New York University, Langone Health, New York, New York, USA.
Arkansas Epilepsy Program, Little Rock, Arkansas, USA.
Epilepsia. 2023 Feb;64(2):374-385. doi: 10.1111/epi.17441. Epub 2022 Dec 7.
Alprazolam administered via the Staccato® breath-actuated device is delivered into the deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision.
Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato alprazolam 1.0 mg or 2.0 mg, or Staccato placebo in an inpatient unit. The primary end point of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 min after administration of study drug and no recurrence of seizure activity within 2 h.
A total of 273 patients were screened, and 116 randomized patients received treatment with the study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato alprazolam 1.0 mg (n = 38; p = .0392) and 2.0 mg (n = 38; p = .0392), compared with 42.5% for Staccato placebo (n = 40). Staccato alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity; there were no treatment-related serious AEs.
Both 1.0 mg and 2.0 mg doses of Staccato alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato alprazolam for rapid cessation of seizures in an outpatient setting.
通过 Staccato®呼吸驱动装置给予阿普唑仑可将药物递送至深肺，实现快速全身暴露，这可能成为快速终止癫痫发作（REST）的一种潜在疗法。我们开展了一项住院患者研究（ENGAGE-E-001 [NCT03478982]），纳入具有刻板性发作且发作持续时间长或反复发作的癫痫患者，旨在确定在直接监督下给予阿普唑仑 Staccato 后，该药能否在小样本观察人群中迅速终止发作。
纳入有局灶性和/或全面性癫痫诊断且有可预测模式的癫痫发作病史的成年患者。他们按照 1:1:1 的比例随机分为 3 组，在住院部接受单剂量阿普唑仑 Staccato 1.0mg、2.0mg 或 Staccato 安慰剂治疗单次发作事件。该研究的主要终点是，给药后 2 分钟内达到发作活动停止且 2 小时内无发作活动复发的各治疗组应答者比例。
共筛选了 273 例患者，116 例随机分组的患者接受了双盲部分的研究药物治疗。阿普唑仑 Staccato 1.0mg（n=38；p=0.0392）和 2.0mg（n=38；p=0.0392）组的治疗患者中，应答者比例分别为 65.8%，而 Staccato 安慰剂组（n=40）为 42.5%。单剂量 1.0mg 或 2.0mg 给予阿普唑仑 Staccato 时具有良好的耐受性：咳嗽和嗜睡最常见（均为 14.5%），其次是味觉障碍（13.2%）。不良事件（AE）大多为轻度或中度，无治疗相关严重 AE。
阿普唑仑 Staccato 1.0mg 和 2.0mg 两种剂量均能迅速终止住院患者的癫痫发作，且具有良好的耐受性。下一步是开展一项 3 期确证性研究，以证明阿普唑仑 Staccato 在外门诊疗环境中快速终止癫痫发作的疗效和安全性。
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