Safety and Efficacy Study of Ramelteon in Subjects With Chronic Insomnia
Condition: Sleep Initiation and Maintenance Disorders
MeSH terms: Sleep Initiation and Maintenance Disorders
Intervention: Ramelteon; Placebo
Intervention description: Ramelteon 4 mg, tablets, orally, once daily for up to 5 weeks.; Ramelteon placebo-matching tablets, orally, once daily for up to 5 weeks.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 259.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: Chronic Insomnia; DIMS (Disorders of Initiating and Maintaining Sleep); Disorders of Initiating and Maintaining Sleep; Insomnia Disorder Sleep Initiation Dysfunction; Transient Insomnia; Drug Therapy; Sleep Disorders, Intrinsic

Summary:

      The purpose of this study is to determine the safety and efficacy of 4 mg of Ramelteon, once
      daily (QD), in subjects with chronic insomnia.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A female subject of childbearing potential who is sexually active agrees to use
             adequate contraception from Screening throughout the duration of the study.

          -  Has a body mass index between 18 and 34, inclusive.

          -  Based on sleep history, the subject has had chronic insomnia for at least 3 months, as
             defined by the following:

               -  The predominant complaint is difficulty initiating or maintaining sleep, or
                  non-restorative sleep, for at least 3 months.

               -  The sleep disturbance (or associated daytime fatigue) causes clinically
                  significant distress or impairment in social, occupational, or other important
                  areas of functioning.

               -  The sleep disturbance does not occur exclusively during the course of narcolepsy,
                  breathing-related sleep disorder, circadian rhythm sleep disorder, or parasomnia.

               -  The disturbance does not occur exclusively during the course of another mental
                  disorder (eg, major depressive disorder, generalized anxiety disorder, delirium).

               -  The disturbance is not due to the direct physiological effects of a substance or
                  a general medical condition.

          -  Based on sleep history, the subject reports a history of subjective sleep latency ≥45
             minutes and a subjective total sleep time ≤6.5 hours for at least 3 months.

          -  Based on sleep history, the subject's habitual bedtime is between 10:00 PM and 1:00
             AM.

          -  On at least 3 of the first 5 nights of single blind run-in placebo treatment, the
             subject must have an subjective sleep latency of ≥45 minutes and a subjective total
             sleep time of <6.5 hours.

          -  The difference of the average subjective sleep latency from first 3 nights of data in
             the first week of single-blind run-in to the average of the last 3 nights of data in
             the first week of single-blind run-in must be ≤30 minutes.

          -  The difference of the average subjective sleep latency from first 3 nights of data in
             the first week of single-blind run-in to the average of the last 3 nights of data in
             the second week of single-blind run-in must be ≤30 minutes.

          -  The difference of the average subjective sleep latency from first 3 nights of data in
             the first week of single-blind run-in to the average of the last 3 nights of data in
             the third week of single-blind run-in must be ≤30 minutes.

          -  Is willing to have a fixed bedtime and agrees to go to bed within ± 30 minutes of the
             habitual bedtime during the entire study, exceptions will be allowed at weekends that
             are not within 2 days of a polysomnography visit.

          -  Has consistent access to a touch-tone phone and is willing to complete all telephone
             questionnaires within 60 minutes of wake time each morning throughout the entire
             duration of the study.

          -  Is willing to remain in bed for at least 6.5 hours each night during the entire study.

          -  Based on sleep history, the subject normally uses pharmacologic assistance to sleep 0
             to 4 (maximum allowable) times per week in the last 3 months. Subjects must agree to
             discontinue the use of all sleep aids beginning 1 week prior to the first dose of
             single-blind study medication and throughout the entire duration of the study.

          -  The subject must complete the post-sleep questionnaire morning questionnaire on at
             least 5 of 7 mornings for all 3 weeks of single-blind run-in.

          -  Has a mean latency to persistent sleep of ≥20 minutes on 2 consecutive screening
             nights, with neither night less than 15 minutes, via polysomnography screening
             assessment during the single-blind placebo run-in period.

