Open Label Study to Assess the Absolute Bioavailability of Tasimelteon (HETLIOZ™)
Condition: Non-24-Hour-Sleep-Wake Disorder
MeSH terms: Sleep Wake Disorders; Sleep Disorders, Circadian Rhythm
Intervention: tasimelteon 20 mg capsule; tasimelteon 2 mg I.V.
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Non-24; absolute bioavailability; tasimelteon; Hetlioz™

Summary:

      Hetlioz™ (tasimelteon) is used in the treatment of Non-24-Hour-Sleep-Wake Disorder (Non-24).
      Non-24 is very common in people who are totally blind because light can not reset their body
      clock. This causes the internal sleep-wake cycle to be out of sync with the 24-hour
      day-night. Non-24 is a serious, chronic circadian rhythm disorder in the blind that causes
      nighttime sleep problems and a wide range of daytime difficulties, including an overwhelming
      urge to nap.

      Tasimelteon will be given in two ways; orally (by mouth) as a 20 mg capsule and intravenously
      (I.V.) by infusion through a catheter (not an injection) into a vein. The oral administration
      is approved by the FDA. The I.V. administration is considered investigational as it has not
      been approved by the FDA. This will be the first time tasimelteon will be given to humans by
      intravenous (I.V.) injection.

      The purposes of this research study are to:

        -  assess how quickly a single 20 mg oral dose of tasimelteon is absorbed into the body;

        -  evaluate the single-dose pharmacokinetics of tasimelteon after a single 20 mg oral dose
           and after a single 2 mg I.V. dose;

        -  evaluate the single-dose pharmacokinetics of tasimelteon metabolites after a single 20
           mg oral dose and after a single 2 mg I.V. dose;

        -  evaluate the safety and tolerability of a single 20 mg oral dose of tasimelteon; and

        -  evaluate the safety and tolerability of a single 2 mg I.V. dose of tasimelteon.

      Pharmacokinetics (PK) is the study of how a drug is absorbed, distributed, metabolized, and
      eventually eliminated by the body. Pharmacokinetics is what the body does to the drug. Blood
      samples will be taken throughout the study for PK analysis.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Men and women ages 18 - 55 years, inclusive;

          2. Non-smokers [abstinence from smoking for at least 6 months before the screening visit]
             and test negative for cotinine at screening and baseline;

          3. Subjects with Body Mass Index (BMI) of ≥18 and ≤25 kg/m2 (BMI = weight (kg)/ [height
             (m)]2);

          4. 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 females must have a
             negative pregnancy test at the screening and baseline visits; Note 1: Acceptable
             methods of birth control include any one of the following: abstinence, vasectomized
             sexual partner, hormonal methods (i.e. pill, hormonal IUD, Depo-Provera, implants,
             patch, intravaginal device [NuvaRing]), intrauterine device (IUD [copper banded
             coils]), diaphragm, cervical cap, or condom with spermicidal jelly or foam

          5. Vital signs (after 3 minutes resting in a semi-supine position) which are within the
             ranges shown below:

               1. Body temperature between 35.0-37.5 °C;

               2. Systolic blood pressure between 90-150 mmHg;

               3. Diastolic blood pressure between 50-95 mmHg;

               4. Pulse rate between 50-100 bpm.

          6. Ability and acceptance to provide written informed consent;

          7. Willing and able to comply with study requirements and restrictions;

          8. Subjects must be in good health as determined by past medical history, physical
             examination, electrocardiogram, clinical laboratory tests and urinalysis;

        Exclusion Criteria:

          1. History of recent (within six months) drug or alcohol abuse as defined in DSM-V,
             Diagnostic Criteria for Drug and Alcohol Abuse or evidence of such abuse as indicated
             by the laboratory assays conducted during the Screening Visit or at Baseline;

          2. Any major surgery within three months of the first Baseline visit or any minor surgery
             within one month;

          3. History or current evidence of cardiovascular, hepatic, hematopoietic, renal,
             gastrointestinal or metabolic dysfunction or psychiatric disease judged by the
             Investigator to be clinically significant;

          4. Subjects who are currently considered a suicide risk, any subject who has ever made a
             suicide attempt, or those who are currently demonstrating active (within the past 6
             months) suicidal ideation as deemed by the Columbia Suicide Severity Rating Scale
             (C-SSRS);

          5. Any condition requiring the regular use of medication except those listed in Section
             8.2;

          6. Exposure to any investigational drug, including placebo, within 30 days or 5
             half-lives (whichever is longer) of baseline

          7. Exposure (within 2 weeks of Day -1) to any over-the-counter medications including
             melatonin, dietary supplements and/or herbal remedies, except those listed on Section
             8.2;

          8. Treatment with any drug known to cause major organ system toxicity (e.g.,
             chloramphenicol or tamoxifen) during the 60 days preceding the Screening visit;

          9. History of intolerance and/or hypersensitivity to tasimelteon, and/or drugs similar to
             tasimelteon including melatonin;

         10. Donation or loss of 400 mL or more of blood within one month prior to the Baseline
             Visit;

         11. Significant illness within the two weeks prior to Baseline;

         12. Pregnant or lactating females;

         13. History of porphyria or liver disease and/or positive for one or more of the following
             serological results:

               1. A positive hepatitis C antibody test (anti-HCV)

               2. A positive hepatitis B surface antigen (HBsAg)

               3. A positive HIV test result

         14. Use of any food or beverage containing grapefruit or grapefruit juice, apple or orange
             juice, vegetables from the mustard green family (e.g. kale, broccoli, watercress,
             collard greens, kohlrabi, Brussels sprouts, mustard greens) and charbroiled meats for
             at least 2 weeks before the Baseline Visit until the end of the study;

         15. Inability to be venipunctured and/or tolerate venous access;

         16. Previous participation in a BMS-214778, VEC-162, or tasimelteon study;

         17. Subjects who are unable to read or speak English;

         18. Any other sound medical reason as determined by the clinical Investigator.