Withdrawal Study to Demonstrate the Maintenance Effect in the Treatment of Non-24-Hour Sleep-Wake Disorder

Non-24-Hour Sleep-Wake Disorder (N24HSWD) occurs when individuals are unable to synchronize
their endogenous circadian pacemaker to the 24-hour light-dark cycle, and the timing of
their circadian rhythm instead reflects the intrinsic period of their endogenous circadian
pacemaker. As a result, the circadian rhythm of sleep-wake propensity in these individuals
moves gradually later and later each day if there circadian period is > 24 hours and earlier
and earlier is < 24 hours. These individuals will be able to sleep well at night when their
sleep-wake propensity rhythm is approximately aligned with the 24-hour light-dark and social
cycle. However, after a short time, the endogenous sleep-wake propensity rhythm and the
24-hour light-dark cycle will move out of synchrony with each other, and they may have
difficulty falling asleep until well into the night. In addition to problems sleeping at the
desired time, the subjects experience daytime sleepiness and daytime napping. As time
progresses, the endogenous circadian rhythm of sleep-wake propensity in these individuals
moves further and further away from the 24-hour light-dark cycle and gradually, these
individuals are unable to sleep at night and as a result experience extreme sleepiness
during the daytime hours and more frequent naps with a longer duration. Eventually, the
sleep-wake time moves back into alignment with the social time for sleep and the individuals
sleep well at night and have decreased daytime napping. The alignment between their
endogenous circadian rhythms and the 24-hour day is temporary as they are continually
drifting later and later each day.

This will be a multicenter, randomized withdrawal, double-masked, placebo-controlled,
parallel study. The study has three phases: the tasimelteon run-in phase, the tau estimation
phase, and the randomized withdrawal phase. Subjects who have participated in study
VP-VEC-162-3201 that meet the entry criteria for this study will be eligible for the run-in
phase The run-in phase comprises a screening visit where subject's initial eligibility will
be evaluated. Subjects that meet the inclusion/exclusion criteria at screening will enter
the run-in phase and will be dosed with 20 mg of tasimelteon daily for 6 weeks. The tau
estimation phase (48 hour urine collection samples to evaluate response to tasimelteon) will
follow the run-in phase and will last approximately 6 weeks long. The randomized withdrawal
phase comprises approximately eight weeks of treatment with either placebo or tasimelteon 20
mg taken approximately 1 hour prior to their target bedtime in a double-masked fashion.

Inclusion Criteria:

1. Ability and acceptance to provide informed consent;

2. Males, non-fecund females (i.e., surgically sterilized, if procedure was done 6
months before screening or subject is postmenopausal, without menses for 6 months
before screening), or females of child-bearing potential using an acceptable method
of birth control for a period of 35 days before the first dosing and must have a
negative pregnancy test at the screening and baseline visits; Note: Women using
hormonal methods of birth control must use an additional method of birth control
during the study and for one month after the last dose.

3. Willing and able to comply with study requirements and restrictions including a
commitment to a fixed 9-hour sleep opportunity during the study;

4. Diagnosis of N24HSWD in a previous clinical trial as measured by a tau value of >
24.1 and the lower bound of the 95% CI is > 24.

Exclusion Criteria:

1. History (within the 12 months prior to screening) of psychiatric disorders including
Major Depressive Disorder, Generalized Anxiety Disorder, Axis II Disorders, delirium
or any other psychiatric disorder, that is not being successfully treated or has not
been resolved and that in the opinion of the clinical investigator would affect
participation in the study or full compliance with study procedures;

2. History of intolerance and/or hypersensitivity to melatonin or melatonin agonists;

3. History of drug or alcohol abuse as defined in DSM-IV, Diagnostic Criteria for Drug
and Alcohol Abuse, within the 12 months prior to screening and/or regular consumption
of alcoholic drinks (> 2 drinks/day or > 14 drinks/week);

a. Note: A standard drink is equal to 13.7 grams (0.6 ounces) of pure alcohol or

- 12-ounces of beer

- 8-ounces of malt liquor

- 5-ounces of wine

- 1.5-ounces or a "shot" of 80-proof distilled spirits or liquor (e.g., gin, rum,
vodka, or whiskey);

4. Subject is at risk of suicide, in the opinion of the Investigator. Evidence of
suicide risk could include any suicide attempt within the past year or any other
suicidal behavior within the past year;

5. Current clinically significant cardiovascular, respiratory, neurologic, hepatic,
hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently
controlled and stable;

6. Subjects who have estimated creatinine clearance (CLcr; based on the Cockcroft-Gault
equation) ≤ to 55 mL/min;

7. Clinically significant deviation from normal in clinical laboratory results, vital
signs measurements, or physical examination findings at screening as determined by
the clinical investigator;

8. Indication of impaired liver function (values for AST, ALT or bilirubin > 2 times
Upper Limit of Normal);

9. Pregnant or lactating females;

10. A positive test for drugs of abuse at the screening visit; Note: A positive drug
screen at Visit 1 needs to be discussed with the medical monitor and will be
evaluated on a case-by-case basis.

11. Smoke more than 10 cigarettes/day;

12. Worked night, rotating, or split (period of work, followed by break, and then return
to work) shift work within 1 month of the screening visit or plan to work these
shifts during the study;

13. Unwilling or unable to follow the medication restrictions described in Section 8.2.,
or unwilling or unable to sufficiently wash-out from use of a restricted medication

14. Unable to perform calls to the study IVR system to report questionnaire results;

15. Any other sound medical reason as determined by the clinical investigator;

16. Legal incompetence or limited legal competence, detainment in an institution for
official or legal reasons.