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
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
136
20 mg tasimelteon capsules, PO daily for 6 months
Placebo capsules, PO daily for 6 months
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.
Time frame: 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.
Time frame: 6 months
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.
Time frame: 1 month
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Pulmonary Associates, PA
Phoenix, Arizona, United States
SDS Clinical Trials Inc.
Orange, California, United States
VA Palo Alto Health Care System/PAIRE (San Fransisco Bay Area)
Palo Alto, California, United States
St. Johns Sleep Disorder Center - St. Johns Medical Plaza
Santa Monica, California, United States
Radiant Research - Denver
Denver, Colorado, United States
PAB Clinical Research Inc.
Brandon, Florida, United States
Kendall South Medical Center, Inc.
Miami, Florida, United States
Ocean Sleep Disorders Center - Ormond Beach
Ormond Beach, Florida, United States
Sleep Disorders Center Of Georgia
Atlanta, Georgia, United States
Suburban Lung Associates SC (Chicago Metropolitan Area)
Elk Grove Village, Illinois, United States
...and 18 more locations
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 6 months