A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design, Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia

Study Overview
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Brief Summary
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This is a multicenter, multiple dose, randomized, double-blind, placebo-controlled, parallel-group, Bayesian adaptive, dose response study in subjects with chronic insomnia. Subjects will be randomized to 1 of 6 doses of E2006 (1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, or 25 mg) or placebo.

Detailed Description
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The study will have 2 phases, Prerandomization and Randomization. The Prerandomization Phase will last up to 21 days and will consist of a Screening Period (Days -21 to -2) and a Baseline Period (Day -1). Following the Baseline Period, all eligible subjects will be randomized, in a double-blind manner, to receive E2006 or placebo for 15 nights during the Treatment Period (Days 1 to 15), then all subjects will receive placebo, in a single-blind manner, for 2 nights (Days 16 to 17) during the Rebound Insomnia Assessment Period (Days 16 to 18). Subjects will not receive any treatment during the Follow-up Period (Days 19 to 29). All subjects will come to the clinic for screening procedures. During the Screening Period, subjects will complete the Sleep Diary each day. Polysomnographic sleep will be measured during the Screening Period on 2 consecutive nights between Day -9 and Day -3. These 8-hour polysomnograms (PSGs) will start at the median habitual bedtime calculated from responses on the Sleep Diary completed 7 days immediately prior to the first PSG night. Subjects may leave the clinic between the screening/baseline PSG nights.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Bayesian Adaptive Randomization Design, Dose Response Study of the Efficacy of E2006 in Adults and Elderly Subjects With Chronic Insomnia

Conditions
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Chronic Insomnia, Adults, Elderly

Intervention / Treatment
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* Drug: E2006
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Subjects must meet all of the following criteria to be included in this study: Male or female subjects age 18 to 80 years 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 Subjective Sleep Onset Latency (sSOL) typically greater than or equal to 30 minutes in the last 4 weeks and/or subjective WASO (sWASO) typically greater than or equal to 60 minutes in the last 4 weeks Regular time in bed between 6.5 and 9.0 hours Regular bedtime between 21:00 and 24:00 and regular waketime between 05:00 and 09:00 Insomnia Severity Index (ISI) score greater than or equal to 15 at Screening Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary completed for 7 nights prior to the first screening/baseline PSG Objective (PSG) evidence of insomnia at the screening/baseline PSGs as follows: LPS average greater than or equal to 30 minutes on the 2 consecutive screening/baseline PSGs, with neither night lesser than 15 minutes and/or WASO average greater than or equal to 30 minutes on the 2 consecutive screening/baseline PSGs, with neither night lesser than 20 minutes SE average lesser than or equal to 85% on the 2 consecutive screening/baseline PSGs, with neither night greater than 87.5% Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use two highly effective method of contraception Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation. Provide written informed consent Willing to stay in bed for at least 8 hours each night spent in the clinic Willing and able to comply with all aspects of the protocol Exclusion Criteria Subjects who meet any of the following criteria will be excluded from this study: Females who are pregnant (positive beta-human chorionic gonadotropin [B-hCG] test) or breastfeeding Any lifetime diagnosis of sleep-related breathing disorder, periodic limb movement disorder, restless legs syndrome, nightmare disorder, sleep terror disorder, sleepwalking disorder, rapid eye movement (REM) behavior disorder, or narcolepsy Aged 18 to 64 years: Apnea-Hypopnea Index greater than or equal to 10, or Periodic Limb Movements with Arousal Index greater than or equal to 10 on first (diagnostic) PSG night at Screening. Aged 65 to 80 years: Apnea-Hypopnea Index greater than 15, or Periodic Limb Movements with Arousal Index greater than 15 on first (diagnostic) PSG night at Screening Beck Depression Inventory (BDI) - II score greater than 19 at Screening Beck Anxiety Inventory (BAI) score greater than 