Efficacy of Ramelteon on Transient Insomnia in Healthy Adults

• Total Sleep Time. [ Time Frame: Days 1 and 2. ] [ Designated as safety issue: No ]
• Sleep Efficiency. [ Time Frame: Days 1 and 2. ] [ Designated as safety issue: No ]
• Wake Time after Persistent Sleep Onset. [ Time Frame: Days 1 and 2. ] [ Designated as safety issue: No ]
• Number of Awakenings after Persistent Sleep. [ Time Frame: Days 1 and 2. ] [ Designated as safety issue: No ]
• Subjective Sleep Latency. [ Time Frame: Day 2 ] [ Designated as safety issue: No ]
• Subjective Total Sleep Time. [ Time Frame: Day 2 ] [ Designated as safety issue: No ]
• Subjective Sleep Quality. [ Time Frame: Day 2 ] [ Designated as safety issue: No ]
• Subjective Wake Time after Sleep Onset. [ Time Frame: Day 2 ] [ Designated as safety issue: No ]
• Subjective Number of Awakenings. [ Time Frame: Day 2 ] [ Designated as safety issue: No ]
• Subjective Ease of Falling Back to Sleep after Awakening. [ Time Frame: Day 2 ] [ Designated as safety issue: No ]
• Stage 1 Nonrapid Eye Movement (NREM) Sleep [ Time Frame: Day 2. ] [ Designated as safety issue: No ]
• Stage 2 Nonrapid Eye Movement (NREM) Sleep [ Time Frame: Day 2. ] [ Designated as safety issue: No ]
• Stage 3/4 Nonrapid Eye Movement (NREM) Sleep [ Time Frame: Day 2. ] [ Designated as safety issue: No ]
• Latency to Rapid Eye Movement (REM) Sleep [ Time Frame: Day 2. ] [ Designated as safety issue: No ]
• Percentage of Total Sleep Time in REM Sleep [ Time Frame: Day 2. ] [ Designated as safety issue: No ]

• Objective and subjective measures of efficacy. [ Time Frame: Single dose, one day ] [ Designated as safety issue: No ]
• Sleep architecture variables. [ Time Frame: Single dose, one day ] [ Designated as safety issue: No ]
• Residual pharmacological effects. [ Time Frame: Single dose, one day ] [ Designated as safety issue: No ]
• Safety variables including adverse events, laboratory tests, vital signs, ECG results, and physical examination findings. [ Time Frame: Single dose, one day ] [ Designated as safety issue: Yes ]

The purpose of this study is to evaluate the safety and efficacy of Ramelteon, once daily (QD), in healthy subjects within a sleep lab.

Insomnia is characterized by difficulties initiating and maintaining sleep, or of non-restorative and non-refreshing sleep. Transient insomnia affects approximately one-third to one-half of the US population, based on the results of 2 surveys of representative samples of the adult US population conducted by the Gallup Organization in which respondents were asked if they had "ever had difficulty sleeping." Based on reports of "regular" or "frequent" sleep difficulty, results from the same studies suggest that approximately one-tenth of the US population experiences chronic insomnia. The ideal treatment for insomnia would reduce the latency to onset of sleep and increase total sleep time, without a negative impact on sleep architecture and without safety concerns or next-day effects.

Ramelteon is a selective melatonin-1 receptor agonist under global development by Takeda Chemical Industries, Ltd., for the treatment of transient and chronic insomnia and for the treatment of Circadian Rhythm Sleep Disorders.

This study is being conducted to evaluate the safety and efficacy of a single dose of Ramelteon in normal healthy subjects in a sleep lab model of transient insomnia. Participation is this study is anticipated to be about 3 weeks.

• Drug: Ramelteon
  Ramelteon 8 mg, tablets, orally for one night only.
  Other Names:

  • Rozerem™
  • ramelteon
  • TAK-375
• Drug: Ramelteon
  Ramelteon 16 mg, tablets, orally for one night only
  Other Names:

  • Rozerem™
  • ramelteon
  • TAK-375
• Drug: Placebo
  Ramelteon placebo-matching tablets, orally for one night only

• Experimental: Ramelteon 8 mg QD
  Intervention: Drug: Ramelteon
• Experimental: Ramelteon 16 mg QD
  Intervention: Drug: Ramelteon
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria

• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
• Habitual bedtime is between 8:30 p.m. and 12:00 a.m.
• Sleeps 6.5 to 8 hours per night and has a subjective sleep latency of less than or equal to 30 minutes.
• Body mass index between 18 and 34, inclusive.

Exclusion Criteria:

• Any history of insomnia.
• Spent one or more nights in a sleep laboratory.
• Epworth Sleepiness Scale score of greater than 10.
• Known hypersensitivity to Ramelteon or related compounds, including melatonin.
• Previously participated in a study involving Ramelteon.
• Participated in any other investigational study and/or taken any investigational drug within 30 days or five half-lives prior to Day 1, whichever is longer.
• Sleep schedule changes required by employment (ie, shift work) within three months preceding Day 1 or has flown across greater than three time zones within seven days prior to screening.
• Participated in a weight loss program or substantially altered their exercise routine within 30 days prior to Day 1.
• History of seizures, sleep apnea, chronic obstructive pulmonary disease, restless leg syndrome, schizophrenia, bipolar disorder, mental retardation, or cognitive disorder.
• History of a psychiatric disorder (including anxiety or depression) within the past 12 months.
• History of drug addiction or drug abuse within the past 12 months.
• Any physical or psychiatric disorder that may be associated with sleep disturbance.
• History of alcohol abuse within the past 12 months, as defined in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Revised and/or regularly consumes 4 or more alcoholic drinks per day.
• Current significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, hematologic or metabolic disease.
• Uses tobacco products during nightly awakenings.
• Any clinically important abnormal finding as determined by a medical history, physical examination, electrocardiogram, or clinical laboratory tests, as determined by the investigator.
• Positive hepatitis panel.
• Positive urine drug screen including alcohol at screening or a positive breathalyzer test at check-in.

• 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.

• Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication, including:

  • Anxiolytics
  • Hypnotics
  • Antidepressants
  • Anticonvulsants
  • Sedating H1 antihistamines
  • Systemic steroids
  • Respiratory stimulants (eg, theophylline)
  • Decongestants
  • Over-the-counter and prescription stimulants
  • Over-the-counter and prescription diet aids
  • Central nervous system active drugs
  • Narcotic analgesics
  • All beta blockers
  • St. John's Wort
  • Kava-kava
  • gingko biloba