Efficacy and tolerability of ramelteon in a double-blind, placebo-controlled, crossover study in Japanese patients with chronic primary insomnia

Abstract

The aim of this study was to evaluate the efficacy and safety of ramelteon 4, 8, 16 or 32 mg and placebo in Japanese patients with chronic insomnia using a randomized, double-blind, five-period crossover design. A total of 65 Japanese patients with chronic primary insomnia received ramelteon or placebo for two nights each in sleep laboratories. Changes in sleep parameters were assessed objectively by polysomnography and subjectively by postsleep questionnaires. Safety and tolerability was evaluated by assessment of the occurrence of adverse events, next-day residual effects and laboratory and ECG investigations. Ramelteon 8 and 32 mg significantly shortened the mean latency to persistent sleep in comparison with placebo, and there was a statistically significant trend for linear dose-response for this sleep parameter. Overall changes in sleep architecture were modest (<3% changes vs placebo), with increases in stage 1 and decreases in stage 3/4. Ramelteon was well tolerated, the most common adverse effect being somnolence, which was similar to placebo at doses up to 8 mg, but increased with higher doses. Next-day residual effects occurred no more frequently with ramelteon at any dose than with placebo. When compared with sleep latency data from a similarly-designed US study, there was no evidence of any ethnic differences in the efficacy of ramelteon between Japanese and US patients. Overall, ramelteon 8 mg showed the most favorable balance between sleep-promoting effects and tolerability. The unique efficacy profile of ramelteon, promoting sleep initiation without affecting other sleep parameters, may be due to its circadian shifting effect.

0395 Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline

“…[118][119][120][121] The overall quality of evidence from these studies was downgraded to very low due to substantial heterogeneity across studies, imprecision and potential publication bias. The overall evidence for ramelteon 8 mg. was weakly in favor of its effectiveness for the treatment of sleep onset disturbance only.…”

“…[118][119][120][121] Subjects in all studies demonstrated chronic primary insomnia with associated daytime complaints. All studies required mean objective LPS of > 20 min on two nights of PSG screening.…”

“…Additional studies not included in meta-analysis supported these results. 122,125,126 Wake after Sleep onSet: Meta-analysis of objective WASO from the two studies reporting adequate data 118,121 show a clinically insignificant increase (+3.5 min; CI: +2.77 to +4.23 min) in WASO for the ramelteon group, well below the significance threshold of 20 min. The quality of evidence was downgraded to moderate due to potential publication bias.…”

“…118,120,121 Objective sleep latency data in the study by Mayer and colleagues 119 were not adequate for meta-analysis and therefore could not be included.…”

“…All four studies included in the metaanalysis evaluated objective total sleep time for ramelteon 8 mg. [118][119][120][121] Although small improvements in TST were observed in some individual studies, ranging from 1.2 to 12.5 min longer, the meta-analysis reveals minimal increase (+6.58 min; CI: +1.36 to +11.80 min) which falls well below the threshold for clinical significance. The quality of evidence was downgraded to LOW due to the high degree of heterogeneity across studies, and due to the risk of publication bias since all these studies were funded by industry.…”