15 at Screening Used a prescription for any modality of treatment for insomnia, including cognitive behavioral therapy, within 2 weeks prior to screening/baseline PSG, or between Screening and Baseline Used any medication or sleep aid with known effects on sleep, within 2 weeks prior to screening/baseline PSG, or between Screening and Baseline Used any prohibited prescription or over-the-counter concomitant medications within the week prior to the first screening/baseline PSG. Transmeridian travel across 3 or more time zones in the 2 weeks prior to Screening, or plans to travel across 3 or more time zones during study Unwilling to limit caffeine consumption to lesser than or equal to 600 mg caffeine (approximately four 6-oz cups of caffeinated coffee, or three 12-oz caffeinated sodas, or three 8-oz caffeinated tea beverages), avoid caffeine after 18:00 throughout the study, and avoid caffeine after 13:00 on PSG visits Unwilling to limit alcohol intake to two or fewer drinks per day throughout the study, or to refrain from any alcohol for 3 hours prior to bedtime while at home throughout the study, or any alcohol on days and nights spent in the clinic. A drink is defined as approximately 12 oz (360 mL) of beer, 4 oz (120 mL) of wine, or 1 oz (30 mL) of liquor. Any subject that has a known history of malaria or has traveled to a country with known malarial risk (i.e., are designated as 'high' or 'moderate' risk country according to the list available at http://www.cdc.gov/malaria) within the last year. A prolonged QT/QT interval corrected for heart rate (QTc) interval (QTc greater than 450 ms) as demonstrated by a repeated electrocardiogram (ECG) at Screening (repeated only if initial ECG indicates a QTc interval greater than 450 ms). A history of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolong the QT/QTc interval. Any suicidal ideation with intent with or without a plan at Screening, Baseline, or within 6 months before Screening (i.e., answering Yes to questions 4 or 5 on the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale [C-SSRS]) Any lifetime suicidal behavior (per the Suicidal Behavior Section of the C-SSRS) Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments Hypersensitivity to the study drug or any of the excipients Any history of a medical condition or a concomitant medical condition that in the opinion of the investigator(s) would compromise the subject's ability to safely complete the study Scheduled for surgery during the study Known to be human immunodeficiency virus (HIV) positive Active viral hepatitis (B or C) as demonstrated by positive serology Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years History of drug or alcohol dependency or abuse within approximately the last 2 years Unwilling to refrain from use of illegal (or legalized) recreational drugs during the study or test positive for illegal (or legalized) drugs at Screening, Baseline, or Day 14 Currently enrolled in another clinical trial or used any investigational drug or device within 30 days or 5x the half-life, whichever is longer preceding informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: E2006<br>E2006 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, or 25 mg, in tablet form, taken orally, 30 minutes prior to bedtime, each night for 15 consecutive nights | Drug: E2006<br>* E2006 1 mg, 2.5 mg, 5 mg, 10 mg, 15 mg, or 25 mg, in tablet form, taken orally, 30 minutes prior to bedtime, each night for 15 consecutive nights<br>|
| Placebo Comparator: Placebo<br>E2006-matched placebo in tablet form, taken orally, 30 minutes prior to bedtime, each night for 15 consecutive nights | Drug: Placebo<br>* E2006-matched placebo in tablet form, taken orally, 30 minutes prior to bedtime, each night for 15 consecutive nights<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Having Utility Function Greater Than (>) 1 Based on Bayesian Analysis | The utility of a dose was a function of both Sleep Efficiency (SE) and Karolinska Sleepiness Scale (KSS), constructed by specifying the 1-dimensional component for each outcome measure and then combining them multiplicatively. Sufficient utility was defined as a probability of having utility function >1. Probability of having utility function >1 at the end of study visit (full analysis) was reported. | Baseline up to Day 3 | 
