Tasimelteon

Total sleep time during the first 2/3 of the night following an 8-hour phase advance bedtime, as measured by PSG. This is representative of trans meridian travel across 8 time zones.

Treatment-emergent adverse events will be summarized by presenting the number and percentage of patients having any treatment-emergent AE, having an AE in each body system, and having each individual AE.

Entrainment is a measure of synchronization of the master body clock to the 24-hour day. The circadian period (τ) was calculated using urinary aMT6s collected over four separate 48 hour periods, approximately 1 week apart, during the run-in and randomized phases of the trial. Maintenance of entrainment is defined as the proportion of subjects who become non-entrained to a 24 hour day after randomization to tasimelteon or placebo. Non-entrainment was defined as having a post-baseline τ value ≥ 24.1 or the lower bound of the 95% CI \>24.0.

Entrainment is a measure of synchronization of the master body clock to the 24-hour day. The circadian period (τ) was calculated using urinary aMT6s collected over four 48 hour periods , collected approximately 1 week apart for 4 separate weeks, during the screening and month 1 of the randomization phase of the trial. Entrainment was defined as having a post-baseline τ value less than 24.1 and a 95% CI that included 24.0.

Clinical response is defined as the coincident demonstration of entrainment (aMT6) and a score ≥ 3 on the Non-24 Clinical Response Scale (N24CRS). N24CRS measures improvement in sleep-wake measures and overall functioning (LQ-nTST, UQ-dTSD, MoST and CGI-C). Each assessment is scored as a 1 or 0 depending on the pre-specified threshold (see below). LQ-nTST: \>45 minutes increase in average nighttime sleep duration; UQ-dTSD: \>45 minutes decrease in average daytime sleep duration; MoST: \>30 minutes increase and a standard deviation \<2 hours during double-masked phase (6 months); CGI-C: \<2.0 from the average of D112 and Day 183 compared to baseline For patients randomized to tasimelteon 20 mg and who also participated in the screening phase of Study 3203 (month 7 of treatment), the screening τ from Study 3203 was used if the patient did not become entrained in Study 3201 but did become entrained during the screening phase of Study 3203.

Measured using polysomnography (PSG) and analyzed as change from baseline. Examination of the observational phase baseline data demonstrated that Night 3 was the night most disrupted.

Hamilton Rating Scale for Depression (HAM-D) assesses the range of symptoms that are most frequently observed in subjects with major depressive disorder (MDD) on a scale from 0 to 52. Higher HAM-D scores indicate more severe levels of depressive symptoms, thus, a negative change from baseline indicates a reduction (or improvement) in depressive symptoms.

as measured by plasma concentrations

as measured by incidence of adverse events and clinically significant changes in laboratory values, ECG parameters, and vital signs

Differences will be calculated for the following comparisons: * Ethanol Alone vs. Placebo-Placebo * Ethanol Alone vs. Tasimelteon + Ethanol * Tasimelteon Alone vs. Placebo-Placebo * Tasimelteon Alone vs. Tasimelteon + Ethanol

Plasma concentrations and pharmacokinetics of tasimelteon of group 1 (smokers) will be compared to group 2 (non-smokers)

Pharmacokinetics of tasimelteon will be compared using all three groups (smokers, non-smokers and elderly). Group 1 and Group 2 will be gender, age and BMI category matched.

Composite of 24 hour pharmacokinetic parameters of midazolam will be compared between Day 1 and Day 18.

Composite of 24 hour pharmacokinetic parameters of rosiglitazone will be compared between Day 3 and 20.

To assess plasma concentrations and pharmacokinetics of tasimelteon in subjects with mild or moderate hepatic impairment compared to healthy subjects with normal hepatic function.