Study to Evaluate the Effect of 2 Dosage Strengths of Lemborexant (E2006) on a Multiple Sleep Latency Test in Participants With Insomnia Disorder

Study Overview
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Brief Summary
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This is a single-dose, randomized, placebo-controlled, 3-way crossover study of 2 dosage strengths of lemborexant (5 mg and 10 mg) in participants with insomnia disorder.

Detailed Description
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The study will have 2 phases: Prerandomization and Randomization. The Prerandomization Phase will consist of 2 periods that taken together, will last up to a maximum of 21 days: a Screening Period and a Baseline Period. The Randomization Phase will comprise 4 treatment periods (Treatment 1, Treatment 2, Treatment 3, Treatment 4) with intervening washout periods between treatment periods (Washout 1, Washout 2, Washout 3). A single dose of study drug will be administered in a randomized, 3-way double-blind crossover manner at Treatment Periods 1-3; flurazepam 30 mg will be administered in an open-label manner at Treatment Period 4.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, 3-Way Crossover Study to Evaluate the Effect of 2 Dosage Strengths of E2006 on a Multiple Sleep Latency Test in Subjects With Insomnia Disorder

Conditions
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Insomnia Disorder

Intervention / Treatment
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* Drug: Lemborexant 5 mg
* Drug: Lemborexant 10 mg
* Drug: Lemborexant-matched placebo.
* Drug: Flurazepam 30 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 18 or older, at the time of informed consent. Meets the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for Insomnia Disorder, as follows: Complains of dissatisfaction with nighttime sleep despite adequate opportunity for sleep, with complaint being one or more of the following: difficulty getting to sleep, difficulty staying asleep, or awakening earlier in the morning than desired. Frequency of complaint greater than or equal to 3 times per week. Duration of complaint greater than or equal to 3 months. Associated with complaint of daytime impairment. Insomnia Severity Index score greater than or equal to 15 at Screening. Regular time in bed between 7 and 9 hours as reported at Screening. Regular bedtime, defined as the time the participant attempts to fall asleep, between 21:00 and 24:00 and regular wake time between 05:00 and 09:00 as reported at Screening. Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary completed for 7 nights during Screening, such that participant Sleep Onset Latency (sSOL) greater than or equal to 30 minutes on at least 3 nights and subjective Wake After Sleep Onset (sWASO) greater than or equal to 60 minutes on at least 3 nights. Exclusion Criteria: Excessive morning sleepiness at Baseline as determined by average SOL at Baseline less than 10 minutes. Females must not be lactating or pregnant at Screening or Baseline (documented by a negative beta-human chorionic gonadotropin [beta-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG or hCG). (Note: A negative urine pregnancy test is required at check-in before each dose of study drug and flurazepam). If females of childbearing potential: Had unprotected sexual intercourse within 30 days before study entry and do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 28 days after study drug discontinuation. Are currently abstinent, and do not agree to use a double barrier method (as described above) or refrain from sexual activity during the study period or for 28 days after study drug discontinuation. Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and do not agree to use the same contraceptive during the study or for 28 days after study drug discontinuation. NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). A current diagnosis of sleep-related breathing disorder, periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorder, or narcolepsy, or an exclusionary score on screening instruments to rule out individuals with symptoms of certain sleep disorders other than insomnia. Reports experiencing within the past year confusional arousals, symptoms of REM Behavior Disorder, or sleep-related violent behavior on Munich Parasomnia Scale (MUPS), or a history of aberrant nocturnal behaviors including sleep-driving or sleep-eating. Habitually naps more than 3 times per week. History of drug or alcohol dependency or abuse within approximately the last 2 years. Has a positive drug screen at Screening. A prolonged QT/QTc interval (QTc greater than 450 ms) as demonstrated by a repeated ECG at Screening (repeated only if initial ECG indicates a QTc interval greater than 450 ms). Any suicidal ideation with intent with or without a plan at Screening or within 6 months of Screening or any lifetime suicidal behavior. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal, psychiatric or neurological disease, or chronic pain) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments. Used any prohibited prescription or over-the-counter concomitant medications within 2 weeks prior to Screening, or between Screening and Randomization. Used any modality of treatment for insomnia, including cognitive behavioral therapy or marijuana within 2 weeks prior to Screening, or between Screening and Randomization. Scheduled for surgery during the study. Transmeridian travel across more than 3 time zones in the 2 weeks before Screening, or between Screening and Baseline, or plans to travel more than 3 times zones during the study. Hypersensitivity to flurazepam, the study drug, or any of the excipients. Currently enrolled in another clinical trial or used any investigational drug or device within 28 days or 5 x the half-life, whichever is longer preceding informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lemborexant 5 mg<br>Participants will receive a single, oral tablet formulation dose of lemborexant 5 mg within 5 minutes before bedtime. | Drug: Lemborexant 5 mg<br>* Lemborexant 5 mg tablet.<br>* Other names: E2006;|
| Experimental: Lemborexant 10 mg<br>Participants will receive a single, oral tablet formulation dose of lemborexant 10 mg within 5 minutes before bedtime. | Drug: Lemborexant 10 mg<br>* Lemborexant 10 mg tablet.<br>* Other names: E2006;|
| Placebo Comparator: Lemborexant-matched Placebo<br>Participants will receive a single, oral tablet formulation dose of lemborexant-matched placebo within 5 minutes before bedtime. | Drug: Lemborexant-matched placebo.<br>* Lemborexant-matched placebo tablet.<br>* Other names: E2006;|
| Active Comparator: Flurazepam 30 mg<br>Participants will receive a single, oral capsule formulation dose of flurazepam 30 mg within 5 minutes before bedtime. | Drug: Flurazepam 30 mg<br>* Flurazepam 30 mg capsule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Average Sleep Onset Latency (SOL) From Modified-Multiple Sleep Latency Test (M-MSLT) for Each Treatment in Treatment Periods 1 to 3 | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The multiple sleep latency test (MSLT) is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four Sleep Latency Tests (SLTs), with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. | Baseline, Day 2 of each of three treatment periods that were separated by approximately 2 weeks (for a total of up to 4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Average SOL of Less Than (<) 8.0 Minutes for Each Treatment | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. | Day 2 of each of three treatment periods that were separated by approximately 2 weeks (for a total of up to 6 weeks) | 
| Number of Participants Whose Treatment Difference (Under Either Dose of Lemborexant) Average SOL Score is More Than (>) 6.0 Minutes Shorter Than Placebo | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. | Day 2 of each of three treatment periods that are separated by approximately 2 weeks (for a total of up to 6 weeks) | 
| Number of Participants Whose Average SOL is <8.0 Minutes and >6.0 Minutes Shorter Than Placebo | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. | Day 2 of each of three treatment periods that are separated by approximately 2 weeks (for a total of up to 6 weeks) | 
| Mean Change From Baseline in the Average SOL From the M-MSLT in Treatment Period 4 | SOL is defined as the length of time that it takes to accomplish the transition from full wakefulness to sleep. The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. The four SLTs for each participant were averaged to obtain the mean SOL. | Baseline, Day 2 of Treatment Period 4 (Week 6) | 
| Mean Plasma Concentrations of Lemborexant and Metabolite M10 in the Morning Following M-MSLT | The MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. | Days 2, 16 and 30 within 20 minutes after the end of 4th SLT (up to 155 minutes after wake time) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) That Led to Death and Study Drug Discontinuation |  | From first dose of study drug up to Day 54 | 
| Number of Participants With Clinically Significant Abnormal Laboratory Values |  | From first dose of study drug up to Day 54 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values |  | From first dose of study drug up to Day 54 | 
| Number of Participants With Clinically Significant Shifts From Baseline in Electrocardiogram (ECG) Parameters |  | From first dose of study drug up to Day 54 | 
| Relationship Between PK Concentrations of Lemborexant and Sleepiness as Measured by M-MSLT | Pearson correlation was used to calculate the relationship between PK concentration of lemborexant and sleepiness. The M-MSLT is a widely used method for objectively quantifying excessive, pathological, or pharmacologically induced residual sleepiness by measuring the number of minutes that it takes a participant to fall asleep. The MSLT was modified to include four SLTs, with the first starting at 45 minutes after morning wake time, and the subsequent three occurring at 30-minute intervals for a total of 4 SLT's per M-MSLT. Each SLT was scored to determine the latency in minutes (with precision to 0.5 minute) from lights off to sleep onset; trials during which sleep onset did not occur were assigned a latency of 20 minutes. | Baseline up to Day 44 (Week 6) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E2006, Insomnia Disorder, Multiple Sleep Latency Test, Lemborexant