Lemborexant for Shift Work Sleep Disorder

Overseen By Alex Desautels, M.D., Ph.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal

Must not be taking: Hypnotics, Neuroleptics, Antidepressants, others

Disqualifiers: Sleep disorders, Epilepsy, Psychiatric disorders, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 4 days per visit, with a 2-week washout period between visits

24 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires participants to stop using certain medications, especially those affecting sleep or wakefulness, like hypnotics, stimulants, and some antidepressants, at least one week before screening. If you're taking medications that are moderate or strong CYP3A4 inhibitors or inducers, you may also need to stop those. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug lemborexant for treating sleep disorders?

Lemborexant has been shown to be effective in treating insomnia, helping people fall asleep faster and stay asleep longer, with studies indicating improvements in sleep efficiency and reductions in wakefulness after sleep onset. ^{1 2 3 4 5}

Is lemborexant safe for human use?

Lemborexant has been studied for safety in humans, primarily for treating insomnia. Common side effects were similar to those seen with a placebo, including drowsiness and mild infections, and it was generally well-tolerated without the need for dose adjustments. ^{1 4 6 7 8}

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 work by adjusting the body's internal clock. ^{9 10 11 12 13}

What is the purpose of this trial?

This study aim to evaluate whether a dose of 5 mg of lemborexant, as compared to a placebo, may improve daytime recovery sleep, without producing lingering sleepiness during wakefulness, using a 3-day simulated night shift protocol in the lab under constant monitoring.

Eligibility Criteria

This trial is for individuals with sleep disorders linked to their work schedules, like shift workers who struggle to sleep during the day. Participants should be healthy adults willing to follow a simulated night shift schedule in a lab setting.

Inclusion Criteria

Be willing and able to give informed consent for study participation

Self-reported bedtime was between 9 pm and midnight on 4-7 nights per week

I will use effective contraception during and for 30 days after the study.

Exclusion Criteria

Participation in any other trial within 30 days before the screening visit

Individuals may be excluded from participating in the study based on the clinician's judgement

I have not traveled across more than one time zone in the month before screening or during the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

2 visits (in-person)

Treatment

Participants undergo a 3-day simulated night shift protocol in the lab under constant monitoring, receiving either lemborexant or placebo in a double-blind, counterbalanced order

4 days per visit, with a 2-week washout period between visits

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Lemborexant

Trial Overview The study tests if taking 5 mg of Lemborexant helps improve daytime sleep without causing drowsiness when awake. It's compared against a placebo over three days under lab conditions with constant monitoring.

Participant Groups

Group I: Active treatment condition Active Control 1 Intervention

Lemborexant at a 5mg dose is delivered in a film-coated tablet

Group II: Placebo condition Placebo Group 1 Intervention

Placebo is delivered in a film-coated tablet

Lemborexant is already approved in United States, Canada, Japan 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

Who Is Running the Clinical Trial?

Centre Integre Universitaire de Sante et Services Sociaux du Nord de l'ile de Montreal

Lead Sponsor

Trials

17

Recruited

4,600+

Findings from Research

Lemborexant is a dual orexin receptor antagonist approved in December 2019 for treating insomnia in adults, effectively helping with both sleep onset and maintenance.

In addition to its use for insomnia, lemborexant is being studied for treating irregular sleep-wake rhythm disorder in patients with mild to moderate Alzheimer's disease, indicating its potential broader applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lemborexant: First Approval. Scott, LJ.[2021]

In a study involving 291 adults with insomnia, lemborexant doses of 2.5 to 10 mg significantly improved sleep efficiency and reduced sleep onset latency compared to placebo, while minimizing next-morning sleepiness.

The 15 mg dose of lemborexant was particularly effective, leading to early success in the trial, and was associated with mostly mild to moderate side effects like somnolence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. Murphy, P., Moline, M., Mayleben, D., et al.[2018]

In a study of 61 patients over 3 months, switching to lemborexant significantly reduced insomnia symptoms, as measured by the Athens Insomnia Scale, indicating its efficacy as a treatment for insomnia.

The study also found that switching to lemborexant helped decrease the use of benzodiazepines and Z-drugs, potentially reducing the associated risks of these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. Horikoshi, S., Miura, I., Suzuki, Y., et al.[2023]

In a phase 3 trial involving 321 subjects, those who initially received placebo for 6 months showed improvements in sleep outcomes, but further enhancements were observed when switched to lemborexant (LEM) treatment, particularly in sleep onset latency and total sleep time.

Among participants who did not respond to placebo, 11%-15% experienced positive effects from lemborexant after switching, indicating that lemborexant can provide additional benefits even after prior treatment with placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of lemborexant in subjects previously treated with placebo for 6 months in a randomized phase 3 study. Yardley, J., Inoue, Y., Pinner, K., et al.[2023]

In a 12-month phase 3 study involving 949 subjects with moderate to severe insomnia, lemborexant significantly reduced insomnia severity compared to placebo, with improvements maintained over time.

