Phase II pilot randomized trial of zonisamide for disease modification in prodromal Lewy body disease

Abstract

Zonisamide exhibits potential neuroprotective properties, but its efficacy during the prodromal stage of Lewy body disease (LBD) remains unclear. In this phase II randomized, double-blind pilot trial, 29 high-risk individuals aged 50–80 years with ≥2 prodromal symptoms and abnormal DaT-SPECT and/or cardiac MIBG were randomized to zonisamide (50–100 mg/day, n = 14) or placebo (n = 15) and treated for 96 weeks. Participants with Parkinson’s disease or dementia with Lewy bodies were excluded. No significant between-group difference was observed in the primary outcome, change in DaT-SPECT specific binding ratio from baseline to week 96 (0.072; 95% CI −0.565 to 0.709; p = 0.817), or in secondary outcomes including MIBG parameters and motor and cognitive functions. Non-motor symptoms worsened with zonisamide, whereas two placebo recipients developed Parkinson’s disease. Somnolence, fatigue, decreased appetite, and constipation were frequent adverse events. Although findings are inconclusive due to limited power, this study provides valuable methodological insights for preventive LBD trials.