Conditions: Sleep Initiation and Maintenance Disorders
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
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 259
Healthy volunteers: no

Brief 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.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Ramelteon intervention 2: Placebo
Intervention descriptions: intervention 1: Ramelteon 4 mg, tablets, orally, once daily for up to 5 weeks. intervention 2: Ramelteon placebo-matching tablets, orally, once daily for up to 5 weeks.

Protocol document: