14.1 Controlled Clinical Trials

Chronic Insomnia

Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of Ramelteon's effectiveness in sleep initiation.

One study enrolled younger adults (aged 18 to 64 years, inclusive) with chronic insomnia and employed a parallel design in which the subjects received a single, nightly dose of Ramelteon Tablets (8 or 16 mg) or matching placebo for 35 days. PSG was performed on the first two nights in each of Weeks 1, 3, and 5 of treatment. Ramelteon Tablets reduced the average latency to persistent sleep at each of the time points when compared to placebo. The 16 mg dose conferred no additional benefit for sleep initiation.

The second study employing PSG was a three-period crossover trial performed in subjects aged 65 years and older with a history of chronic insomnia. Subjects received Ramelteon Tablets (4 or 8 mg) or placebo and underwent PSG assessment in a sleep laboratory for two consecutive nights in each of the three study periods. Both doses of Ramelteon Tablets reduced latency to persistent sleep when compared to placebo.

The third study evaluated long term efficacy and safety in adults with chronic insomnia. Subjects received a single, nightly dose of Ramelteon Tablets 8 mg or matching placebo for six months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. Ramelteon Tablets reduced sleep latency at each time point when compared to placebo. In this study, when the PSG results from nights 1 and 2 of Month 7 were compared to the results from nights 22 and 23 of Month 6, there was a statistically significant increase in LPS of 33% (9.5 minutes) in the ramelteon group. There was no increase in LPS in the placebo group when the same time periods were compared.

A randomized, double-blind, parallel group study was conducted in outpatients aged 65 years and older with chronic insomnia and employed subjective measures of efficacy (sleep diaries). Subjects received Ramelteon Tablets (4 or 8 mg) or placebo for 35 nights. Ramelteon Tablets reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18 to 64 years) using 8 and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo.

While the 16 mg dose was evaluated as a potential treatment for adults, it was shown to confer no additional benefit for sleep initiation and was associated with higher incidences of fatigue, headache and next-day somnolence.

Transient Insomnia

In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or Ramelteon Tablets before spending one night in a sleep laboratory and being evaluated with PSG. Ramelteon Tablets demonstrated a decrease in mean latency to persistent sleep as compared to placebo.

14.2 Studies Pertinent to Safety Concerns for Sleep-Promoting Drugs

Results from Human Laboratory Abuse Liability Studies

A human laboratory abuse potential study was performed in 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse. Subjects received single oral doses of Ramelteon Tablets (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the seven treatments separated by a wash-out period and underwent multiple standard tests of abuse potential. No differences in subjective responses indicative of abuse potential were found between Ramelteon Tablets and placebo at doses up to 20 times the recommended therapeutic dose. The positive control drug, triazolam, consistently showed a dose-response effect on these subjective measures, as demonstrated by the differences from placebo in peak effect and overall 24 hour effect.

Residual Pharmacological Effect in Insomnia Trials

In order to evaluate potential next-day residual effects, the following scales were used: a Memory Recall Test, a Word List Memory Test, a Visual Analog Mood and Feeling Scale, the Digit-Symbol Substitution Test, and a post sleep questionnaire to assess alertness and ability to concentrate. There was no evidence of next-day residual effect seen after two nights of ramelteon use during the crossover studies.

In a 35 night, double-blind, placebo-controlled, parallel-group study in adults with chronic insomnia, measures of residual effects were performed at three time points. Overall, the magnitudes of any observed differences were small. At Week 1, patients who received 8 mg of Ramelteon Tablets had a mean VAS score (46 mm on a 100 mm scale) indicating more fatigue in comparison to patients who received placebo (42 mm). At Week 3, patients who received 8 mg of Ramelteon Tablets had a lower mean score for immediate recall (7.5 out of 16 words) compared to patients who received placebo (8.2 words); and the patients treated with Ramelteon Tablets had a mean VAS score indicating more sluggishness (27 mm on a 100 mm VAS) in comparison to the placebo-treated patients (22 mm). Patients who received Ramelteon Tablets did not have next-morning residual effects that were different from placebo at Week 5.

Rebound Insomnia/Withdrawal

Potential rebound insomnia and withdrawal effects were assessed in four studies in which subjects received Ramelteon Tablets or placebo for up to six months; three were 35 day studies, one was a six month study. These studies included a total of 2533 subjects, of whom 854 were elderly.

Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)

The BWSQ is a self-report questionnaire that solicits specific information on 20 symptoms commonly experienced during withdrawal from benzodiazepine receptor agonists; Ramelteon Tablets are not a benzodiazepine receptor agonist.

In two of the three 35 day insomnia studies, the questionnaire was administered one week after completion of treatment; in the third study, the questionnaire was administered on Days 1 and 2 after completion. In all three of the 35 day studies, subjects receiving Ramelteon Tablets 4, 8, or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo.

In the six month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ.

Rebound Insomnia

Rebound insomnia was assessed in the 35 day studies by measuring sleep latency after abrupt treatment discontinuation. One of these studies employed PSG in younger adult subjects receiving Ramelteon Tablets 8 or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving Ramelteon Tablets 4 or 8 mg, and in younger adult subjects receiving Ramelteon Tablets 8 or 16 mg. There was no evidence that Ramelteon Tablets caused rebound insomnia during the posttreatment period.

14.3 Studies to Evaluate Effects on Endocrine Function

Two controlled studies evaluated the effects of Ramelteon Tablets on endocrine function.

In the first trial, Ramelteon Tablets 16 mg once daily or placebo was administered to 99 healthy volunteer subjects for four weeks. This study evaluated the thyroid axis, adrenal axis and reproductive axis. No clinically significant endocrinopathies were demonstrated in this study. However, the study was limited in its ability to detect such abnormalities due to its limited duration.

In the second trial, Ramelteon Tablets 16 mg once daily or placebo was administered to 122 subjects with chronic insomnia for six months. This study evaluated the thyroid axis, adrenal axis and reproductive axis. There were no significant abnormalities seen in either the thyroid or the adrenal axes. Abnormalities were, however, noted within the reproductive axis. Overall, the mean serum prolactin level change from baseline was 4.9 mcg/L (34% increase) for women in the Ramelteon Tablet group compared with -0.6 mcg/L (4% decrease) for women in the placebo group (p=0.003). No differences between active- and placebo-treated groups occurred among men. Thirty two percent of all patients who were treated with ramelteon in this study (women and men) had prolactin levels that increased from normal baseline levels compared to 19% of patients who were treated with placebo. Subject-reported menstrual patterns were similar between the two treatment groups.

In a 12 month, open-label study in adult and elderly patients, there were two patients who were noted to have abnormal morning cortisol levels, and subsequent abnormal ACTH stimulation tests. A 29-year-old female patient was diagnosed with a prolactinoma. The relationship of these events to Ramelteon Tablets therapy is not clear.