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
Condition: Chronic Insomnia; Adults; Elderly
MeSH terms: Sleep Initiation and Maintenance Disorders
Intervention: E2006; Placebo
Intervention description: 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; E2006-matched placebo in tablet form, taken orally, 30 minutes prior to bedtime, each night for 15 consecutive nights
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 291.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Chronic Insomnia; Adults; Elderly

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.
    

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