| Mean Change From Baseline in Karolinska Sleepiness Scale (KSS) Score at End of Treatment | The KSS was used to measure next-day residual effects at prespecified time points. The KSS was a 9-point scale on which the participant rated their sleepiness from 1 (extremely alert) to 9 (extremely sleepy/fighting sleep), where higher scores indicated an increase in sleepiness. The end of treatment score was calculated by the mean scores at the timepoint at 1 hour after morning wake time of Day 15 and 16. | 1 hour after morning wake time at Baseline and Days 15-16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Sleep Efficiency (SE) After Dosing on Days 1-2 and Days 14-15 | Sleep efficiency was calculated as total sleep time divided by time spent in bed multiplied by 100. An increase in SE indicated improvement in sleeping, such that, the participant spends more time in bed asleep. Mean scores of Days 1-2 and Days 14-15 were used to evaluate change from baseline. | Baseline, Days 1-2, and Days 14-15 | 
| Mean Change From Baseline in Latency to Persistent Sleep (LPS) After Dosing on Days 1-2 and Days 14-15 | LPS was calculated as minutes from lights off to the first 30-second epoch of 20 consecutive epochs of non-wakefulness. A decrease in LPS indicated improvement in time needed to fall asleep. Mean scores of Days 1-2 and Days 14-15 were used to evaluate change from baseline. | Baseline, Days 1-2, and Days 14-15 | 
| Mean Change From Baseline in Wakefulness After Sleep Onset (WASO) After Dosing on Days 1-2 and Days 14-15 | WASO was calculated as minutes of wakefulness from the onset of persistent sleep until lights on. A decrease in WASO indicated improvement in sleep maintenance. Mean scores of Days 1-2 and Days 14-15 were used to evaluate change from baseline. | Baseline, Days 1-2, and Days 14-15 | 
| Potential Habituation Effect: Comparison Between Mean Change From Baseline in SE on Days 1-2 and Mean Change From Baseline in SE on Days 14-15 | Potential habituation effect evaluated the possibility of participants being habituated to changes in sleep during the 15 days of treatment with lemborexant. Data reported here was calculated as change from baseline of mean SE of Days 14-15 minus change from baseline of mean SE of Days 1-2. An increase in SE indicated improvement in sleeping, such that, the participant spends more time in bed asleep. | Baseline, Days 1-2, and Days 14-15 | 
| Potential Habituation Effect: Comparison Between Mean Change From Baseline in Latency to Persistent Sleep (LPS) on Days 1-2 and Mean Change From Baseline in LPS on Days 14-15 | Potential habituation effect evaluated the possibility of participants being habituated to changes in sleep during the 15 days of treatment with lemborexant. Data reported here was calculated as change from baseline of mean LPS of Days 14-15 minus change from baseline of mean LPS of Days 1-2. LPS was calculated as minutes from lights off to the first 30-second epoch of 20 consecutive epochs of non-wakefulness. A decrease in LPS indicated improvement in time needed to fall asleep. | Baseline and Days 1-2, and Days 14-15 | 
| Potential Habituation Effect: Comparison Between Mean Change From Baseline in Wakefulness After Sleep Onset (WASO) on Days 1-2 and Mean Change From Baseline in WASO on Days 14-15 | Potential habituation effect evaluated the possibility of participants being habituated to changes in sleep during the 15 days of treatment with lemborexant. Data reported here was calculated as change from baseline of mean WASO of Days 14-15 minus change from baseline of mean WASO of Days 1-2. WASO was calculated as minutes of wakefulness from the onset of persistent sleep until lights on. A decrease in WASO indicated improvement in sleep maintenance. | Baseline, Days 1-2, and Days 14-15 | 
| Rebound Insomnia: Mean Change From Baseline in Sleep Efficiency (SE) After Dosing on Days 16-17 | Rebound insomnia was assessed by comparing the change from baseline of the mean SE on Days 16-17. Sleep efficiency was calculated as total sleep time divided by time spent in bed multiplied by 100. An increase in SE indicated improvement in sleeping, such that, the participant spends more time in bed asleep. A negative change from baseline in SE indicated that SE was worse on Days 16 and 17 than at Baseline, which was considered as evidence for rebound insomnia. | Baseline and Days 16-17 | 
| Percentage of Participants With Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) |  | TEAEs: Baseline up to Day 30, SAEs: Baseline up to 30 days after last dose of study drug (up to 47 days) | 
| Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Parameters |  | Baseline up to Day 30 | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs |  | Baseline up to Day 30 | 
| Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECGs) |  | Baseline up to Day 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Insomnia, Adults, Elderly