Safety of Ramelteon in Elderly Subjects

Insomnia affects more than half of the US population. Epidemiological data indicate that between 36% and 56% of American adults report occasional insomnia, while 9% to 17% report chronic or severe problems with insomnia. This condition is most prevalent in the elderly. Elderly insomnia sufferers may experience more difficulty staying asleep than younger adults; increasing wakefulness during the sleep period and resulting in the opportunity to get out of bed.

Elderly individuals with insomnia are at risk of falling when they get out of bed during the sleep period. It is not known if this risk merely is the result of being out of bed, or if insomnia or some other physiological processes (eg, postural hypotension) contribute. This risk is significant because falling may result in severe injuries, including hip fractures, for which morbidity and mortality statistics are remarkable. Approximately one-third of those who sustain a hip fracture are placed in long-term care facilities. Of those patients hospitalized due to a hip fracture, 15% die while in the hospital and 33% die within one year of sustaining the fracture.

One important concern regarding the risk of falling in elderly patients with insomnia relates to the commonly accepted pharmacological treatments of insomnia. Although normal control of the sleep-wake cycle is exerted by the suprachiasmatic nucleus via melatonin receptor subtypes 1 and 2 receptors, current pharmacologic treatments for insomnia mainly involve GABAergic (gamma aminobutyric acid) mechanisms: most currently prescribed sleep agents are benzodiazepine receptor agonists, which bind to the benzodiazepine receptor site of the gamma aminobutyric acid 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 receptors activated. These include sedative, anxiolytic, muscle-relaxant, and amnesic effects. Drugs that act at this receptor complex, specifically the benzodiazepines, have deleterious effects on body sway.

Ramelteon is marketed in the United States as Rozerem for the treatment of insomnia characterized by difficulty with sleep initiation. It's mechanism of action is based on the agonism of melatonin receptor subtype 1 and 2.

This study will investigate the effects of ramelteon on balance, mobility and memory impairment awakening in the middle of the night following bedtime dosing. Participation in this study is anticipated to be about 1 to 1.5 months.

Inclusion criteria

• Self-reported sleep latency of 30 minutes or greater on at least 3 nights per week during the last 3 months.
• Body mass index between 18 and 34, inclusive
• Habitual bedtime between 9 pm and 1 am.

Exclusion criteria

• Performance outside of normal limits on the EquiTest Motor Control Test at the Screening Visit.
• Average score on the EquiTest Sensory Organization Test #5 of less than 40 at the Screening Visit.
• Average score on the EquiTest Sensory Organization Test #6 of less than 40 at the Screening Visit.
• History of sleep apnea, restless leg syndrome, period limb movement syndrome, or other known disorders which affect sleep with the exception of insomnia.
• Current vestibular system disorder or inner ear disease.
• Recent history of clinically significant head injury.
• Significant visual acuity or field abnormalities that are not improved with the use of corrective lenses.
• History of balance disturbance or frequent falling.
• History of seizures, strokes, degenerative neurological disease, fibromyalgia, diabetic neuropathy, thyroid dysfunction, hypotension, clinically significant arthritis or musculoskeletal disorder.
• History of cancer, other than basal cell carcinoma, that has not been in remission for at least five years prior to the first dose of study drug.
• Current significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematologic, or metabolic disease, unless currently controlled and stable.
• Acute clinically significant illness within two weeks or has been hospitalized within four weeks prior to the Screening Visit.
• History of treatment for a psychiatric disorder (including anxiety, depression, mental retardation, cognitive disorder, bipolar illness and schizophrenia) within the past six months.
• History of drug addiction or drug abuse within the past 12 months, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Revised.
• History of alcohol abuse within the past 12 months.
• Any clinically important abnormal finding, as determined by medical history, physical examination, electrocardiogram or clinical laboratory tests, as determined by the investigator.
• Positive hepatitis panel.
• Positive urine drug screen for drugs known to alter sleep.
• Participated in any other investigational study and/or taken any investigational drug within 30 days or five half-lives prior to the first dose of single-blind study medication, whichever is longer.
• Any additional condition 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.
• Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

• Melatonin and all other drugs or supplements known to affect sleep/wake function
• Anxiolytics
• Sedatives
• Hypnotics
• Central nervous system active drugs (including herbal)
• Antidepressants
• Narcotic analgesics
• Anticonvulsants
• Beta blockers
• Sedating H1 antihistamines
• St. John's Wort
• Systemic steroids
• Kava-kava
• Respiratory stimulants
• Ginkgo-biloba
• Decongestants
• Over-the-counter and prescription stimulants
• Antipsychotics
• Over-the-counter and prescription diet aids
• Muscle relaxants