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High-Dose Ubiquinol Supplementation in Multiple-System Atrophy: A Multicentre, Randomised, Double-Blinded, Placebo-Controlled Phase 2 Trial

25 Pages Posted: 23 May 2022

See all articles by Jun Mitsui

Jun Mitsui

The University of Tokyo - Department of Molecular Neurology

Takashi Matsukawa

The University of Tokyo - Department of Molecular Neurology

Yukari Uemura

National Center for Global Health and Medicine - Biostatistics Section; National Center for Global Health and Medicine - Department of Clinical Research

Takuya Kawahara

The University of Tokyo - Clinical Research Promotion Center

Ayaka Chikada

The University of Tokyo - Department of Neurology

Kristine Joyce L. Porto

The University of Tokyo - Department of Molecular Neurology

Hiroya Naruse

The University of Tokyo - Department of Neurology

Masaki Tanaka

International University of Health and Welfare, Narita Campus - Institute of Medical Genomics

Hiroyuki Ishiura

The University of Tokyo - Department of Neurology

Tatsushi Toda

The University of Tokyo - Department of Neurology

Haruko Kuzuyama

The University of Tokyo - Clinical Research Promotion Center

Mari Hirano

The University of Tokyo - Clinical Research Promotion Center

Ikue Wada

The University of Tokyo - Clinical Research Promotion Center

Toshio Ga

The University of Tokyo - Clinical Research Promotion Center

Takashi Moritoyo

The University of Tokyo - Clinical Research Promotion Center

Yuji Takahashi

National Center of Neurology and Psychiatry (NCNP) Hospital - Department of Neurology

Hidehiro Mizusawa

National Center of Neurology and Psychiatry; National Center of Neurology and Psychiatry (NCNP) Hospital - Department of Neurology

Kinya Ishikawa

Tokyo Medical and Dental University - Department of Neurology and Neurological Science

Takanori Yokota

Tokyo Medical and Dental University - Department of Neurology and Neurological Science

Satoshi Kuwabara

Chiba University - Department of Neurology

Nobukatsu Sawamoto

Kyoto University - Department of Neurology

Ryosuke Takahashi

Kyoto University - Department of Neurology

Koji Abe

Okayama University - Department of Neurology

Tomohiko Ishihara

Niigata University - Department of Neurology

Osamu Onodera

Niigata University - Department of Neurology

Dai Matsuse

Kyushu University - Department of Neurology

Ryo Yamasaki

Kyushu University - Department of Neurology

Jun-Ichi Kira

Kyushu University - Department of Neurology

Masahisa Katsuno

Nagoya University - Department of Neurology

Ritsuko Hanajima

Tottori University - Division of Neurology

Katsuhisa Ogata

National Hospital Organization (NHO) - Department of Neurology

Hiroshi Takashima

Kagoshima University - Department of Neurology and Geriatrics

Masaaki Matsushima

Hokkaido University - Department of Neurology

Ichiro Yabe

Hokkaido University - Department of Neurology

Hidenao Sasaki

Hokkaido University - Department of Neurology

Shoji Tsuji

The University of Tokyo - Department of Molecular Neurology

More...

Abstract

Background: Functionally impaired variants of COQ2 , encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients.

Methods: This syudy was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either a group with ubiquinol (1,500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who received at least one efficacy assessment (full analysis set). Safety analyses included patients who received at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771).

Findings: Between June 26, 2018, and May 27, 2019, 139 were randomly assigned to the ubiquinol group (n=69) or the placebo group (n=70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (−1.9 [95% CI, −3.1 to −0.6]; P=0.003). The ubiquinol group also showed better secondary efficacy outcomes, as assessed by Barthel index, Scale for the Assessment and Rating of Ataxia (SARA), and time required to walk 10 meters. Subgroup analysis supported the clinical efficacy in the MSA-P and MSA-C cases, as well as in non-carriers and carriers of V393A. Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n=15 [23.8%]) and placebo (n=21 [30.9%]).

Interpretation: High-dose ubiquinol given up to 48-weeks was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo.

Clinical Trial: This study is registered with UMIN Clinical Trials Registry (UMIN-CTR, https://www.umin.ac.jp/ctr/), UMIN000031771.

Funding: This study was supported by grants (17lk1403008h0001, 18lk1403008h0002, 19lk1403008h0003, 20lm0203141h0001, 21lm0203141h0002) from the Japan Agency for Medical Research and Development (AMED).

Declaration of Interest: JM reports honoraria from Kyowa Kirin, Alnylam Japan, Sanofi, Sumitomo Pharma, Pfizer, Daiichi Sankyo, and Takeda Pharmaceutical Company; grants from Japan Agency for Medical Research and Development (AMED), Japan Society for the Promotion of Science (JSPS), and Takeda Science Foundation. TM reports honoraria from Eisai and Sumitomo Pharma; grants from JSPS. HI reports honoraria from Takeda Pharmaceutical Company, Eisai, Biogen Japan, Sumitomo Pharma, FP Pharmaceutical Corporation, Kyowa Kirin, UCB Japan, Chugai Pharmaceutical, and Daiichi Sankyo Company; grants from AMED, JSPS, and Kato Memorial Trust for Nanbyo Research. TT reports honoraria from Sumitomo Pharma. OO reports honoraria from Kyowa Hakko Kirin Co., Ltd., BristolMyers Squibb, Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharm, Takeda, Daiichi-Sankyo, FUJIFILM, SANOFI, and FP-pharm; grants from AMED, JSPS, Japanese Ministry of Health, Labor, and Welfare, Takeda Science Foundation, and Life Science Foundation of Japan. ST reports consulting fees from Sanwakagaku Kenkyusho, and Ono Pharmaceutical; honoraria from Sanofi, Senju Pharmaceutical, Novartis, Kyowa Kirin, and Daiichisankyo; grants from AMED, JSPS, and Nobel Pharma. All other authors declare no competing interests.

Ethical Approval: The trial was approved by the participating institutional review boards and was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients provided written informed consent.

Keywords: Multiple system atrophy, COQ2, ubiquinol, clinical trial, disease-modifying therapy

Suggested Citation

Mitsui, Jun and Matsukawa, Takashi and Uemura, Yukari and Kawahara, Takuya and Chikada, Ayaka and Porto, Kristine Joyce L. and Naruse, Hiroya and Tanaka, Masaki and Ishiura, Hiroyuki and Toda, Tatsushi and Kuzuyama, Haruko and Hirano, Mari and Wada, Ikue and Ga, Toshio and Moritoyo, Takashi and Takahashi, Yuji and Mizusawa, Hidehiro and Ishikawa, Kinya and Yokota, Takanori and Kuwabara, Satoshi and Sawamoto, Nobukatsu and Takahashi, Ryosuke and Abe, Koji and Ishihara, Tomohiko and Onodera, Osamu and Matsuse, Dai and Yamasaki, Ryo and Kira, Jun-Ichi and Katsuno, Masahisa and Hanajima, Ritsuko and Ogata, Katsuhisa and Takashima, Hiroshi and Matsushima, Masaaki and Yabe, Ichiro and Sasaki, Hidenao and Tsuji, Shoji, High-Dose Ubiquinol Supplementation in Multiple-System Atrophy: A Multicentre, Randomised, Double-Blinded, Placebo-Controlled Phase 2 Trial. Available at SSRN: https://ssrn.com/abstract=4117370 or http://dx.doi.org/10.2139/ssrn.4117370

Jun Mitsui

The University of Tokyo - Department of Molecular Neurology ( email )

Japan

Takashi Matsukawa

The University of Tokyo - Department of Molecular Neurology ( email )

Yukari Uemura

National Center for Global Health and Medicine - Biostatistics Section ( email )

Japan

National Center for Global Health and Medicine - Department of Clinical Research ( email )

Tokyo
Japan

Takuya Kawahara

The University of Tokyo - Clinical Research Promotion Center ( email )

Japan

Ayaka Chikada

The University of Tokyo - Department of Neurology ( email )

Japan

Kristine Joyce L. Porto

The University of Tokyo - Department of Molecular Neurology ( email )

Hiroya Naruse

The University of Tokyo - Department of Neurology ( email )

Masaki Tanaka

International University of Health and Welfare, Narita Campus - Institute of Medical Genomics ( email )

Japan

Hiroyuki Ishiura

The University of Tokyo - Department of Neurology ( email )

Tatsushi Toda

The University of Tokyo - Department of Neurology ( email )

Haruko Kuzuyama

The University of Tokyo - Clinical Research Promotion Center ( email )

Mari Hirano

The University of Tokyo - Clinical Research Promotion Center ( email )

Ikue Wada

The University of Tokyo - Clinical Research Promotion Center ( email )

Toshio Ga

The University of Tokyo - Clinical Research Promotion Center ( email )

Takashi Moritoyo

The University of Tokyo - Clinical Research Promotion Center ( email )

Yuji Takahashi

National Center of Neurology and Psychiatry (NCNP) Hospital - Department of Neurology ( email )

Japan

Hidehiro Mizusawa

National Center of Neurology and Psychiatry ( email )

Tokyo
Japan

National Center of Neurology and Psychiatry (NCNP) Hospital - Department of Neurology ( email )

Kinya Ishikawa

Tokyo Medical and Dental University - Department of Neurology and Neurological Science ( email )

Takanori Yokota

Tokyo Medical and Dental University - Department of Neurology and Neurological Science ( email )

Satoshi Kuwabara

Chiba University - Department of Neurology ( email )

Japan

Nobukatsu Sawamoto

Kyoto University - Department of Neurology ( email )

Japan

Ryosuke Takahashi

Kyoto University - Department of Neurology ( email )

Koji Abe

Okayama University - Department of Neurology ( email )

Japan

Tomohiko Ishihara

Niigata University - Department of Neurology ( email )

Japan

Osamu Onodera

Niigata University - Department of Neurology

Dai Matsuse

Kyushu University - Department of Neurology ( email )

Japan

Ryo Yamasaki

Kyushu University - Department of Neurology ( email )

Jun-Ichi Kira

Kyushu University - Department of Neurology ( email )

Masahisa Katsuno

Nagoya University - Department of Neurology ( email )

Nagoya
Japan

Ritsuko Hanajima

Tottori University - Division of Neurology ( email )

Japan

Katsuhisa Ogata

National Hospital Organization (NHO) - Department of Neurology ( email )

Japan

Hiroshi Takashima

Kagoshima University - Department of Neurology and Geriatrics ( email )

Japan

Masaaki Matsushima

Hokkaido University - Department of Neurology ( email )

Japan

Ichiro Yabe

Hokkaido University - Department of Neurology ( email )

Hidenao Sasaki

Hokkaido University - Department of Neurology ( email )

Shoji Tsuji (Contact Author)

The University of Tokyo - Department of Molecular Neurology ( email )

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