Safety and Efficacy Study of Ramelteon in Subjects With Chronic Insomnia
Condition: Sleep Initiation and Maintenance Disorders
MeSH terms: Sleep Initiation and Maintenance Disorders
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      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.
    

Intervention name(s): Ramelteon; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Ramelteon 4 mg, tablets, orally, once daily for up to 5 weeks.; Ramelteon placebo-matching tablets, orally, once daily for up to 5 weeks.
Other intervention name(s): Rozerem™; TAK-375
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
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