Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

Vanda Pharmaceuticals Inc.

Introduction

Circadian rhythm sleep disorders are common causes of insomnia that affect millions of individuals, including those who work at night or who cross multiple time zones during travel. These primary sleep disorders are characterised by persistent and recurrent sleep disturbances, insomnia when trying to sleep, and excessive sleepiness while trying to remain awake.¹ They occur when scheduled or desired sleep times are incompatible with endogenous circadian rhythms generated by the hypothalamic suprachiasmatic nuclei.² For example, when timing of sleep is advanced such that it occurs during the circadian forbidden zone for sleep (occurring a few hours before habitual bedtime),³ sleep latency, duration, and efficiency are adversely affected.⁴

When timed appropriately, ocular light exposure and hypnotic drugs have been used as therapies for circadian rhythm sleep disorders, but both have limitations. Light exposure promotes circadian readjustment,⁵ but guidelines for best possible dosing and treatment are scarce.⁶ Furthermore, such treatment is often impractical because it requires a high degree of commitment and a strict regimen to which many patients are not willing to adhere. No evidence exists that hypnotics affect the underlying endogenous circadian mechanisms. The best possible treatment for patients with circadian rhythm sleep disorders would simultaneously improve sleep and facilitate circadian readjustment.

The pineal hormone melatonin—produced mainly during the biological night—is involved in circadian regulation of sleep and wake. Increased objective and subjective sleepiness coincide with high endogenous melatonin concentrations.7, 8, 9 Exogenous melatonin can shift sleep time¹⁰ and hormones,¹¹ and increase sleep propensity, particularly during times of day when endogenous melatonin production is low.¹² Melatonin effects are mediated by the melatonin MT₁ and MT₂ receptors,13, 14 although the precise role of each receptor subtype in circadian phase shifting and sleep promotion is unknown.

Although melatonin is a popular treatment for patients with circadian rhythm sleep disorders, two caveats exist. First, melatonin products available over the counter in the USA are not recommended because their potency, purity, and safety are not regulated by the US Food and Drug Administration.15, 16 Second, despite substantial evidence that exogenous melatonin10, 12, 17, 18, 19, 20, 21, 22, 23, 24 and melatonin agonists25, 26 promote sleep and entrain endogenous circadian rhythms,27, 28 a meta-analysis²⁹ concluded that melatonin is not efficacious for treatment of patients with secondary sleep disorders or sleep disorders accompanying sleep restrictions (eg, jet lag and shift-work disorder). This conclusion is controversial³⁰ and could have resulted from variations in quality and content of individual melatonin preparations, and absence of large randomised controlled trials. Other meta-analyses have shown that melatonin is effective in the treatment of jet lag³¹ and reducing sleep complaints associated with delayed sleep phase syndrome,³² which are two common circadian rhythm sleep disorders.

Tasimelteon (VEC-162) is a novel MT₁ and MT₂ agonist with high affinity for human melatonin receptors (Vanda Pharmaceuticals, Rockville, MD, USA, unpublished data). We hypothesised that this melatonin agonist would reduce sleep disruption and promote circadian readjustment in a standard model33, 34, 35 of transient insomnia induced by an abrupt advance in sleep–wake time. Transient insomnia refers to impaired sleep initiation, sleep maintenance, or both, assessed in this study by latency to sleep onset and sleep efficiency in the middle of the sleep episode, respectively. This model is appropriate both for jet lag and early-riser shift workers—a rapidly increasing number of people³⁶ who have to awaken and work at times when their endogenous melatonin concentrations are high. We assessed the physiological mechanism and efficacy of tasimelteon in a phase II trial, and confirmed its efficacy in a phase III trial.