Clinical trial NCT01995838: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Insomnia
Adults
Elderly
Keywords: Chronic Insomnia
Adults
Elderly
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2013-11-27
Enrollment: 291
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Probability of Having Utility Function Greater Than (>) 1 Based on Bayesian Analysis
timeFrame: Baseline up to Day 3
measure: Mean Change From Baseline in Karolinska Sleepiness Scale (KSS) Score at End of Treatment
timeFrame: 1 hour after morning wake time at Baseline and Days 15-16
Secondary outcomes:
measure: Mean Change From Baseline in Sleep Efficiency (SE) After Dosing on Days 1-2 and Days 14-15
timeFrame: Baseline, Days 1-2, and Days 14-15
measure: Mean Change From Baseline in Latency to Persistent Sleep (LPS) After Dosing on Days 1-2 and Days 14-15
timeFrame: Baseline, Days 1-2, and Days 14-15
measure: Mean Change From Baseline in Wakefulness After Sleep Onset (WASO) After Dosing on Days 1-2 and Days 14-15
timeFrame: Baseline, Days 1-2, and Days 14-15
measure: 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
timeFrame: Baseline, Days 1-2, and Days 14-15
measure: 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
timeFrame: Baseline and Days 1-2, and Days 14-15
measure: 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
timeFrame: Baseline, Days 1-2, and Days 14-15
measure: Rebound Insomnia: Mean Change From Baseline in Sleep Efficiency (SE) After Dosing on Days 16-17
timeFrame: Baseline and Days 16-17
measure: Percentage of Participants With Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
timeFrame: TEAEs: Baseline up to Day 30, SAEs: Baseline up to 30 days after last dose of study drug (up to 47 days)
measure: Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Parameters
timeFrame: Baseline up to Day 30
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Baseline up to Day 30
measure: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECGs)
timeFrame: Baseline up to Day 30
Other outcomes:
Locations:
city: Glendale
country: United States
state: Arizona
city: Phoenix
country: United States
state: Arizona
city: Fountain Valley
country: United States
state: California
city: Oceanside
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Diego
country: United States
state: California
city: Thousand Oaks
country: United States
state: California
city: Colorado Springs
country: United States
state: Colorado
city: Colorado Springs
country: United States
state: Colorado
city: Brandon
country: United States
state: Florida
city: Hallandale Beach
country: United States
state: Florida
city: Hollywood
country: United States
state: Florida
city: South Miami
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Chicago
country: United States
state: Illinois
city: Overland Park
country: United States
state: Kansas
city: Glen Burnie
country: United States
state: Maryland
city: Las Vegas
country: United States
state: Nevada
city: New York
country: United States
state: New York
city: Raleigh
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Cincinnati
country: United States
state: Ohio
city: Philadelphia
country: United States
state: Pennsylvania
city: Columbia
country: United States
state: South Carolina
city: Austin
country: United States
state: Texas
city: Austin
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Vienna
country: United States
state: Virginia
Study officials:
References:
citation: 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.