血后第90天获得良好转归的受试者比例（格拉斯哥预后评分范围6-8）。在蒙特利尔认知评估中，在90天时获得良好结果的受试者比例，以及延迟性脑缺血和梗死的发生率，抢救疗法的使用和安全性进行了评估。结果-这项研究在独立数据监测委员会结束后终止对210名受试者（随机分组289名）进行了计划中的中期分析，得出90天的结果，该研究不太可能达到其主要终点。在对所有受试者进行第90天的随访后，EG-1962扩大格拉斯哥结局量表中具有良好结局的比例为45％（65/144），安慰剂组为42％（62/145）（风险比， 1.01 [95％CI，0.83–1.22]，结果-对210名受试者（随机分组289名）进行了计划中的中期分析（第90天的结果）后，该研究被独立数据监控委员会终止，发现该研究不太可能达到其主要终点。在对所有受试者进行第90天的随访后，EG-1962扩大格拉斯哥结局量表中具有良好结局的比例为45％（65/144），安慰剂组为42％（62/145）（风险比， 1.01 [95％CI，0.83–1.22]，结果-对210名受试者（随机分组289名）进行了计划中的中期分析（第90天的结果）后，该研究被独立数据监控委员会终止，发现该研究不太可能达到其主要终点。在对所有受试者进行第90天的随访后，EG-1962扩大格拉斯哥结局量表中具有良好结局的比例为45％（65/144），安慰剂组为42％（62/145）（风险比， 1.01 [95％CI，0.83–1.22]，P＝ 0.95）。与其作用机制一致，EG-1962显着降低了血管痉挛（50％[69/138] EG-1962对63％[91/144]，P = 0.025）和低血压（7％[9/138]对10％） [14/144]）。预先确定的受试者分层分析表明，在世界神经外科医师联合会3-4个受试者中具有潜在的疗效（46％[32/69] EG-1962与32％[24/75]安慰剂相比，优势比为1.22 [95％CI，0.94– 1.58]，P = 0.13）。未发现有安全隐患导致该研究中断或阻止其进一步发展。结论–与总体研究人群的护理标准相比，EG-1962的有利结局并未显着增加。安全配置文件是可以接受的。注册-URL：https：//www.clinicaltrials.gov；唯一标识符：NCT02790632。