Objective: To verify the efficacy and safety of zonisamide (ZNS) for parkinsonism in patients with dementia with Lewy bodies (DLB).

Background: DLB parkinsonism is responsive to levodopa, but the responsive rate is moderate and the higher dose has a risk of worsening underlying psychiatric symptoms. In Japan, ZNS is now available as anti-Parkinson drug. Previously, our randomized studies with Parkinson’s disease showed ZNS improves motor symptoms and wearing off without affecting psychiatric symptoms[1]. Therefore, we hypothesized ZNS would improve DLB parkinsonism and conducted the randomized phase 2 trial[2]. Here, we will show results of a randomized phase 3 trial using larger number of patients.

Methods: The trial consisted of 12-week randomized double-blind confirmatory and subsequent 40-week open-label extension phases. Outpatients diagnosed with probable DLB were enrolled. The patients randomized into placebo (PLA), ZNS 25 or 50 mg/d groups and received any of drugs at fixed dose for 12 weeks in the confirmatory phase. In the extension phase, the patients received ZNS at an initial dose of 25 mg/d over 2 weeks, and then at a flexible dose of 25 or 50 mg/d depending on patients’ condition. Change from baseline (BL) in UPDRS part3 (UPDRS3) score at Week (W) 12 was the primary endpoint. Throughout the trial, UPDRS3, MMSE, NPI-10 as well as safety were evaluated.

Results: Of 373 patients screened, 351 were randomized. Patients’ background for primary endpoint was following, mean age, 77.2 years; mean durations of dementia and motor dysfunction, 3.6 and 2.7 years; mean UPDRS3 score, 31.2. Although any groups showed the score reduction in UPDRS3 at W12 (change from BL; -1.4 [PLA], -4.1 [ZNS25], -4.0 [ZNS50]), the reduction in both ZNS groups was statistically greater than in PLA (figure 1). Subsequently, the UPDRS3 scores further reduced until W24-28 in both ZNS groups (-5.1 to -6.3) and then were almost constant until W52 (figure 2). In contrast, the score reduction in MMSE at W12 was greater in ZNS50 than in PLA, but in term of long-term evaluation, the scores of MMSE as well as NPI-10 were not affected by ZNS treatment. Of 335 patients for long-term evaluation, 230 completed the 52-week treatment. There was no remarkable adverse event throughout the trial.

Conclusions: Zonisamide improves DLB parkinsonism and is well-tolerated. (A part of the results has been presented at several meetings such as WCN [Sep 2017] and IAPRD [Nov 2017].)

References: [1] Murata M, Hasegawa K, Kanazawa I, et al. Zonisamide improves wearing-off in Parkinson’s disease: a randomized, double-blind study. Mov Disord. 2015; 30: 1343–1350. [2] Murata M, Odawara T, Hasegawa K, et al. Adjunct zonisamide to levodopa for DLB parkinsonism: a randomized, double-blind phase 2 study. Neurology. 2018; 90: e664–e672.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/zonisamide-improves-parkinsonism-in-dlb-patients-a-randomized-phase-3-trial/