Gunther Birznieks

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

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.

Delayed sleep phase disorder risk is associated with absenteeism and impaired functioning

STUDY OBJECTIVES The absence of a screening questionnaire for delayed sleep phase disorder (DSPD) remains a barrier to its detection and subsequent clinical evaluation. We developed a questionnaire to screen for DSPD risk and assessed its impact on self-reported absenteeism and functioning in work/school, social, and family life. DESIGN Cross-sectional, with 13,844 individuals responding to a survey through an Internet survey provider, from which 1315 completed surveys were obtained from eligible participants. PARTICIPANTS A total of 1315 individuals who self-identified as evening type (n=979) or as non-evening type (n=356). MEASUREMENTS AND RESULTS A total of 295 participants were at high risk for DSPD, which is 5.1% of the total eligible survey respondents and 22.4% of our final sample with completed surveys. Compared to those who were not at high risk for DSPD, those who were at high risk were more likely to report frequent absenteeism, frequent loss of productivity, disruption to work or school activities, disruption to social life or leisure activities, and disruption to family life or home responsibilities. Difficulty with daytime sleepiness was more common in those at high risk for DSPD than those who were not. Increased sleep deficit on nights before school or work was also associated with more frequent difficulties with daytime sleepiness; 15.4% of those with no sleep deficit reported always or usually having difficulties with daytime sleepiness compared to 55.7% of those with a sleep deficit of 3hours or more. CONCLUSIONS DSPD risk is associated with increased absenteeism and impaired functioning in work/school, social, and family life.