Effect of rovatirelin in patients with cerebellar ataxia: two randomised double-blind placebo-controlled phase 3 trials

Masatoyo Nishizawa, Osamu Onodera, Akihiro Hirakawa, Yoshitaka Shimizu, Masayuki Yamada, Rovatirelin Study Group, Takao Hashimoto, Masashiro Sugawara, Masahiko Tomiyama, Kazuhiro Takamatsu, Masaru Kuriyama, Shigeki Hirano, Takahide Nagashima, Kensho Okamoto, Ryuji Saigo, Ryuichi Okubo, Akira Iwasaki, Hiroyuki Enomoto, Akio Kimura, Yoshio Ikeda, Mikio Shoji, Tetsuya Takahashi, Tsuneo Fujita, Ichiro Yabe, Hidenao Sasaki, Asako Takei, Hirotaka Shimizu, Hiroo Yoshikawa, Tatsui Nagadou, Katsuhiko Kayanuma, Tomoko Ogawa, Masanori Mizuno, Yoji Goto, Hiroyuki Yahikozawa, Takuji Yasude, Akiyo Hineno, Kazuma Kaneko, Haruo Shimazaki, Kazuyuki Noda, Kazushi Deguchi, Hiroshi Takashima, Tatsuhiko Yuasa, Makoto Matsui, Satoshi Kaneko, Yoshihide Sunada, Susumu Kusunoki, Yusaku Nakamura, Kazutoshi Nishiyama, Tatsushi Toda, Kenji Sekiguchi, Yasushi Osaki, Yasushi Maeda, Mika Jikumaru, Satoshi Yamashita, Hirofumi Yamashita, Takakuni Maki, Taira Uehara, Ryo Yamasaki, Hiroo Yamaguchi, Shinji Ohara, Akinori Nakamura, Akira Taniguchi, Atsushi Inoue, Naoki Atsuta, Masahisa Katsuno, Yuji Takahashi, Sagiri Isose, Katsuhisa Ogata, Naonobu Futamura, Ryoichi Kurisaki, Taro Yamashita, Yoshito Sonoda, Ryusuke Matsumura, Takashi Nakajima, Ryoko Koike, Tokio Shimomura, Hideyuki Sawada, Satoshi Kamei, Shuichi Igarashi, Kunihiko Makino, Masayoshi Tada, Masayuki Ueda, Mineo Yamazaki, Hiroshi Nagayama, Youichi Hokezu, Etsuro Matsubara, Yasuhiro Aso, Koji Abe, Fumiharu Kimura, Shigeki Arawaka, Makio Takahashi, Kuni Konaka, Kousuke Baba, Kazuko Hasegawa, Jun Miki, Chinatsu Kobayashi, Yasutaka Tajima, Shin Hisahara, Shuichi Ikeda, Yoshiki Sekijima, Kunihiro Yoshida, Sadayuki Matsumoto, Toshihiko Suenaga, Hiroshi Yaguchi, Akira Kurita, Masahiko Suzuki, Masashi Hamada, Shoji Tsuji, Ryuji Sakakibara, Masaaki Kato, Hitoshi Warita, Kentaro Tokuoka, Eiichiro Nagata, Yoshimichi Miyazaki, Koji Fujita, Wataru Sako, Takanori Yokota, Hidehiro Mizusawa, Kazunori Nanri, Hiroo Terashi, Hitoshi Aizawa, Akihiro Kawata, Eiji Isozaki, Kenji Nakashima, Akira Tamaoka, Yoshihisa Takiyama, Toru Kawanami, Fumiaki Tanaka, Masatoyo Nishizawa, Osamu Onodera, Akihiro Hirakawa, Yoshitaka Shimizu, Masayuki Yamada, Rovatirelin Study Group, Takao Hashimoto, Masashiro Sugawara, Masahiko Tomiyama, Kazuhiro Takamatsu, Masaru Kuriyama, Shigeki Hirano, Takahide Nagashima, Kensho Okamoto, Ryuji Saigo, Ryuichi Okubo, Akira Iwasaki, Hiroyuki Enomoto, Akio Kimura, Yoshio Ikeda, Mikio Shoji, Tetsuya Takahashi, Tsuneo Fujita, Ichiro Yabe, Hidenao Sasaki, Asako Takei, Hirotaka Shimizu, Hiroo Yoshikawa, Tatsui Nagadou, Katsuhiko