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Article History

Received: 10 May 2025

Accepted: 14 October 2025

First Online: 4 December 2025

Declarations

:

: Y.Taka. has received lecture fees from Eisai, Takeda Pharmaceutical, Sumitomo Pharma, Otsuka Pharmaceutical, Mochida Pharmaceutical, Lundbeck Japan, Viatris Pharmaceuticals Japan, Nobelpharma, Meiji Seika Pharma, MSD, Daiichi Sankyo, and Shionogi & Co. outside the submitted work. H.M. has received honoraria from Eisai, Otsuka Pharmaceutical, Mochida Pharmaceutical, Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, MSD, Meiji Seika Pharma, Janssen Pharmaceutical, Yoshitomi Pharmaceutical Industries, and Viatris Pharmaceuticals Japan. M.T. has received honoraria from Takeda Pharmaceutical, Otsuka Pharmaceutical, Daiichi Sankyo, Sumitomo Pharma, Meiji Seika Pharma, Viatris Pharmaceuticals, MSD, Eisai, and Yoshitomi Pharmaceutical. M.Ka. has received consulting fees from Sumitomo Pharma, Otsuka Pharmaceutical, Lundbeck Japan, and Shionogi & Co. and honoraria from Sumitomo Pharma, Eisai, Janssen Pharmaceutical, Meiji Seika Pharma, Otsuka Pharmaceutical, Takeda Pharmaceutical, Viatris, Mitsubishi Tanabe Pharma, MSD, Eli Lilly, Shionogi & Co., Lundbeck Japan, Kyowa Pharmaceutical, and Ono Pharmaceutical. H.Hi. received all support for the present manuscript from Eisai. H.Ho. received all support for the present manuscript from Eisai, and received honoraria from Sumitomo Pharma, Eisai, Janssen Pharmaceutical, Meiji Seika Pharma, Otsuka Pharmaceutical, Takeda Pharmaceutical, and Viatris. K.I. received all support for the present manuscript from Eisai, and honoraria from Eisai, MSD, Otsuka Pharmaceutical, Kyowa Kirin, Kowa Pharmaceutical, Shionogi & Co., Sumitomo Pharma, Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Eli Lilly Japan, Boehringer Ingelheim Japan, Novartis Pharma, Pfizer Japan, Meiji Seika Pharma, Mochida Pharmaceutical, Janssen Pharmaceutical, Lundbeck Japan, Yoshitomi Pharmaceutical Industries, Ono Pharmaceutical, Nipro, Nexera Pharma, EA Pharma, and Viatris Pharmaceuticals Japan. H.S. has received grants from Japan Society for the Promotion of Science, Japan Research Foundation Clinical Pharmacology, and Takeda Science Foundation, and honorarium from Viatris, Eisai, Takeda Pharmaceutical, Otsuka Pharmaceutical, Meiji Seika Pharma, Shionogi Pharma, Yoshitomi Pharmaceutical Industries, Sumitomo Pharma, Kyowa Pharmaceutical, MSD, Mochida Pharmaceutical, and Lundbeck Japan. M.O. has received grants from Mitsubishi Tanabe Pharma, Tsumura, Shionogi & Co., Mochida Pharmaceutical, Sumitomo Pharma, Otsuka Pharmaceutical, Kyowa Kirin, Teijin Pharma and honoraria from Eisai, Tsumura, MSD, Meiji Seika Pharma, Takeda Pharmaceutical, Nobel pharma, Taisho Pharmaceutical, Daiichi Sankyo, and Shionogi & Co. Y.Ko. received all support for the present manuscript from Eisai; grants from JSPS KAKENHI; consulting fees from Takeda Pharmaceutical; and honoraria from Takeda Pharmaceutical, Lundbeck Japan, Sumitomo Pharma, Otsuka Pharmaceutical, and Sanwa Kagaku Kenkyusho. T.M. has received honoraria from Sumitomo Pharma, Otsuka Pharmaceutical, Takeda Pharmaceutical, Viatris, and Shionogi & Co. T.T. has received lecture fees from Sumitomo Pharma, Daiichi Sankyo, Viatris, Eisai, Mochida Pharmaceutical, and Shionogi & Co. K.W. received all support for the present manuscript; received grants from Eisai, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, and Takeda Pharmaceutical; consulting fees from Boehringer Ingelheim, Daiichi Sankyo, Eisai, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Luye Pharma, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, and Viatris; honoraria from Boehringer Ingelheim, Eisai, Janssen Pharmaceutical, Kyowa Pharmaceutical, Lundbeck Japan, Meiji Seika Pharma, Mitsubishi Tanabe Pharma, MSD, Otsuka Pharmaceutical, Shionogi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Viatris; and has participated on DSMB or advisory board of Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Nippon Chemiphar, and Otsuka Pharmaceutical. H.Y. received all support for the present manuscript from Eisai. M.Ko. and Y.Ka. are full-time employees of Eisai Co., Ltd. Y.Take. has received grant funding from the Japan Society for the Promotion of Science and speaker’s honoraria from Eisai, Meiji Seika Pharma, Sumitomo Pharma, Janssen Pharmaceutical, Otsuka, Lundbeck, Daiichi Sankyo, Takeda Pharmaceutical, UCB Japan, Novartis, Teijin Pharma, Nippon Boehringer Ingelheim, and Mitsubishi Tanabe Pharma.

: The study protocol, protocol amendments, and all study-related documents were reviewed and approved by the review board of the University of the Ryukyus for clinical research (approval no.: 19-2). Study registration number is jRCTs071220037. The study was conducted in accordance with the protocol, and complied with the Clinical Trials Act, the Declaration of Helsinki, and all local laws.

: All patients provided written informed consent to participate in the study.

: Not applicable.

: The dataset generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

: No custom code or scripts were developed specifically for this study.

: Conceptualization and design of the study: Y.Taka., T.T., K.W., and M.Ko. Data collection and investigation: Y.Taka., H.M., M.T., M.Ka., H.Hi., H.Ho., K.I., H.S., M.O., Y.Ko., T.M., T.T., K.W., H.Y., and Y.Take. Project management: Y.Taka., M.Ko., and Y.Ka. Writing and revising of the original draft: Y.Taka., M.Ko., and Y.Ka. Writing review and editing: Y.Taka., H.M., M.T., M.Ka., H.Hi., H.Ho., K.I., H.S., M.O., Y.Ko., T.M., T.T., K.W., H.Y., M.Ko., Y.Ka., and Y.Take. All authors have read and approved the final submitted manuscript and agree to be accountable for the work.