Open Label Study to Assess the Absolute Bioavailability of Tasimelteon (HETLIOZ™)

Study Overview
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Brief Summary
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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.

Official Title
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A Single Dose, Open-Label, Randomized Two-Period Crossover Study in Healthy Young Subjects to Assess the Absolute Bioavailability of Tasimelteon (HETLIOZ™)

Conditions
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Non-24-Hour-Sleep-Wake Disorder

Intervention / Treatment
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* Drug: tasimelteon 20 mg capsule
* Drug: tasimelteon 2 mg I.V.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ages 18 - 55 years, inclusive; Non-smokers [abstinence from smoking for at least 6 months before the screening visit] and test negative for cotinine at screening and baseline; Subjects with Body Mass Index (BMI) of ≥18 and ≤25 kg/m2 (BMI = weight (kg)/ [height (m)]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 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 Vital signs (after 3 minutes resting in a semi-supine position) which are within the ranges shown below: Body temperature between 35.0-37.5 °C; Systolic blood pressure between 90-150 mmHg; Diastolic blood pressure between 50-95 mmHg; Pulse rate between 50-100 bpm. Ability and acceptance to provide written informed consent; Willing and able to comply with study requirements and restrictions; Subjects must be in good health as determined by past medical history, physical examination, electrocardiogram, clinical laboratory tests and urinalysis; Exclusion Criteria: 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; Any major surgery within three months of the first Baseline visit or any minor surgery within one month; History or current evidence of cardiovascular, hepatic, hematopoietic, renal, gastrointestinal or metabolic dysfunction or psychiatric disease judged by the Investigator to be clinically significant; 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); Any condition requiring the regular use of medication except those listed in Section 8.2; Exposure to any investigational drug, including placebo, within 30 days or 5 half-lives (whichever is longer) of baseline 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; Treatment with any drug known to cause major organ system toxicity (e.g., chloramphenicol or tamoxifen) during the 60 days preceding the Screening visit; History of intolerance and/or hypersensitivity to tasimelteon, and/or drugs similar to tasimelteon including melatonin; Donation or loss of 400 mL or more of blood within one month prior to the Baseline Visit; Significant illness within the two weeks prior to Baseline; Pregnant or lactating females; History of porphyria or liver disease and/or positive for one or more of the following serological results: A positive hepatitis C antibody test (anti-HCV) A positive hepatitis B surface antigen (HBsAg) A positive HIV test result 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; Inability to be venipunctured and/or tolerate venous access; Previous participation in a BMS-214778, VEC-162, or tasimelteon study; Subjects who are unable to read or speak English; Any other sound medical reason as determined by the clinical Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence A<br>Single oral dose of tasimelteon 20 mg on Day 1 Single I.V. dose of tasimelteon 2 mg on Day 6 | Drug: tasimelteon 20 mg capsule<br> <br> * Other names: Hetlioz™ 20 mg;Drug: tasimelteon 2 mg I.V.<br> <br> |
| Experimental: Sequence B<br>Single I.V. dose of tasimelteon 2 mg on Day 1 Single oral dose of tasimelteon 20 mg on Day 6 | Drug: tasimelteon 20 mg capsule<br> <br> * Other names: Hetlioz™ 20 mg;Drug: tasimelteon 2 mg I.V.<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Bioavailability After a Single Oral Dose of Hetlioz™(Tasimelteon) 20mg | The absolute bioavailability (F) of tasimelteon will be estimated from the dose-corrected AUC(inf) after oral and I.V. administration using an analysis of variance (ANOVA) model with treatment, period, sequence, and subject within sequence as the classification variables, using natural log-transformed data. The geometric mean ratio (GMR), oral-to-I.V., and its associated 90% confidence interval (CI) will be used as the estimate of F and its variability. | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Tasimelteon After a Single 20 mg Oral Dose and After a Single 2 mg I.V. Administration. | Cmax of tasimelteon will be compared when given orally or administered as an I.V. | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose | 
| AUC (Inf) of Tasimelteon After a Single 20 mg Oral Dose and After a Single 2 mg I.V. Administration. | AUC (inf) of Tasimelteon will be compared when given orally or administered as an I.V. | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose | 
| T1/2 of Tasimelteon After a Single 20 mg Oral Dose and After a Single 2 mg I.V. Administration. | T1/2 of tasimelteon will be compared when given orally or administered as an I.V. | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours pos-dose | 
| Total Clearance of Tasimelteon After a Single 20 mg Oral Dose and After a Single 2 mg I.V. Administration. | CL of tasimelteon will be compared when given orally or administered as an I.V. | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose | 
| Cmax of Tasimelteon's Metabolites After an Oral and I.V. Dose of Tasimelteon | The mean +/- SD for the Cmax of tasimelteon's metabolites after a single 20 mg oral dose of tasimelteon and after a single 2 mg I.V. administration of tasimelteon | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose | 
| AUC(Inf) of Tasimelteon's Metabolites After a Single Oral and I.V. Dose | The mean +/- SD for the AUC(inf) of tasimelteon's metabolites after a single 20 mg oral dose of tasimelteon and after a single 2 mg I.V. administration of tasimelteon | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose | 
| Metabolite-to-parent AUC(Inf) Ratios After Oral Administration of a Single 20 mg Dose and IV Administration of a Single 2 mg Dose of Tasimelteon | Comparison of the metabolite-to-parent AUC(inf) ratios for the oral and IV routes. | pre-dose, -0.125, 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose | 
| Number of Participants With Adverse Events | Number of participants with treatment-emergent adverse event per treatment arm and overall. | From Baseline to End of Study; Day 5 (± 2 days). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-24, absolute bioavailability, tasimelteon, Hetlioz™