Melatonin Agonist Tasimelteon (VEC-162) for Transient Insomnia After Sleep-Time Shift: Two Randomized Controlled Multicentre Trials

Abstract

Substantial evidence suggests that exogenous melatonin and melatonin agonists promote sleep and entrain endogenous circadian rhythms. Two previous meta-analyses evaluated the efficacy of melatonin treatment in patients with secondary sleep disorders or circadian rhythm sleep disorders and reached opposite conclusions on efficacy. This study presents the results of 2 randomized, double-blind, placebo-controlled, parallel-group trials, which evaluated tasimelteon (VEC-162), a novel melatonin agonist, in a model of transient insomnia induced by a 5-hour advance in the sleep-wake schedule. The investigators hypothesized that the melatonin agonist would reduce the sleep disruption produced by transient insomnia and readjust circadian rhythms. The study subjects in the phase II study were 39 healthy individuals who were randomized to receive either tasimelteon (in doses of 10 [n = 9], 20 [n = 8], 50 [n = 7], or 100 mg [n = 7]) or placebo (n = 8) 30 minute before bedtime. The plasma melatonin concentration was measured for circadian phase assessment. The study subjects in the phase III study were 411 healthy individuals who were randomized to receive either tasimelteon (20 [n = 100], 50 [n = 102], or 100 mg [n = 106]) or placebo (n = 103) 30 minute before bedtime. Changes in sleep patterns were assessed by polysomnography in the phase II and III studies with prespecified primary efficacy outcomes. Safety was assessed by daily queries about adverse events and physical examinations. In the phase II study, compared with placebo, tasimelteon increased sleep efficiency and duration, and reduced sleep latency and latency to persistent sleep. There was a dose-dependent shift in plasma melatonin to an earlier hour associated with treatment. In addition to improvements in sleep latency, efficiency, duration, and latency to persistent sleep, treated-individuals in the phase III study had reduced wake after sleep onset (improved sleep maintenance). The frequency and severity of adverse events were low and similar among all treatment groups. These findings indicate that tasimelteon improves sleep initiation and maintenance simultaneously with a shift in endogenous circadian rhythms and has therapeutic potential for transient insomnia associated with circadian rhythm sleep disorders.