Lemborexant treatment resulted in higher rates of clinically meaningful responses and remissions, with 44%-57% of subjects achieving a significant reduction in insomnia severity after 1 to 6 months, compared to 30%-41% in the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of lemborexant treatment on insomnia severity: analyses from a 12-month study of adults with insomnia disorder. Roth, T., Rosenberg, R., Morin, CM., et al.[2022]

Lemborexant, a new treatment for insomnia, is primarily eliminated through metabolism, with 86.5% of the administered dose recovered in urine and feces, indicating effective processing by the body.

The study found that while lemborexant and its metabolites have similar binding affinities for orexin receptors, the metabolites are unlikely to contribute significantly to its sleep-promoting effects due to limited brain penetration, supporting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disposition and Metabolism of [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites. Ueno, T., Ishida, T., Aluri, J., et al.[2022]

Lemborexant, an orexin receptor antagonist approved for insomnia, was studied in a large population of 1,892 subjects, showing that its pharmacokinetics are influenced by factors like body mass index and age, particularly in older adults.

The incidence of treatment-emergent adverse events (TEAEs) with lemborexant was low (3% to 8%) and similar to placebo, indicating that it can be safely administered without requiring dose adjustments based on patient characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Lalovic, B., Majid, O., Aluri, J., et al.[2021]

Lemborexant has been shown to significantly reduce the time it takes to fall asleep compared to placebo and is also effective when compared to the active control zolpidem ER, based on two phase 3 trials.

The medication is generally well-tolerated, with fewer severe side effects like cognitive impairment and complex sleep-related behaviors compared to traditional insomnia treatments, making it a suitable option, especially for older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of the Efficacy and Safety of Lemborexant, a Dual Receptor Orexin Antagonist (DORA), in the Treatment of Adults With Insomnia Disorder. Waters, K.[2022]

In a study involving 23 patients with Delayed Sleep-Wake Phase Disorder (DSWPD), administering an ultra-low dose of ramelteon (median 0.571 mg) in the early evening significantly advanced their sleep schedules and improved clinical symptoms.

Most patients had previously tried normal doses of ramelteon, suggesting that lower doses may be effective and potentially safer for managing DSWPD, especially in cases where traditional melatonin is not available or reliable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. Shimura, A., Kanno, T., Inoue, T.[2023]

Shift work disorder (SWD) affects up to 2 million Americans and is linked to serious health issues like cardiovascular diseases, depression, and increased risk of accidents.

Treatment options for SWD include behavioral strategies and pharmacologic interventions like modafinil and armodafinil, which have been shown to effectively reduce insomnia and excessive sleepiness, improving alertness during work shifts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is shift work making your patient sick? Emerging theories and therapies for treating shift work disorder. Rosenberg, R., Doghramji, PP.[2011]

Tasimelteon is a melatonin receptor agonist that effectively reduces sleep onset latency and resets circadian rhythms, making it a potential treatment for jet lag, shift work, and circadian rhythm sleep disorders, as shown in phase II and III clinical trials.

The drug is well tolerated and does not impair next-day functioning or cause dependence, indicating a favorable safety profile for short-term use, although long-term safety data is still needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders. Hardeland, R.[2013]

Melatonin effectively phase shifts circadian rhythms, making it a useful treatment for sleep disorders related to circadian misalignment, such as jet lag and shift work.

In specific conditions like delayed sleep phase syndrome (DSPS) and non-24-hour sleep-wake disorder, melatonin has been shown to advance sleep onset and improve overall sleep quality compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of melatonin in the treatment of phase shift and sleep disorders. Skene, DJ., Lockley, SW., Arendt, J.[2019]

Circadian rhythm sleep-wake disorders (CRSWDs) affect millions and significantly impact quality of life, highlighting a critical need for effective treatments.

Melatonin receptor agonists, particularly tasimelteon, have shown promise in treating CRSWDs, with distinct pharmacologic profiles that may guide their clinical use, though further research is necessary to fully understand their therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders. Williams, WP., McLin, DE., Dressman, MA., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Lemborexant: First Approval. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

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]

3. United States pubmed.ncbi.nlm.nih.gov

Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy and safety of lemborexant in subjects previously treated with placebo for 6 months in a randomized phase 3 study. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Impact of lemborexant treatment on insomnia severity: analyses from a 12-month study of adults with insomnia disorder. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Disposition and Metabolism of [14C]Lemborexant in Healthy Human Subjects and Characterization of Its Circulating Metabolites. [2022]

7. England pubmed.ncbi.nlm.nih.gov

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]

8. United States pubmed.ncbi.nlm.nih.gov

Review of the Efficacy and Safety of Lemborexant, a Dual Receptor Orexin Antagonist (DORA), in the Treatment of Adults With Insomnia Disorder. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Ultra-low-dose early night ramelteon administration for the treatment of delayed sleep-wake phase disorder: case reports with a pharmacological review. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Is shift work making your patient sick? Emerging theories and therapies for treating shift work disorder. [2011]

11. England pubmed.ncbi.nlm.nih.gov

Tasimelteon, a melatonin agonist for the treatment of insomnia and circadian rhythm sleep disorders. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

Use of melatonin in the treatment of phase shift and sleep disorders. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders. [2022]