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

A Randomized Withdrawal Study to Demonstrate the Maintenance of Effect of 20 mg Tasimelteon in the Treatment of N24HSWD

The purpose of this study is to evaluate the maintenance effect and safety of 20 mg tasimelteon versus placebo in subjects suffering from 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.