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

• ClinicalTrials.gov Identifier: NCT01995838
• Recruitment Status: Completed
• First Posted: November 27, 2013
• Results First Posted: January 31, 2020
• Last Update Posted: January 31, 2020
• Sponsor: Eisai Inc.
• Information provided by (Responsible Party): Eisai Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Insomnia; Adults; Elderly	Drug: E2006; Drug: Placebo	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 291 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 13, 2013
• Actual Primary Completion Date: April 29, 2014
• Actual Study Completion Date: April 29, 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: E2006; 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; 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
Placebo Comparator: Placebo; E2006-matched placebo in tablet form, taken orally, 30 minutes prior to bedtime, each night for 15 consecutive nights	Drug: Placebo; E2006-matched placebo in tablet form, taken orally, 30 minutes prior to bedtime, each night for 15 consecutive nights

Outcome Measures

Primary Outcome Measures :

1. Probability of Having Utility Function Greater Than (>) 1 Based on Bayesian Analysis [ Time Frame: Baseline up to Day 3 ]
   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.
2. Mean Change From Baseline in Karolinska Sleepiness Scale (KSS) Score at End of Treatment [ Time Frame: 1 hour after morning wake time at Baseline and Days 15-16 ]
   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.

Secondary Outcome Measures :

1. Mean Change From Baseline in Sleep Efficiency (SE) After Dosing on Days 1-2 and Days 14-15 [ Time Frame: Baseline, 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.
2. Mean Change From Baseline in Latency to Persistent Sleep (LPS) After Dosing on Days 1-2 and Days 14-15 [ Time Frame: Baseline, 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.
3. Mean Change From Baseline in Wakefulness After Sleep Onset (WASO) After Dosing on Days 1-2 and Days 14-15 [ Time Frame: Baseline, 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.
4. 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 [ Time Frame: Baseline, Days 1-2, and 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.
5. 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 [ Time Frame: Baseline and Days 1-2, and 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.
6. 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 [ Time Frame: Baseline, Days 1-2, and 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.
7. Rebound Insomnia: Mean Change From Baseline in Sleep Efficiency (SE) After Dosing on Days 16-17 [ Time Frame: Baseline and 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.
8. Percentage of Participants With Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) [ Time Frame: TEAEs: Baseline up to Day 30, SAEs: Baseline up to 30 days after last dose of study drug (up to 47 days) ]
9. Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Parameters [ Time Frame: Baseline up to Day 30 ]
10. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to Day 30 ]
11. Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECGs) [ Time Frame: Baseline up to Day 30 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

Subjects must meet all of the following criteria to be included in this study:

1. Male or female subjects age 18 to 80 years at the time of informed consent
2. Meets the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for Insomnia Disorder
3. 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
4. Regular time in bed between 6.5 and 9.0 hours
5. Regular bedtime between 21:00 and 24:00 and regular waketime between 05:00 and 09:00
6. Insomnia Severity Index (ISI) score greater than or equal to 15 at Screening
7. Confirmation of current insomnia symptoms as determined from responses on the Sleep Diary completed for 7 nights prior to the first screening/baseline PSG

8. Objective (PSG) evidence of insomnia at the screening/baseline PSGs as follows:

   1. 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
   2. WASO average greater than or equal to 30 minutes on the 2 consecutive screening/baseline PSGs, with neither night lesser than 20 minutes
   3. SE average lesser than or equal to 85% on the 2 consecutive screening/baseline PSGs, with neither night greater than 87.5%
9. 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
10. 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.
11. Provide written informed consent
12. Willing to stay in bed for at least 8 hours each night spent in the clinic
13. 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:

1. Females who are pregnant (positive beta-human chorionic gonadotropin [B-hCG] test) or breastfeeding
2. 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
3. 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
4. Beck Depression Inventory (BDI) - II score greater than 19 at Screening
5. Beck Anxiety Inventory (BAI) score greater than 15 at Screening
6. 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
7. Used any medication or sleep aid with known effects on sleep, within 2 weeks prior to screening/baseline PSG, or between Screening and Baseline
8. Used any prohibited prescription or over-the-counter concomitant medications within the week prior to the first screening/baseline PSG.
9. 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
10. 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
11. 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.
12. 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.
13. 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.
14. 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])
15. Any lifetime suicidal behavior (per the Suicidal Behavior Section of the C-SSRS)
16. 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
17. Hypersensitivity to the study drug or any of the excipients
18. 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
19. Scheduled for surgery during the study
20. Known to be human immunodeficiency virus (HIV) positive
21. Active viral hepatitis (B or C) as demonstrated by positive serology
22. 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
23. History of drug or alcohol dependency or abuse within approximately the last 2 years
24. 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
25. 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

Contacts and Locations

Locations

United States, Arizona

Glendale, Arizona, United States, 85306

Phoenix, Arizona, United States, 85006

United States, California

Fountain Valley, California, United States, 92708

Oceanside, California, United States, 92054

San Diego, California, United States, 92103

San Diego, California, United States, 92123

Thousand Oaks, California, United States, 91360

United States, Colorado

Colorado Springs, Colorado, United States, 80907

Colorado Springs, Colorado, United States, 80909

United States, Florida

Brandon, Florida, United States, 33511

Hallandale Beach, Florida, United States, 33009

Hollywood, Florida, United States, 33024

South Miami, Florida, United States, 33143

United States, Georgia

Atlanta, Georgia, United States, 30342

United States, Illinois

Chicago, Illinois, United States, 60634

Chicago, Illinois, United States, 60637

United States, Kansas

Overland Park, Kansas, United States, 66212

United States, Maryland

Glen Burnie, Maryland, United States, 21061

United States, Nevada

Las Vegas, Nevada, United States, 89104

United States, New York

New York, New York, United States, 10019

United States, North Carolina

Raleigh, North Carolina, United States, 27612

United States, Ohio

Cincinnati, Ohio, United States, 45212

Cincinnati, Ohio, United States, 45255

United States, Pennsylvania

Philadelphia, Pennsylvania, United States, 19118

United States, South Carolina

Columbia, South Carolina, United States, 29201-2953

United States, Texas

Austin, Texas, United States, 78731

Austin, Texas, United States, 78744

Dallas, Texas, United States, 75230

United States, Virginia

Vienna, Virginia, United States, 22182

Sponsors and Collaborators

Eisai Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Murphy P, Moline M, Mayleben D, Rosenberg R, Zammit G, Pinner K, Dhadda S, Hong Q, Giorgi L, Satlin A. Lemborexant, A Dual Orexin Receptor Antagonist (DORA) for the Treatment of Insomnia Disorder: Results From a Bayesian, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Sleep Med. 2017 Nov 15;13(11):1289-1299. doi: 10.5664/jcsm.6800.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT01995838
• Other Study ID Numbers: E2006-G000-201
• First Posted: November 27, 2013
• Results First Posted: January 31, 2020
• Last Update Posted: January 31, 2020
• Last Verified: November 2015

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Eisai Inc.:

Chronic Insomnia; Adults; Elderly

Additional relevant MeSH terms:

Sleep Initiation and Maintenance Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders