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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 2022More...
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
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