Rajaratnam Shantha Mw, Polymeropoulos Mihael H, Fisher Dennis M, Roth Thomas, Scott Christin, Birznieks Gunther, Klerman Elizabeth B
Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
Lancet. 2009 Feb 7;373(9662):482-91. doi: 10.1016/S0140-6736(08)61812-7. Epub 2008 Dec 4.
Circadian rhythm sleep disorders are common causes of insomnia for millions of individuals. We did a phase II study to establish efficacy and physiological mechanism, and a phase III study to confirm efficacy of the melatonin agonist tasimelteon (VEC-162) for treatment of transient insomnia associated with shifted sleep and wake time.
We undertook phase II and phase III randomised, double-blind, placebo-controlled, parallel-group studies. In a phase II study, 39 healthy individuals from two US sites were randomly assigned to tasimelteon (10 [n=9], 20 [n=8], 50 [n=7], or 100 mg [n=7]) or placebo (n=8). We monitored individuals for 7 nights: 3 at baseline, 3 after a 5-h advance of sleep-wake schedule with treatment before sleep, and 1 after treatment; we measured plasma melatonin concentration for circadian phase assessment. In a phase III study, 411 healthy individuals from 19 US sites, who had transient insomnia induced in a sleep clinic by a 5-h advance of the sleep-wake schedule and a first-night effect in a sleep clinic, were given tasimelteon (20 [n=100], 50 [n=102], or 100 mg [n=106]) or placebo (n=103) 30 min before bedtime. Prespecified primary efficacy outcomes were polysomnographic sleep efficiency (phase II study), latency to persistent sleep (phase III study), and circadian phase shifting (phase II study). Analysis was by intention to treat. Safety was assessed in both studies. These trials are registered with ClinicalTrials.gov, numbers NCT00490945 and NCT00291187.
In the phase II study, tasimelteon reduced sleep latency and increased sleep efficiency compared with placebo. The shift in plasma melatonin rhythm to an earlier hour was dose dependent. In the phase III study, tasimelteon improved sleep latency, sleep efficiency, and wake after sleep onset (ie, sleep maintenance). The frequency of adverse events was similar between tasimelteon and placebo.
After an abrupt advance in sleep time, tasimelteon improved sleep initiation and maintenance concurrently with a shift in endogenous circadian rhythms. Tasimelteon may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.
昼夜节律性睡眠障碍是数百万人失眠的常见原因。我们开展了一项II期研究以确定褪黑素激动剂他司美琼（VEC - 162）治疗与睡眠和觉醒时间改变相关的短暂性失眠的疗效及生理机制，并进行了一项III期研究以确认其疗效。
我们进行了II期和III期随机、双盲、安慰剂对照、平行组研究。在II期研究中，来自美国两个地点的39名健康个体被随机分配至他司美琼组（10mg [n = 9]、20mg [n = 8]、50mg [n = 7]或100mg [n = 7]）或安慰剂组（n = 8）。我们对个体进行了7晚的监测：3晚为基线期，3晚为睡眠 - 觉醒时间表提前5小时且睡前接受治疗后的时期，1晚为治疗后时期；我们测量血浆褪黑素浓度以进行昼夜节律相位评估。在III期研究中，来自美国19个地点的411名健康个体，他们在睡眠诊所因睡眠 - 觉醒时间表提前5小时及睡眠诊所首夜效应而出现短暂性失眠，在睡前30分钟给予他司美琼（20mg [n = 100]、50mg [n = 102]或100mg [n = 106]）或安慰剂（n = 103）。预先设定的主要疗效指标为多导睡眠图睡眠效率（II期研究）、持续睡眠潜伏期（III期研究）和昼夜节律相位偏移（II期研究）。分析采用意向性治疗。在两项研究中均评估了安全性。这些试验已在ClinicalTrials.gov注册，注册号为NCT00490945和NCT00291187。
在II期研究中，与安慰剂相比，他司美琼缩短了睡眠潜伏期并提高了睡眠效率。血浆褪黑素节律提前至更早时间呈剂量依赖性。在III期研究中，他司美琼改善了睡眠潜伏期、睡眠效率以及睡眠起始后的觉醒（即睡眠维持）。他司美琼组和安慰剂组不良事件的发生率相似。
睡眠时间突然提前后，他司美琼改善了睡眠起始和维持，同时内源性昼夜节律发生了偏移。他司美琼可能对昼夜节律性睡眠障碍中的短暂性失眠具有治疗潜力。
