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.

Keywords::

• insomnia
• melatonin
• polysomnographic evaluation
• ramelteon
• sleep latency
• sleep time

Acknowledgements

We would like to express our sincere appreciation to the following investigators and study sites for their participation and thoughtful advice during the conduct of the study: Dr Shigeru Chiba (Asahikawa Medical College Hospital, Hokkaido, Japan); Dr Masahiko Fujita (Wellness Boyo Hospital, Hokkaido, Japan); Dr Hisakazu Furuta (Hokuriku National Hospital, Toyama, Japan); Dr Hideyuki Ikematsu (Haradoi Hospital, Fukuoka, Japan); Dr Toshiya Inada (Nagoya University Hospital, Aichi, Japan); Dr Yuichi Inoue (Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan); Dr Naofumi Kajimura, (National Center of Neurology and Psychiatry [NCNP], Tokyo, Japan); Dr Takashi Kanbayashi (Akita University Hospital, Akita, Japan); Dr Seiichi Kawada (Kagamigawa Hospital, Kochi, Japan); Dr Yuji Kumagai (Kitasato University East Hospital, Kanagawa, Japan); Dr Kenji Kuroda (Osaka Medical College Hospital, Osaka, Japan); Dr Toru Nakajima (Kyorin University Hospital, Tokyo, Japan); Dr Hiroshi Nakamura (Nakamura Clinic, Okinawa, Japan); Dr Tamotsu Okada (Okada Clinic, Aichi, Japan); Dr Masako Okawa (Shiga University of Medical Science Hospital, Shiga, Japan); Dr Yoshiro Sugita (Osaka University Hospital, Osaka, Japan); Dr Yasurou Takahashi (Neurologic Research Center Clinic for Sleep Breathing Disorder, Tokyo, Japan); Dr Yuji Takasaki (Ohta Nishinouchi Hospital, Fukushima, Japan); Dr Mitsutaka Taniguchi (Osaka Kaisei Hospital, Osaka, Japan); Dr Naohisa Uchimura (Kurume University Hospital, Fukuoka, Japan); Dr Makoto Uchiyama (Kohnodai Hospital, International Medical Center of Japan, Chiba, Japan) and Dr Yuji Yamaguchi (Fukuoka Urazoe Clinic, Fukuoka, Japan).

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Financial & competing interests disclosure

This clinical trial was supported by a financial grant from Takeda Pharmaceutical Co., Ltd, Osaka, Japan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editorial assistance was provided by Trevor Speight and Content Ed Net and funded by Takeda Pharmaceutical Co., Ltd.