Phase II pilot randomized trial of zonisamide for disease modification in prodromal Lewy body disease
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.
Authors
- Noriyuki Matsukawa (ORCID: https://orcid.org/0000-0002-6638-4516)
- Keita Hiraga (ORCID: https://orcid.org/0000-0002-0134-2956)
- Takashi Tsuboi (ORCID: https://orcid.org/0000-0001-5042-3181)
- Keisuke Suzuki (ORCID: https://orcid.org/0000-0001-5790-1289)
- Daigo Tamakoshi
- Taiki Fukushima (ORCID: https://orcid.org/0000-0002-3844-3099)
- Masahisa Katsuno (ORCID: https://orcid.org/0000-0001-9453-9311)
- Makoto Hattori (ORCID: https://orcid.org/0000-0001-6913-1509)
- Hiroshi Matsuda (ORCID: https://orcid.org/0000-0002-6297-9897)
- Yutaka Arahata (ORCID: https://orcid.org/0000-0001-7810-8984)
- Fumie Kinoshita (ORCID: https://orcid.org/0000-0002-3008-0748)
- Yoshino Ueki (ORCID: https://orcid.org/0000-0002-4772-6314)
- Masakazu Wakai
- Katsunori Yokoi
- Akihiro Murata
- Masayuki Yamamoto (ORCID: https://orcid.org/0000-0002-9073-9436)
- Takashi Uematsu (ORCID: https://orcid.org/0009-0006-5752-3875)
- Yuki Satake
- Yukihiko Washimi
- Yuki Saito
- Maki Sato
Institutions
- Nagoya City University (JP)
- Nagoya University Hospital (JP)
- Nihon Medi-Physics (Japan) (JP)
- National Center for Geriatrics and Gerontology (JP)
- Southern Tohoku General Hospital (JP)
- Daido University (JP)
- Nagoya University (JP)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1038/s41531-025-01198-3
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- National Center for Geriatrics and Gerontology