治疗发作性睡病患者的 Enerisant（TS-091）最佳剂量确定：两项随机、双盲、安慰剂对照试验。
Optimal dose determination of enerisant (TS-091) for patients with narcolepsy: two randomized, double-blind, placebo-controlled trials.
机构信息
Japan Somnology Center, Institute of Neuropsychiatry, 5-10-10 Yoyogi, Shibuya-ku, Tokyo, 151-0053, Japan.
Department of Somnology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
出版信息
BMC Psychiatry. 2022 Feb 22;22(1):141. doi: 10.1186/s12888-022-03785-7.
BACKGROUND
The histamine H3 receptor has emerged as one of the most promising targets of novel pharmacotherapy for narcolepsy. Studies now aim to investigate the optimal dose of enerisant, a novel H3 antagonist/inverse agonist, for the treatment of excessive daytime sleepiness in patients with narcolepsy.
METHODS
We conducted two phase 2, fixed-dose, double-blind, randomized, placebo-controlled trials in patients with narcolepsy. The first phase 2 study (Study 1) was conducted to investigate the efficacy and safety of enerisant at dosages of 25, 50, and 100 mg/day administered for 3 weeks based on the results of a phase 1 study conducted on healthy volunteers. The primary endpoint was mean sleep latency in maintenance of wakefulness test (MWT), and the secondary endpoint was the total score on the Epworth Sleepiness Scale (ESS). The dosages of enerisant in the second phase 2 study (Study 2) were set at 5 and 10 mg/day based on the simulation of receptor occupancy results from positron emission tomography study.
RESULTS
Forty-six and fifty-three patients were randomized in Study 1 and Study 2, respectively. The efficacy of enerisant was partially confirmed in Study 1 with ESS; however, the doses were not tolerated, and there were many withdrawals due to adverse events (mainly insomnia, headache, and nausea). The doses in Study 2 were well tolerated, with a lower incidence of adverse events in Study 2 than in Study 1, although the efficacy could not be confirmed with MWT and ESS in Study 2.
CONCLUSIONS
The optimal dose of enerisant could not be determined in these two studies. Although enerisant has a favorable pharmacokinetic profile, it is thought to have large interindividual variabilities in terms of efficacy and safety, suggesting the necessity of tailored dosage adjustments.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT03267303 ; Registered 30 August 2017 (Study 2). Japic identifier: JapicCTI-142529 ; Registered 7 May 2014 (Study 1) and JapicCTI-173689 ; Registered 30 August 2017, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=29277 (Study 2).
背景
组胺 H3 受体已成为新型嗜睡症药物治疗的最有希望的靶点之一。目前的研究旨在探讨新型 H3 拮抗剂/反向激动剂 enerisant 治疗嗜睡症患者日间过度嗜睡的最佳剂量。
方法
我们在嗜睡症患者中进行了两项 2 期、固定剂量、双盲、随机、安慰剂对照试验。第 2 期 1 期研究（研究 1）旨在根据在健康志愿者中进行的 1 期研究的结果，研究 enerisant 25、50 和 100mg/天的剂量治疗 3 周的疗效和安全性。主要终点是维持清醒试验（MWT）中的平均睡眠潜伏期，次要终点是 Epworth 嗜睡量表（ESS）的总评分。根据正电子发射断层扫描研究的受体占有率结果模拟，第 2 期 2 期研究（研究 2）中的 enerisant 剂量设定为 5 和 10mg/天。
结果
研究 1 和研究 2 分别有 46 例和 53 例患者随机分组。研究 1 中 ESS 部分证实了 enerisant 的疗效；然而，剂量不耐受，由于不良反应（主要是失眠、头痛和恶心）导致许多患者退出。研究 2 中的剂量可耐受，研究 2 中的不良反应发生率低于研究 1，尽管 MWT 和 ESS 未能证实研究 2 的疗效。
结论
在这两项研究中无法确定 enerisant 的最佳剂量。尽管 enerisant 具有良好的药代动力学特征，但在疗效和安全性方面具有较大的个体间变异性，表明需要进行个体化剂量调整。
试验注册
ClinicalTrials.gov 标识符：NCT03267303；注册于 2017 年 8 月 30 日（研究 2）。Japic 标识符：JapicCTI-142529；注册于 2014 年 5 月 7 日（研究 1）和 JapicCTI-173689；注册于 2017 年 8 月 30 日，https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?clinicalTrialId=29277（研究 2）。
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