Lemborexant for Shift Work Sleep Disorder
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 4
Recruiting
Sponsor: University of California, San Francisco
Must not be taking: Sleep aids, Digoxin, CYP3A4 drugs
Disqualifiers: Pregnancy, Narcolepsy, Hepatic impairment, others
Prior Safety Data
Approved in 4 Jurisdictions
Trial Summary
What is the purpose of this trial?
Insomnia and daytime sleepiness are common complaints among night shift workers, but effective sleep treatments in shift workers are lacking. The aim of this Phase IV double-blind, placebo-controlled, randomized study is to test whether a dual orexin antagonist, Lemborexant (5mg or 10mg), which would be expected to block the clock-driven orexin-mediated wakefulness during the day, will increase daytime sleep time in shift workers who complain of difficulty sleeping during the daytime compared to placebo.
Will I have to stop taking my current medications?
The trial requires participants to stop using sleep aids (both prescription and non-prescription) during the study. Additionally, if you are taking digoxin or certain medications that affect liver enzymes (cytochrome P450 3A4), you cannot participate in the trial.
What data supports the effectiveness of the drug lemborexant for treating shift work sleep disorder?
Is lemborexant safe for humans?
How does the drug Lemborexant differ from other treatments for Shift Work Sleep Disorder?
Lemborexant is unique because it works by blocking orexin receptors, which are involved in wakefulness, helping to promote sleep. This is different from other treatments like melatonin agonists, which adjust the body's internal clock, or stimulants like modafinil, which help with alertness.910111213
Research Team
AP
Aric Prather, PhD
Principal Investigator
University of California, San Francisco
Eligibility Criteria
This trial is for full-time night shift workers who've been working nights for at least 3 months and are struggling with daytime sleepiness and trouble sleeping during the day. Pregnant or breastfeeding individuals, those with severe depression, untreated medical conditions, or using certain medications can't participate.Inclusion Criteria
You have worked night shifts for at least 3 months.
You have reported problems with feeling sleepy during the day and difficulty sleeping during the day.
You work night shifts for at least 6 hours per shift, 4 days per week or 32 hours per week.
Exclusion Criteria
Pregnancy (verified by urine pregnancy test) or plan to become pregnant in the next 3 months
Currently breastfeeding
You didn't have enough chance to sleep during the day (less than 7 hours) after working overnight.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Baseline Assessment
Participants undergo baseline assessment to measure initial sleep patterns
2 weeks
Daily actigraphy data collection
Treatment
Participants receive Lemborexant (5mg or 10mg) or placebo to test its effect on daytime sleep time
2 weeks
Daily sleep diary completion
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- Lemborexant (Dual Orexin Antagonist)
Trial OverviewThe study is testing Lemborexant, a medication intended to help night shift workers sleep better during the day by blocking wakefulness signals in the brain. Participants will randomly receive either Lemborexant or a placebo to compare effectiveness.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Active TreatmentExperimental Treatment1 Intervention
Participants randomized into this arm will receive Lemborexant (5-10mg).
Group II: Placebo TreatmentPlacebo Group1 Intervention
Participants randomized into this arm will receive a placebo medication which appears the same as the active treatment.
Lemborexant is already approved in United States, Canada, Japan, Australia for the following indications:
🇺🇸 Approved in United States as Dayvigo for:
- Insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults
🇨🇦 Approved in Canada as Dayvigo for:
- Insomnia characterized by difficulties with sleep onset and/or sleep maintenance, with or without associated impairment in daily functioning
🇯🇵 Approved in Japan as Dayvigo for:
- Treatment of insomnia
🇦🇺 Approved in Australia as Dayvigo for:
- Insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California, San FranciscoSan Francisco, CA
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Who Is Running the Clinical Trial?
University of California, San Francisco
Lead Sponsor
Trials
2636
Patients Recruited
19,080,000+
References
Lemborexant: First Approval. [2021]Lemborexant (DAYVIGO™) is an orally administered, dual orexin receptor (OXR) antagonist that exhibits reversible competitive antagonism at OXR1 and OXR2 (> affinity at OXR2) that was discovered and developed by Eisai Inc. for the treatment of adult patients with insomnia. In December 2019, lemborexant received its first approval (with final interim scheduling) in the USA for the treatment of adult patients with insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. In January 2020, lemborexant also received approval in Japan for the treatment of insomnia. It is also being investigated for the treatment of irregular sleep-wake rhythm disorder (ISWRD) associated with mild to moderate Alzheimer's disease. This article summarizes the milestones in the development of lemborexant leading to its first global approval.
Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. [2018]To identify dose(s) of lemborexant that maximize insomnia treatment efficacy while minimizing next-morning residual sleepiness and evaluate lemborexant effects on polysomnography (PSG) measures (sleep efficiency [SE], latency to persistent sleep [LPS], and wake after sleep onset [WASO]) at the beginning and end of treatment.
Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. [2023]We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months.
Impact of lemborexant treatment on insomnia severity: analyses from a 12-month study of adults with insomnia disorder. [2022]Evaluate changes in insomnia severity in subjects with moderate to severe insomnia (Insomnia Severity Index [ISI] score ≥15) treated for 12 months nightly with lemborexant.
Efficacy and safety of lemborexant in subjects previously treated with placebo for 6 months in a randomized phase 3 study. [2023]To examine the effects of lemborexant (LEM) 5 mg (LEM5) or LEM 10 mg (LEM10) following extended placebo treatment. This post-hoc analysis used subject-reported sleep outcomes data from a phase 3 trial.
Review of the Efficacy and Safety of Lemborexant, a Dual Receptor Orexin Antagonist (DORA), in the Treatment of Adults With Insomnia Disorder. [2022]To provide an overview of the efficacy and safety of lemborexant in the treatment of insomnia disorder by assessing the currently available literature.
Disposition and Metabolism of [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites. [2022]Lemborexant is a novel dual orexin receptor antagonist recently approved for the treatment of insomnia in the United States and Japan. Here, disposition and metabolic profiles were investigated in healthy human subjects. After single oral administration of 10 mg [14C]lemborexant (100 µCi), plasma concentrations of lemborexant and radioactivity peaked at 1 hour postdose and decreased biphasically. Cumulative recovery of the administered radioactivity within 480 hours was 86.5% of the dose, with 29.1% in urine and 57.4% in feces. Unchanged lemborexant was not detected in urine but accounted for 13.0% of the dose in feces, suggesting that the main elimination pathway of lemborexant was metabolism. Metabolite analyses revealed that the major metabolic pathways of lemborexant are oxidation of the dimethylpyrimidine moiety and subsequent further oxidation and/or glucuronidation. In plasma, lemborexant was the dominant component, accounting for 26.5% of total drug-related exposure. M4, M9, M10, and M18 were detected as the major radioactive components; M10 was the only metabolite exceeding 10% of total drug-related exposure. Although M4, M9, and M10 showed binding affinity for orexin receptors comparable to that of lemborexant, their contributions to the sleep-promoting effects of lemborexant are likely low because of the limited brain penetration by P-glycoprotein. Exposure comparison between humans and nonclinical toxicology species confirmed that plasma exposure of M10 was higher in at least one animal species compared with that in humans, indicating that there is no disproportionate metabolite in humans, as defined by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use M3(R2) and U.S. Food and Drug Administration Metabolite in Safety Testing guidance; therefore, no additional toxicology studies are needed. SIGNIFICANCE STATEMENT: This study provides detailed data of the disposition and metabolism of lemborexant, a novel therapeutic drug for insomnia, in humans, as well as a characterization of the circulating metabolites and assessment of their contributions to efficacy and safety. The information presented herein furthers our understanding of the pharmacokinetic profiles of lemborexant and its metabolites and will promote the safe and effective use of lemborexant in the clinic.
Population Pharmacokinetics and Exposure-Response Analyses for the Most Frequent Adverse Events Following Treatment With Lemborexant, an Orexin Receptor Antagonist, in Subjects With Insomnia Disorder. [2021]Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (Cav,ss ) to the probability of most frequent treatment-emergent adverse events (TEAEs). The 12 230-observation, 1892-subject PK data set included data from 12 clinical studies with predominantly female subjects (66%) ranging in age from 18 to 88 years and from 37 to 168 kg in body weight. The 1664-subject exposure-response data set included data from 3 late-stage studies. Lemborexant pharmacokinetics were described by a 3-compartment model with combined first- and zero-order absorption with lag time and linear elimination. Oral clearance decreased with increasing body mass index (exponent, -0.428), increasing alkaline phosphatase levels (exponent, -0.118), and was 26% lower in the elderly (≥65 years). Across the adverse event analysis, the frequency of subjects experiencing TEAEs during active treatment ranged from approximately 3% to 8%, in the range estimated for placebo. With and without adjustment for age, lemborexant exposure (Cav,ss ) was not a clinically meaningful linear predictor of the probability of specific TEAEs: somnolence, nasopharyngitis, flu/influenza, urinary tract infection, upper respiratory tract infection, or headache. Given the small effect sizes of covariates of the PK model and a low degree of association of lemborexant TEAEs and exposure over the range of phase 3 (therapeutic) 5- and 10-mg doses, lemborexant can be safely administered without the need for dose adjustment.
Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. [2023]Delayed sleep-wake phase disorder (DSWPD) is a common circadian sleep-wake phase disorders brings serious social impairment of the patients. Melatonin is the main medication option; however, it has not been approved in some countries, and over-the-counter melatonin is under poor quality control. The melatonin receptor agonist ramelteon might be a potential treatment option, but there are few reports regarding its use in DSWPD patients. Existing pharmacological and chronobiological studies suggest that an ultra-low dose of ramelteon in the early night is beneficial for DSWPD. Here, we present our clinical experience together with a pharmacological review and discussion. Twenty-three DSWPD patients, of whom 18 patients had a treatment history of a normal dose of ramelteon, were prescribed low-dose ramelteon (median: 0.571 mg, 1/14 of a tablet) to be taken in the early night (mean: 18:10). After the treatment, the mean sleep schedule was significantly advanced, and clinical symptoms were improved.
Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders. [2022]Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.
Is shift work making your patient sick? Emerging theories and therapies for treating shift work disorder. [2011]"Shift work" is a term that applies to a wide array of nontraditional work schedules. Shift work disorder (SWD) is a circadian rhythm sleep disorder experienced by a subset of shift workers that is characterized by excessive sleepiness during work and/or insomnia during scheduled sleep times. It is estimated to affect up to 2 million Americans, and is associated with increased morbidity and mortality from metabolic risk factors, cardiovascular and gastrointestinal diseases, depression, accidents, and some kinds of cancers. Patient history is all that is needed to make a diagnosis with the International Classification of Sleep Disorders-Second Edition criteria as described herein. Circadian rhythm disorders, in which an underlying misalignment of circadian rhythm with the sleep-wake cycle occurs, may be treated by behavioral and pharmacologic approaches, including the use of hypnotics to improve the duration of sleep. However, evidence is limited with these approaches in patients diagnosed with SWD. Other treatment options may include pharmacologic interventions such as modafinil and armodafinil, which have shown efficacy in this population. Combined therapy can reduce insomnia and excessive sleepiness, and improve attention and alertness during work shifts and the subsequent commute home.
Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders. [2013]Tasimelteon, developed by Vanda Pharmaceuticals Inc under license from Bristol-Myers Squibb Co, is a melatonin receptor agonist. Because of the high density of melatonin receptors in the circadian pacemaker, the suprachiasmatic nucleus, melatonergic actions can phase-shift circadian rhythms and promote sleep. Tasimelteon was effective in reducing sleep onset latency (in phase II and III clinical trials) and in resetting the circadian melatonin rhythm (in phase II trials), which indicated its potential suitability as treatment for jet lag, shift work and circadian rhythm sleep disorders. Statistically significant improvements in sleep maintenance have also been observed with the drug. Tasimelteon has been claimed to be useful in the treatment of depression, and preclinical evidence in this respect is to be confirmed in a phase II clinical trial, which was ready to be initiated at the time of publication. It is plausible that the drug may be effective in the treatment of depressive disorders, at least those that are related to circadian dysfunction, and that it may attenuate sleep problems in depressed patients of different subtypes. A general suitability in mitigating other symptoms of major depressive disorder cannot be deduced from the actions of tasimelteon via the melatonin receptors MT1 and MT2. The drug is well tolerated, does not induce impairment of next-day functioning or dependence, and seems to be safe in short-term treatment; however, toxicological data would be required for assessing its long-term safety.
Use of melatonin in the treatment of phase shift and sleep disorders. [2019]When administered to humans the pineal hormone melatonin can phase shift a number of circadian rhythms. This property has prompted the investigation of exogenous melatonin in sleep disorders known to have an underlying chronophysiological basis (i.e. circadian rhythm sleep disorders). Both in field and simulated studies of jet lag and shift work suitably timed melatonin improved sleep and, in some cases, hastened readaptation of the circadian rhythms following the phase shift. Melatonin treatment has also been evaluated in the circadian sleep disorders: delayed sleep phase syndrome (DSPS) and non-24-hour sleep wake disorder. Compared with placebo, melatonin advanced the sleep period in subjects with DSPS. Melatonin also improved a number of sleep parameters in blind subjects suffering from non-24-hour sleep wake disorder.