Safety and Efficacy Study of Ramelteon in Subjects With Chronic Insomnia

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.

In the western world, there are several people affected by chronic insomnia. Numerous studies estimate that 30% to 40% of the general population is affected at some time in their lives with a form of insomnia that goes on for several months, and about one third of those are described as severely affected. Daytime symptoms of insomnia include tiredness, lack of energy, difficulty concentrating and irritability. Recent epidemiologic research focusing on the quality of life has identified significant insomnia-related morbidities that relate to work productivity, health care utilization, and risk of depression. Insomnia is associated with diminished work output, absenteeism, and greater rates of accidents.

Although normal control of the sleep-wake cycle is exerted by the suprachiasmatic nucleus via melatonin receptor subtype 1 and 2 (MT1 and MT2) receptors (melatonin receptor subtype), most current pharmacologic treatments for insomnia mainly involve GABAergic (gamma-aminobutyric acid) mechanisms. Most currently prescribed sleep agents are benzodiazepine receptor agonists, which induce sleep by binding to the benzodiazepine receptor site of the gamma-aminobutyric acid-A receptor complex. Gamma-aminobutyric acid is the major inhibitory transmitter in the central nervous system, and its receptors are distributed widely throughout the brain. In addition to sleep, benzodiazepine receptor agonists can cause a wide range of ancillary effects not directly related to sleep, depending on the precise subset of gamma-aminobutyric acid-A receptors activated. These include sedative, anxiolytic, muscle-relaxant, and amnesic effects. The risk of tolerance, dependence development, and abuse potential associated with the benzodiazepine receptor agonists also may reflect effects of these drugs on the gamma-aminobutyric acid-A receptor complex.

The sleep-wake cycle results from the interaction of circadian and homeostatic mechanisms. The homeostatic mechanism refers to the accumulation of sleep load during time awake; the organism falls asleep when the sleep load is high, and the reduction of sleep load during sleep results in waking.

A circadian rhythm is superimposed on the homeostatic mechanism. Circadian rhythms are controlled by the suprachiasmatic nucleus, which emits alerting signals; this signal is believed to be attenuated by melatonin, which is produced in response to darkness. It is believed that binding of melatonin to MT1 and MT2 receptors in the suprachiasmatic nucleus inhibits firing of specific neurons, and this is thought to attenuate the alerting signal, allowing the homeostatic mechanism to express itself and promote sleep.

An agent that is selective for the MT1 and MT2 receptors would be expected to be devoid of the ancillary effects of agents that act at the gamma-aminobutyric acid-A receptor complex. It would promote sleep by specifically targeting the alerting signal in the suprachiasmatic nucleus, allowing the homeostatic mechanism to produce sleep.

Ramelteon is under global development by Takeda Pharmaceuticals as a nonscheduled sleep agent for the treatment of difficulty with sleep initiation, and is marketed under the brand name of Rozerem™ in the United States. In vitro, ramelteon demonstrates affinity and selectivity for human melatonin MT1 and MT2 receptors compared to melatonin. It also demonstrates full agonist activity in cells expressing human MT1 or MT2 receptors relative to melatonin.

In the European Union, Takeda is seeking marketing approval for the long-term treatment of transient and chronic insomnia as characterized by difficulty with sleep onset. Because most of the European clinical studies to date have used the 8 mg dose, the aim of this study is to assess the safety and efficacy of 4mg of ramelteon in a larger number of adults with chronic insomnia.

Subjects participating in this study will be required to report to a sleep laboratory and have polysomnography recordings over two consecutive nights for three sittings during a five week period. The total duration of the study is approximately 10 weeks.

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.