Efficacy of Tasimelteon (HETLIOZ®) in the Treatment of Jet Lag Disorder Evaluated in an 8-h Phase Advance Model; a Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

Abstract

Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18–73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST 2/3 ), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive tasimelteon ( n = 160) or placebo ( n = 160). Tasimelteon treatment increased TST 2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by −15.1 min (95% CI −26.2 to −4.0, P = 0.0081). Conclusion: A single dose of tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.

Tasimelteon safely and effectively improves sleep in Smith–Magenis syndrome: a double-blind randomized trial followed by an open-label extension

“…Tasimelteon is a melatonin receptor agonist that demonstrates high affinity for both the human melatonin MT 1 and MT 2 receptors. By acting upon the MT 1 and MT 2 receptors, tasimelteon acts by entraining circadian sleep phase timing and has been shown to improve nighttime sleep as well as daytime sleepiness and functioning [18][19][20]. Tasimelteon is approved by the US FDA and the EMA for the treatment of non-24-hour sleep-wake disorder (non-24) and by the US FDA for the treatment of nighttime sleep disturbances in Smith-Magenis syndrome (SMS).…”

Once-daily tasimelteon (VEC-162) for jet lag following transmeridian travel: A multicenter, randomized, double-blind, placebo-controlled trial

“…These confounders could be reduced by directly assessing the treatment effect of tasimelteon on what is thought to be the underlying cause of the Essential Features of jet lag—the misalignment of the endogenous circadian timing system with that of the external environment—using a phase advance study design. Phase advance studies of 5- and 8-h have been conducted and reported for HETLIOZ® and the results are supportive of the therapeutic effect of HETLIOZ® in that setting ( 13 , 14 ).…”

Melatonergic agents influence the sleep-wake and circadian rhythms in healthy and psychiatric participants: a systematic review and meta-analysis of randomized controlled trials

“…Data on melatonin receptor agonists are limited as compared to exogenous melatonin. Potential effects of tasimelteon have been reported in several studies with N24SWD, jet lag, and primary insomnia [11][12][13][14][15]. In addition, ramelteon has improved sleep quality and reduced latency to persistent sleep in primary insomnia, and corrected the timing of sleep in N24SWD [16,17].…”