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 (TST2/3), 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 TST2/3 (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.

Keywords: Hetlioz; circadian; circadian rhythm; jet lag; jet lag disorder; sleep; tasimelteon.

Copyright © 2020 Polymeropoulos, Mohrman, Keefe, Brzezynski, Wang, Prokosch, Polymeropoulos, Xiao, Birznieks and Polymeropoulos.

Figures

Figure 1

The study consisted of a 1–4 week screening period followed by an evaluation visit where patients were dosed with tasimelteon 20 mg or placebo 30-min prior to their pre-determined 8-h phase advance bedtime. Polysomnography was performed during the 8-h sleeping period. Karolinska Sleepiness Scale (KSS) and Visual Analog Scale (VAS) assessments were completed once during screening, once before the phase advance, and four times after waking.

Figure 2

Representation of the study protocol for an individual with a usual target bedtime of 22:00. Dark blue bars indicate at-home sleep monitored with actigraphy and photometry. Gray bar indicates in-lab sleep monitored with polysomnography following the 8-hour phase advance imposed to model the change of sleep timing required after a trip from Los Angeles to London. Yellow triangle indicates dose administration. Green circles indicate KSS and VAS assessments.

Figure 3

Number of patients screened, enrolled, randomized, and discontinued for the JET8 study.

Figure 4

Data are LS Mean (95% CI) for average TST by hour between tasimelteon and placebo. TST during the 8-h phase advance demonstrated a statistically significant increase in the tasimelteon group compared to placebo for hours 1–7. *P < 0.001.

Figure 5

(A) Data are LS Mean (95% CI) for average Night 1 KSS values between tasimelteon and placebo. KSS values, 1 pt being extremely awake and 9 pts being extremely sleepy/fighting to stay awake, demonstrated a statistically significant decrease following the 8-h phase advance in the tasimelteon group compared to the placebo group for 3.5 and 5.5 h post-lights on. **P < 0.01. (B) Data are LS Mean (95% CI) for average Night 1 VAS values between tasimelteon and placebo. VAS values, 0 mm being very sleepy and 100 mm being very alert, demonstrated a statistically significant increase following the 8-h phase advance in the tasimelteon group compared to the placebo group for 1.5, 3.5, and 5.5 h post-lights on. **P < 0.01, *P < 0.05.