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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

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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:
Information provided by (Responsible Party):
Eisai Inc.

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.

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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

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




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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01995838


Locations
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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.
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01995838    
Other Study ID Numbers: E2006-G000-201
First Posted: November 27, 2013    Key Record Dates
Results First Posted: January 31, 2020
Last Update Posted: January 31, 2020
Last Verified: November 2015

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