Kayanuma, Tomoko Ogawa, Masanori Mizuno, Yoji Goto, Hiroyuki Yahikozawa, Takuji Yasude, Akiyo Hineno, Kazuma Kaneko, Haruo Shimazaki, Kazuyuki Noda, Kazushi Deguchi, Hiroshi Takashima, Tatsuhiko Yuasa, Makoto Matsui, Satoshi Kaneko, Yoshihide Sunada, Susumu Kusunoki, Yusaku Nakamura, Kazutoshi Nishiyama, Tatsushi Toda, Kenji Sekiguchi, Yasushi Osaki, Yasushi Maeda, Mika Jikumaru, Satoshi Yamashita, Hirofumi Yamashita, Takakuni Maki, Taira Uehara, Ryo Yamasaki, Hiroo Yamaguchi, Shinji Ohara, Akinori Nakamura, Akira Taniguchi, Atsushi Inoue, Naoki Atsuta, Masahisa Katsuno, Yuji Takahashi, Sagiri Isose, Katsuhisa Ogata, Naonobu Futamura, Ryoichi Kurisaki, Taro Yamashita, Yoshito Sonoda, Ryusuke Matsumura, Takashi Nakajima, Ryoko Koike, Tokio Shimomura, Hideyuki Sawada, Satoshi Kamei, Shuichi Igarashi, Kunihiko Makino, Masayoshi Tada, Masayuki Ueda, Mineo Yamazaki, Hiroshi Nagayama, Youichi Hokezu, Etsuro Matsubara, Yasuhiro Aso, Koji Abe, Fumiharu Kimura, Shigeki Arawaka, Makio Takahashi, Kuni Konaka, Kousuke Baba, Kazuko Hasegawa, Jun Miki, Chinatsu Kobayashi, Yasutaka Tajima, Shin Hisahara, Shuichi Ikeda, Yoshiki Sekijima, Kunihiro Yoshida, Sadayuki Matsumoto, Toshihiko Suenaga, Hiroshi Yaguchi, Akira Kurita, Masahiko Suzuki, Masashi Hamada, Shoji Tsuji, Ryuji Sakakibara, Masaaki Kato, Hitoshi Warita, Kentaro Tokuoka, Eiichiro Nagata, Yoshimichi Miyazaki, Koji Fujita, Wataru Sako, Takanori Yokota, Hidehiro Mizusawa, Kazunori Nanri, Hiroo Terashi, Hitoshi Aizawa, Akihiro Kawata, Eiji Isozaki, Kenji Nakashima, Akira Tamaoka, Yoshihisa Takiyama, Toru Kawanami, Fumiaki Tanaka

Abstract

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.

Trial registration number: NCT01970098; NCT02889302.

Conflict of interest statement

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.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow chart of patients included in the (A) KPS1301 and (B) KPS1305 studies. The reasons for discontinuation could overlap. AE, adverse event.
Figure 2
Figure 2
Adjusted mean and 95% CI of the change in SARA total score from baseline (primary endpoint) in the (A) KPS1301 and (B) KPS1305 studies. P values were calculated using the ANCOVA method. (C) Pooled analysis of patients from KPS1301 and KPS1305 studies who met the KPS1305 inclusion criteria (SARA gait score of 2–6; stance score of ≥2; finger chase, nose–finger and fast alternating hand movement scores of ≥1 each). ANCOVA, analysis of covariance; SARA, Scale for the Assessment and Rating of Ataxia.
Figure 3
Figure 3
Mean±SD change in SARA total score from baseline for patients in the pooled populations with a baseline SARA score of (A)

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