BACKGROUND A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. METHODS Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. RESULTS The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups. CONCLUSION Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.

中文翻译：

---

NEWTON-2 Cisternal（尼莫地平微粒可在减少蛛网膜下腔出血后的毒性的同时促进恢复）：脑内 EG-1962 治疗动脉瘤性蛛网膜下腔出血的第 2 阶段、多中心、随机、开放标签安全性研究

背景 尼莫地平 (EG-1962) 的缓释微粒制剂被开发用于治疗动脉瘤性蛛网膜下腔出血 (aSAH) 患者。目的 在一项对多达 12 名受试者进行的开放标签、随机、2 期研究中评估脑池内 EG-1962 的安全性、耐受性和药代动力学。方法 受试者为世界神经外科医师联合会 1 至 2 级，改良费舍尔 2 至 4 级，并在 aSAH 后 48 小时内接受动脉瘤夹闭。EG-1962 含有 600 毫克尼莫地平，被注入基底池。评估了扩展格拉斯哥结局量表 (eGOS) 的结局、药代动力学、迟发性脑缺血和梗死、抢救治疗和安全性。结果 当一项脑室内 EG-1962 的 3 期研究停止时，该研究停止，因为该研究不太可能达到其主要终点。六名受试者被随机分配（5 名 EG-1962 和 1 名口服尼莫地平）。90 天随访后，5 名 EG-1962 中的 1 名和单一口服尼莫地平患者的 eGOS 结果良好。四个 EG-1962 和口服尼莫地平受试者有血管造影血管痉挛。1 名 EG-1962 受试者出现迟发性脑缺血，除 1 名 EG-1962 患者外，所有出现血管造影血管痉挛的受试者均接受抢救治疗。一名接受 EG-1962 治疗的受试者在植入 EG-1962 后 5 个月出现右侧颈内动脉和大脑中动脉变窄，导致闭塞和脑梗塞。药代动力学显示两组尼莫地平的血浆浓度相似。结论 放置 EG-1962 后仍会发生血管造影血管痉挛和不利的临床结果。尚未报告在基底池中放置 EG-1962 后颈内动脉变窄和闭塞。