Abstract
BACKGROUND: Therapeutic advancements for the polyglutamine diseases, particularly spinocerebellar degeneration, are eagerly awaited. We evaluated the safety, tolerability, and therapeutic effects of L-arginine, which inhibits the conformational change and aggregation of polyglutamine proteins, in patients with spinocerebellar ataxia type 6 (SCA6). METHODS: A multicenter, randomized, double-blind, placebo-controlled phase 2 trial (clinical trial ID: AJA030-002, registration number: jRCT2031200135) was performed on 40 genetically confirmed SCA6 patients enrolled between September 1, 2020, and September 30, 2021. The main inclusion criteria were as follows: SCA6 diagnosed by genetic testing, 20 years of age or older, Scale for the Assessment and Rating of Ataxia (SARA) "walking" score of at least one point, and SARA "total" score of at least 10 points, and ability to walk 10 m or more with or without an assistive device. The investigational drug was administered orally at 0.50 g/kg/day (L-arginine group: L-arginine 0.38 g/kg/day; placebo group: L-arginine 0.0 g/kg/day) for 48 weeks. Subjects who consented to participate were assigned a subject identification code, and were allocated 1:1 to the L-arginine or the placebo group, according to a predetermined allocation chart. The primary efficacy endpoint was change in total Scale for the Assessment and Rating of Ataxia (SARA) score from baseline to 48 weeks. The secondary endpoints were 1) SARA walking + standing score, 2) each of the eight SARA scales at 0, 4, 8, 16, 24, 32, 40, and 48 weeks, and 3) TUGT, BDI-II, CGI, PGI-I, and SF-8. FINDINGS: Forty patients received the investigational drug, and 37 completed the study (L-arginine group: 18; placebo group: 19). The mean medication adherence rate was 97.2% in the l-arginine group. Regarding the primary endpoint, the difference between the L-arginine group and the placebo group was -1.52 (95% CI: -3.10 to 0.06, P = 0.0582). As the secondary endpoints, the change of SARA total score from baseline was greater in the L-arginine group than in the placebo group at all assessment time points, but the differences were not significant. Two serious (required hospitalization) adverse reactions occurred in the L-arginine group, including one case of pneumonia (severe, death) and one case of abnormal liver function (moderate, recovery). INTERPRETATION: L-arginine treatment resulted in an improvement tendency in SARA total score of SCA6 patients. Our results suggest that a phase 3 study of L-arginine for SCA6, with a 48-week observation period and change in total SARA score as the primary endpoint, may be feasible for further analyzing the therapeutic effect of L-arginine. However, careful consideration of statistical power and sample size is necessary. FUNDING: Japan Agency for Medical Research and Development and Health Labour Sciences Research Grant, Japan.