Efficacy and Safety of DL-3-n-Butylphthalide in Spinocerebellar Ataxia Type 3.

BACKGROUND: Preclinical studies have suggested that DL-3-n-butylphthalide (NBP) may exhibit neuroprotective effects in neurodegenerative diseases; however, no human trial has evaluated NBP in spinocerebellar ataxia type 3 (SCA3). OBJECTIVES: The aim of the study was to evaluate the efficacy and safety of oral NBP in patients with SCA3 over 12 months. METHODS: Patients were randomly assigned (1:1) to oral NBP (200 mg thrice daily) or placebo for 12 months. The primary outcomes were 12-month changes in the Scale for Assessment and Rating of Ataxia (SARA) and Spinocerebellar Ataxia Functional Index (SCAFI). Safety outcomes included adverse events (AEs) and serious adverse events (SAEs). RESULTS: The modified intention-to-treat (mITT) population included 116 patients (NBP, n = 56; placebo, n = 60). The primary endpoints, change in SARA and SCAFI, were significantly different between NBP and placebo groups (SARA, estimated marginal mean difference: -0.86, 95% confidence interval [CI]: -1.56 to -0.16, P = 0.02; SCAFI, estimated marginal mean difference: 0.16, 95% CI: 0.01-0.31, P = 0.03) in mITT population using a mixed-effect model, with improved clinical outcome in the NBP group. Overall, AE rates were not significantly different between groups (13 AEs [23.2%] in NBP vs. 9 AEs [15%] in placebo, P = 0.26), although drug-related AEs were numerically more frequent with NBP (12 [21.4%] vs. 6 [10.0%], P = 0.09); no SAE occurred in either group. CONCLUSIONS: Oral administration of NBP was safe and generally well tolerated. Significant differences in clinical outcomes were observed in the treatment group compared to the placebo. NBP administration showed preliminary evidence of clinical benefit in SCA3. © 2026 International Parkinson and Movement Disorder Society.