        Exclusion Criteria:

          -  Has a known hypersensitivity to ramelteon or related compounds, including melatonin.

          -  Has participated in a study involving ramelteon within 6 months of initial Screening
             Visit.

          -  Has participated in any other investigational study and/or taken any investigational
             drug within 30 days or 5 half-lives (whichever is longer) prior to the first night of
             single-blind study medication.

          -  Has sleep schedule changes required by employment (eg, shift worker) within 3 months
             prior to the first night of single-blind study medication, or has flown across greater
             than 3 time zones within 7 days prior to Screening.

          -  Has participated in a weight loss program or has substantially altered his or her
             exercise routine within 30 days prior to the first night of single-blind study
             medication.

          -  Has ever had a history of seizures, sleep apnea, restless leg syndrome, periodic leg
             movements during sleep, chronic obstructive pulmonary disease, fibromyalgia,
             schizophrenia, bipolar disorder, mental retardation or a cognitive disorder.

          -  Has a history of psychiatric disorder (including anxiety or depression) within the
             past 12 months.

          -  Has a history of drug addiction or alcohol abuse and/or regularly consumes 4 or more
             alcoholic drinks per day within the past 12 months, as defined in Diagnostic and
             Statistical Manual of Mental Disorders, 4th Edition Revised.

          -  Has a current significant neurological (including cognitive and psychiatric
             disorders), hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary,
             hematological, or metabolic disease, unless currently controlled and stable with
             protocol-allowed medication 30 days prior to the first night of single blind study
             medication.

          -  The subject uses tobacco products (including nicotine gum and patch) during nightly
             awakenings.

          -  The subject has any clinically important abnormal finding as determined by a medical
             history, physical examination, electrocardiogram, or clinical laboratory tests, as
             determined by the investigator.

          -  The subject is required to take or intends to continue taking any disallowed
             medication, any prescription medication, herbal treatment or over-the counter
             medication that may interfere with evaluation of the study medication, including:

               -  Anxiolytics

               -  Central nervous system active drugs (including herbal)

               -  Hypnotics

               -  Narcotic analgesics

               -  Antidepressants

               -  Beta-blockers

               -  Anticonvulsants

               -  Systemic steroids

               -  Sedating H1 antihistamines

               -  Respiratory stimulants

               -  Muscle relaxants

               -  Sedatives

               -  Antipsychotics

               -  Sedating decongestants

               -  Kava-kava

               -  St. John's wort

               -  Ginkgo biloba

               -  Over-the counter and prescription stimulants, diet aids and sleep aids

               -  Drugs that are known or are suspected to significantly inhibit CYP450

               -  Melatonin

          -  Has a positive urine drug screen for an illegal substance at the initial Screening
             Visit.

          -  Has a positive urine drug screen at polysomnography screening or a positive alcohol
             breathalyzer test at polysomnography screening or randomization.

          -  Exhibits a placebo response during the single-blind placebo run-in period. A placebo
             response is defined as having:

               -  a difference in average subjective sleep latency >30 minutes from first 3 nights
                  of data in the first week of single-blind run-in to the average of the last 3
                  nights of data in the first week of single-blind run-in.

               -  a difference in average subjective sleep latency >30 minutes from first 3 nights
                  of data in the first week of single-blind run-in to the average of the last 3
                  nights of data in the second week of single-blind run-in.

               -  a difference in average subjective sleep latency >30 minutes from first 3 nights
                  of data in the first week of single-blind run-in to the average of the last 3
                  nights of data in the third week of single-blind run-in.

          -  Has periodic leg movements during sleep with arousal index (per hour of sleep) >10 as
             seen on polysomnography on the first night of polysomnography screening.

          -  Has any additional condition(s) that in the Investigator's opinion would:

               -  Affect sleep/wake function

               -  Prohibit the subject from completing the study

               -  Not be in the best interest of the subject to complete the study.