NPC Archive Item: Tasimelteon for insomnia – early data in healthy people with an artificially disturbed sleep pattern.

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In healthy people whose sleep pattern had been brought forward by five hours, a single dose of tasimelteon reduced the time to persistent sleep compared to placebo. It is not known how effective tasimelteon could be in people with jet lag or in patients with insomnia and one or more co-morbidities. No data are available on the effects of tasimelteon on daytime functioning or on operating complex machinery.

Tasimelteon is still in trials for the treatment of insomnia. However, it has received much media coverage and, if it reaches the market, there may be considerable interest in it due to the relative lack of alternative drug therapy with good evidence of effectiveness, safety and tolerability.  More data are required on chronic use, particularly with regard to the effect on daytime functioning and long-term safety.

What is the background to this?
Circadian rhythm sleep disorders are a common cause of insomnia, affecting shift workers and travellers crossing multiple time zones. Melatonin is thought to be involved in regulating the rhythm of sleeping and waking. A small phase II trial (n=45) of a melatonin agonist, tasimelteon, was carried out to establish efficacy and physiological mechanism.  This was followed by a phase III trial to assess efficacy in the treatment of transient insomnia associated with shifted sleep patterns; the results of that study are discussed below.

What does this study claim?
412 healthy people with no major sleep disorders were randomised to a single dose of either tasimelteon 20mg, 50mg, 100mg or placebo. After an abrupt advance in sleep time, the mean time (standard error, SE) between bedtime and persistent sleep was: tasimelteon 20mg 23.1 (3.7) minutes, 50mg 18.5 (2.1) minutes, 100mg 22.0 (2.9) minutes and placebo 44.6 (6.5) minutes (P<0.01 for all doses compared to placebo).

How does this relate to other studies?
Studies of melatonin have been contradictory. A meta-analysis of exogenous melatonin concluded that there was no evidence that melatonin is effective in sleep disorders accompanying sleep restriction, such as jet lag and shift work. However, a Cochrane Review found eight trials that showed that melatonin decreased jet-lag as assessed via largely qualitative markers. The benefit is likely to be greater when crossing five or more time zones and likely to be less for westward flights.

The conflicting evidence may be due to the fact that melatonin is an unregulated dietary supplement, leading to variation in content and quality. In addition, there are no data from large, randomised controlled trials.

A modified-release formulation of melatonin Circadin®, is available for the short-term management of primary insomnia in adults aged 55 years and above. A melatonin agonist, ramelteon has received a negative opinion from the EMEA.

A NICE technology appraisal for the management of insomnia is available, but only deals with zaleplon, zolpidem and zopiclone. A recent report has highlighted the increased risk of road traffic accidents in patients taking z-drugs.

So what?
This trial used an artificial means of shifting the sleep-wake cycle (in a sleep laboratory) in healthy people, so it is not known how effective tasimelteon could be in people with jet lag or patients with insomnia and one or more co-morbidities. Tasimelteon has not been studied in patients with chronic circadian rhythm sleep disorders. Furthermore, no data are available on the effects of tasimelteon on daytime functioning, avoidance of accidents and being able to use complex machinery in people affected by jet lag or shift work. Such data would be required to be able to determine any future role for this agent. Tasimelteon was not compared with melatonin in this trial, making it difficult to comment on its potential place in the management of circadian rhythm sleep disorders.

Study details

Rajaratnam SMW et al. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. The Lancet, Early Online Publication, 2 December 2008. doi:10.1016/S0140-6736(08)61812-7

Design: a phase III, double-blind, randomised, placebo-controlled trial. Bedtime was advanced by 5 hours compared with the subjects’ normal bedtime. Participants maintained an 8-hour sleep schedule for at least one week followed by a 9-hour sleep schedule for one week, before receiving a single dose of study medication. They were monitored over 8 hours in bed at a sleep clinic.

Patients: healthy people with no major sleep disorders (aged 21 – 50 years). 836 people were screened and 412 were randomised. One individual withdrew before receiving study drug and was excluded from the results.

Intervention: tasimelteon 20 (n=100), 50 (n=102) or 100mg (n=106) 30 minutes before bedtime.

Comparison: placebo (n=103) 30 minutes before bedtime.

Outcomes: blinded evaluators assessed sleep using polysomnography. The prespecified primary outcome was latency to persistent sleep, defined as the interval between bedtime and the first 10 consecutive minutes of any stage of sleep.

Results: primary outcome, mean time to persistent sleep (SE):
tasimelteon 20mg 23.1 (3.7) minutes; 50mg 18.5 (2.1) minutes; 100mg 22.0 (2.9) minutes; placebo 44.6 (6.5) minutes (P<0.01 vs. placebo).

Secondary outcomes included wake after sleep onset and total sleep time. These were both improved by tasimelteon.

Adverse effects: nausea was reported by 3% of participants in each of the treatment and placebo groups. No further statistical data was provided.

Sponsorship: Vanda Pharmaceuticals Inc.

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