Objective To investigate the efficacy of rovatirelin, a thyrotropin-releasing hormone analogue, for ataxias in patients with spinocerebellar degeneration (SCD).
Methods Two multicentre, randomised, double-blind, placebo-controlled phase 3 studies (KPS1301, KPS1305) enrolled patients with predominant cerebellar ataxia, including SCA6, SCA31 or cortical cerebellar atrophy. KPS1301 enrolled patients with truncal ataxia and KPS1305 enrolled patients with truncal and limb ataxia. Each study included 4 weeks of pretreatment, a 28-week or 24-week treatment period and 4 weeks of follow-up. Patients were randomised (1:1:1) to rovatirelin (1.6 or 2.4 mg) or placebo in KPS1301, and randomised (1:1) to rovatirelin 2.4 mg or placebo in KPS1305. The primary endpoint was change in Scale for the Assessment and Rating of Ataxia (SARA) total scores. Pooled analysis was performed in patients who met the SARA recruitment criteria of KPS1305.
Results From October 2013 to May 2014, KPS1301 enrolled 411 patients; 374 were randomised to rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or placebo (n=123). From November 2016 to August 2017, KPS1305 enrolled 241 patients; 203 were randomised to rovatirelin 2.4 mg (n=101) or placebo (n=102). The primary endpoint showed no significant difference between rovatirelin and placebo in these two studies. In the pooled analysis (n=278), the difference between rovatirelin 2.4 mg (n=140) and placebo (n=138) was –0.61 (–1.64 vs –1.03; 95% CI –1.16 to –0.06; p=0.029) in the adjusted mean change in the SARA total score.
Conclusions Rovatirelin is a potentially effective treatment option for SCD.
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Correction notice This article has been corrected since it appeared Online First. 'Department of Neurology' was removed from the corresponding author address. In the sentence "In the subgroup of patients with limb and truncal ataxia…", 'n=13690' has been corrected to 'n=136'.
Collaborators The Rovatirelin Study Group included following physicians: Takao Hashimoto (Aizawa Hospital), Masashiro Sugawara (Akita University Hospital), Masahiko Tomiyama (Aomori Prefectural Central Hospital), Kazuhiro Takamatsu (Brain Attack Center Ota Memorial Hospital), Masaru Kuriyama (Brain Attack Center Ota Memorial Hospital), Shigeki Hirano (Chiba University Hospital), Takahide Nagashima (Dokkyo Medical University Hospital), Kensho Okamoto (Ehime Prefectural Central Hospital), Ryuji Saigo (Fujimoto General Hospital), Ryuichi Okubo (Fujimoto General Hospital), Akira Iwasaki (Fukaya Red Cross Hospital), Hiroyuki Enomoto (Fukushima Medical University Hospital), Akio Kimura (Gifu University Hospital), Yoshio Ikeda (Gunma University Hospital), Mikio Shoji (Hirosaki University Hospital), Tetsuya Takahashi (Hiroshima University Hospital), Tsuneo Fujita (Hitachi General Hospital), Ichiro Yabe (Hokkaido University Hospital), Hidenao Sasaki (Hokkaido University Hospital), Asako Takei (Hokuyukai Neurological Hospital), Hirotaka Shimizu (Hyogo Brain and Heart Center), Hiroo Yoshikawa (Hyogo College of Medicine), Tatsui Nagadou (Imakiire General Hospital), Katsuhiko Kayanuma (Ina Central Hospital), Tomoko Ogawa (International University of Health and Welfare Hospital), Masanori Mizuno (Iwate Medical University Hospital), Yoji Goto (Japanese Red Cross Nagoya Daiichi Hospital), Hiroyuki Yahikozawa (Japanese Red Cross Society Nagano Hospital), Takuji Yasude (Japanese Red Cross Society Suwa Hospital), Akiyo Hineno (Japanese Red Cross Society Suwa Hospital), Kazuma Kaneko (Japanese Red Cross Society Suwa Hospital), Haruo Shimazaki (Jichi Medical University Hospital), Kazuyuki Noda (Juntendo University Shizuoka Hospital), Kazushi Deguchi (Kagawa University Hospital), Hiroshi Takashima (Kagoshima University Hospital), Tatsuhiko Yuasa (Kamagaya General Hospital), Makoto Matsui (Kanazawa Medical University Hospital), Satoshi Kaneko (Kansai Medical University Hirakata Hospital), Yoshihide Sunada (Kawasaki Medical School Hospital), Susumu Kusunoki (Kindai University Hospital), Yusaku Nakamura (Kindai University Sakai Hospital), Kazutoshi Nishiyama (Kitasato University Kitasato Institute Hospital), Tatsushi Toda (Kobe University Hospital), Kenji Sekiguchi (Kobe University Hospital), Yasushi Osaki (Kochi Medical School Hospital), Yasushi Maeda (Kumamoto Saishunso National Hospital), Mika Jikumaru (Kumamoto University Hospital), Satoshi Yamashita (Kumamoto University Hospital), Hirofumi Yamashita (Kyoto University Hospital), Takakuni Maki (Kyoto University Hospital), Taira Uehara (Kyushu University Hospital), Ryo Yamasaki (Kyushu University Hospital), Hiroo Yamaguchi (Kyushu University Hospital), Shinji Ohara (Matsumoto Medical Center), Akinori Nakamura (Matsumoto Medical Center), Akira Taniguchi (Mie University Hospital), Atsushi Inoue (Nagano Prefectural Kiso Hospital), Naoki Atsuta (Nagoya University Hospital), Masahisa Katsuno (Nagoya University Hospital), Yuji Takahashi (National Center of Neurology and Psychiatry), Sagiri Isose (National Hospital Organization Chiba-East-Hospital), Katsuhisa Ogata (National Hospital Organization East Saitama National Hospital), Naonobu Futamura (National Hospital Organization Hyogo-Chuo Hospital), Ryoichi Kurisaki (National Hospital Organization Kumamoto Minami Hospital), Taro Yamashita (National Hospital Organization Kumamoto Minami Hospital), Yoshito Sonoda (National Hospital Organization Minami Kyushu National Hospital), Ryusuke Matsumura (National Hospital Organization Nara Medical Center), Takashi Nakajima (National Hospital Organization Niigata National Hospital), Ryoko Koike (National Hospital Organization Nishi-Niigata Chuo Hospital), Tokio Shimomura (National Hospital Organization Saigata Medical Center), Hideyuki Sawada (National Hospital Organization Utano Hospital), Satoshi Kamei (Nihon University Itabashi Hospital), Shuichi Igarashi (Niigata City General Hospital), Kunihiko Makino (Niigata Prefectural Shibata Hospital), Masayoshi Tada (Niigata University Medical & Dental Hospital), Masayuki Ueda (Nippon Medical School Hospital), Mineo Yamazaki (Nippon Medical School Hospital), Hiroshi Nagayama (Nippon Medical School Hospital), Youichi Hokezu (Oita Prefectural Hospital), Etsuro Matsubara (Oita University Hospital), Yasuhiro Aso (Oita University Hospital), Koji Abe (Okayama University Hospital), Fumiharu Kimura (Osaka Medical College Hospital), Shigeki Arawaka (Osaka Medical College Hospital), Makio Takahashi (Osaka Red Cross Hospital), Kuni Konaka (Osaka University Hospital), Kousuke Baba (Osaka University Hospital), Kazuko Hasegawa (Sagamihara National Hospital), Jun Miki (Saku Central Hospital), Chinatsu Kobayashi (Saku Central Hospital), Yasutaka Tajima (Sapporo City General Hospital), Shin Hisahara (Sapporo Medical University Hospital), Shuichi Ikeda (Shinshu University Hospital), Yoshiki Sekijima (Shinshu University Hospital), Kunihiro Yoshida (Shinshu University Hospital), Sadayuki Matsumoto (Tazuke Kofukai, Medical Research Institute, Kitano Hospital), Toshihiko Suenaga (Tenri Hospital), Hiroshi Yaguchi (The Jikei University Kashiwa Hospital), Akira Kurita (The Jikei University Kashiwa Hospital), Masahiko Suzuki (The Jikei University Katsushika Medical Center), Masashi Hamada (The University of Tokyo Hospital), Shoji Tsuji (The University of Tokyo Hospital), Ryuji Sakakibara (Toho University Sakura Medical Center), Masaaki Kato (Tohoku University Hospital), Hitoshi Warita (Tohoku University Hospital), Kentaro Tokuoka (Tokai University Hachioji Hospital), Eiichiro Nagata (Tokai University Hospital), Yoshimichi Miyazaki (Tokushima University Hospital), Koji Fujita (Tokushima University Hospital), Wataru Sako (Tokushima University Hospital), Takanori Yokota (Tokyo Medical And Dental University, Medical Hospital), Hidehiro Mizusawa (Tokyo Medical And Dental University, Medical Hospital), Kazunori Nanri (Tokyo Medical University Hachioji Medical Center), Hiroo Terashi (Tokyo Medical University Hachioji Medical Center), Hitoshi Aizawa (Tokyo Medical University Hospital), Akihiro Kawata (Tokyo Metropolitan Neurological Hospital), Eiji Isozaki (Tokyo Metropolitan Neurological Hospital), Kenji Nakashima (Tottori University Hospital), Akira Tamaoka (University of Tsukuba Hospital), Yoshihisa Takiyama (University of Yamanashi Hospital), Toru Kawanami (Yamagata University Hospital), Fumiaki Tanaka (Yokohama City University Hospital).
Contributors MN, OO and YS contributed to the concept or design of the study. MY analysed the study data. AH advised the study data analysis. All authors contributed to the data interpretation and writing of the manuscript and approved the final version of the manuscript.
Funding Kissei Pharmaceutical funded the studies and was involved in designing the study, data collection, data analysis, data interpretation and writing of the report. The corresponding author had full access to all the data in the studies and had final responsibility for the decision to submit for publication.
Competing interests MN has received grants and personal fees from Kissei Pharmaceutical during the conduct of the study; and has received grants and personal fees from Astellas Pharma, Daiichi-Sankyo, Sumitomo Dainippon, Eisai, FP, GlaxoSmithKline, Japan Blood Products Organization, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Novartis, Otsuka, Pfizer, Sanofi and Takeda, outside the submitted work. OO has received grants and personal fees from Kissei Pharmaceutical during the conduct of the study; and has received grants and personal fees from Astellas Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, Eli Lilly, FP, GlaxoSmithKline, Japan Blood Products Organization, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Novartis, Otsuka, Pfizer, Sanofi, Shionogi, Sumitomo Dainippon and Takeda, outside the submitted work. AH has received personal fees from Kissei Pharmaceutical during the conduct of the study. YS and MY are employees of Kissei Pharmaceutical. YS has a patent P2017-14198A issued.
Patient consent for publication Not required.
Ethics approval These studies were implemented based on ethical policies expressed in Good Clinical Practice (GCP) and the Declaration of Helsinki. Implementation of these studies was approved by the institutional review board of each facility prior to the start of the studies. Written informed consent was obtained from each patient.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available. Additional data analyses are acceptable on reasonable request.
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