Efficacy and Safety of Tasimelteon Compared With Placebo in Totally Blind Subjects With Non-24-Hour Sleep-Wake Disorder

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of a six month double-mask treatment of tasimelteon or placebo in male and female subjects with Non-24-Hour Sleep-Wake Disorder

Detailed Description
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Non-24-Hour Sleep-Wake Disorder (N24HSWD) occurs when individuals, primarily those without light perception, 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 if < 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. This will be a multicenter, randomized, double-masked, placebo-controlled, parallel study. The study has two phases: the pre-randomization phase followed by either the randomization phase or the open-label extension (OLE). The pre-randomization phase comprises a screening visit where subject's initial eligibility will be evaluated, a circadian period (τ) estimation segment, and a variable-length in-phase transition segment in which subjects will wait to start treatment until their circadian phase is aligned with their target bedtime. Subjects that meet all entry criteria for the study will enter the randomization phase. During the randomization phase, subjects will be asked to take either 20 mg tasimelteon or placebo approximately 1 hour prior to their target bedtime for 26 weeks in a double-masked fashion. Subjects who have a τ greater than 24.0 and meet all entry criteria but that are ineligible for the randomization phase due to their τ estimate may be given the opportunity to participate in the OLE phase. During the OLE phase, subjects will take open-label 20mg tasimelteon for 26 weeks.

Official Title
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A Multicenter, Randomized, Double-Mask, Placebo-Controlled, Parallel Study to Investigate the Efficacy and Safety of 20 mg Tasimelteon Versus Placebo in Totally Blind Subjects With N24HSWD Followed by an OLE Phase

Conditions
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Non-24-Hour Sleep-Wake Disorder

Intervention / Treatment
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* Drug: tasimelteon
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability and acceptance to provide informed consent; No perception of light by the subject's own report; Diagnosis of N24HSWD as determined by: History (within the last 3 months) of trouble sleeping at night difficulty initiating sleep or staying asleep), difficulty awakening in the morning, or daytime sleepiness as determined by answering yes to at least one question in the Sleep Complaint Questionnaire and Urinary aMT6s demonstrates a progressive delay of the aMT6 acrophase time. Willing and able to comply with study requirements and restrictions including a commitment to a fixed 9-hour sleep opportunity during the study; Fluent in English; Exclusion Criteria: Have a probable diagnosis of a current sleep disorder other than N24HSWD that is the primary cause of the sleep disturbance based on clinical investigator medical judgment; Current clinically significant cardiovascular, respiratory, neurologic, hepatic, hematopoietic, renal, gastrointestinal or metabolic dysfunction unless currently controlled and stable; 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 in the opinion of the clinical investigator would affect participation in the study or full compliance with study procedures; History of intolerance and/or hypersensitivity to melatonin or melatonin agonists; 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; Unable to perform calls to the study IVR system to report questionnaire results; Exposure to any investigational drug, including placebo, within 30 days or 5 half lives (whichever was longer) of screening; Use of central nervous system prescription or OTC medications, other than melatonin, that affects the sleep-wake cycle Use of melatonin or melatonin agonist

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tasimelteon<br>20 mg tasimelteon capsules, PO daily for 6 months | Drug: tasimelteon<br>* 20 mg tasimelteon capsules, PO daily for 6 months<br>* Other names: VEC-162;|
| Placebo Comparator: placebo<br>Placebo capsules, PO daily for 6 months | Drug: Placebo<br>* Placebo capsules, PO daily for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Entrained as Assessed by Urinary aMT6 | 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. | 1 month | 
| Proportion of Patients With a Clinical Response: Entrainment of aMT6 and Score of ≥ 3 on N24CRS | 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Entrained as Assessed by Urinary Cortisol | Entrainment is a measure of synchronization of the master body clock to the 24-hour day. The circadian period (τ) was calculated using urinary cortisol collected over four 48 hour periods, 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. | 1 month | 
| Average Clinical Global Impression of Change (CGI-C) | CGI-C scores range from 1 (very much improved) to 7 (very much worse). The average post-randomization score was obtained for each patient by averaging the last 2 scheduled assessments (Day D112 and Day D183). Lower number indicates improvement. | Day 112 and 183 | 
| Proportion of Responders With a Combined Sleep/Wake Response for LQ-nTST (≥ 90 Minutes) and UQ-dTSD (≤ 90 Minutes) | The sleep/wake response represents measurement of the combined improvement in the nighttime sleep duration and daytime sleep duration. Individuals that have an improvement in nighttime sleep and daytime sleep, defined as an increase of 90 minutes or more in the lower quartile of subjective nighttime total sleep time (LQ-nTST) and a decrease of 90 minutes or more in the upper quartile of daytime total sleep duration (UQ-dTSD) are considered to be a responder. | 6 months | 
| Average Lower Quartile of Nights of Nighttime Total Sleep Time (LQ-nTST) | LQ-nTST measures the difference in average nighttime sleep during the patient's worst 25% of nights (shortest total nighttime sleep) between the randomized phase (6 months)and the screening phase (  6 weeks). The higher number indicates improvement. | 6 months | 
| Average Upper Quartile of Days of Subjective Daytime Sleep Duration (UQ-dTSD) | UQ-dTSD measures the difference in average daytime sleep during the patient's worst 25% of days (longest total daytime sleep) between the randomized phase (6 months) and the screening phase (  6 weeks). Lower number indicates improvement. | 6 months | 
| Average Midpoint of Sleep (MoST) | Midpoint of Sleep Timing (MoST) is the measurement of the average midpoint of sleep time relative to bedtime. The average MoST value will trend to 0 as an individual's sleep becomes more fragmented. Improvement is defined as an increase in the average. | 6 months | 
| Number of Patients With a Treatment Emergent Adverse Event (Open Label Extension Phase Only) | Adverse events were recorded in the source documents from the time of the patient's informed consent signature until the end of the patient's study participation. An AE was defined as any untoward medical occurrence in a clinical investigation patient who does not necessarily have causal relationship with treatment. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blindness, Eye Diseases, Nap Disorders, Circadian Rhythm Disorders, Sleep disorders, Circadian Rhythm Sleep Disorders, Dyssomnias, Nervous System Diseases