Efficacy and Safety of Zonisamide in Dementia with Lewy Bodies Patients with Parkinsonism: A Post Hoc Analysis of Two Randomized, Double-Blind, Placebo-Controlled Trials

Abstract

Background: Although previous phase II and III clinical trials conducted in Japan showed that zonisamide improved parkinsonism in patients with dementia with Lewy bodies (DLB), some differences in efficacy outcomes were observed between the trials.

Objective: We aimed to further examine the efficacy and safety of zonisamide in DLB patients with parkinsonism in a post hoc analysis of pooled data from the previous phase II and III trials.

Methods: Both trials featured a 4-week run-in period followed by a 12-week treatment period with a double-blind, placebo-controlled, parallel-group, randomized, multicenter trial design. In our pooled analysis, the primary outcome was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part III total score. Other outcomes included the changes in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory-10 (NPI-10) scores, and the incidence of adverse events.

Results: Zonisamide significantly decreased the UPDRS part III total and individual motor symptom scores but did not affect the MMSE or NPI-10 scores at week 12. There was no difference in the incidence of adverse events between the zonisamide and placebo groups except for decreased appetite, which had an increased frequency in the zonisamide 50 mg group compared with placebo.

Conclusion: Our findings indicate that zonisamide improved parkinsonism with DLB without deterioration of cognitive function and or worsening behavioral and psychological symptoms of dementia.

Keywords: Dementia; lewy bodies; parkinsonism; zonisamide.

Fig. 1

Patient disposition in the phase II and phase III trials used in the current analysis.

Fig. 2

Efficacy of zonisamide for parkinsonism as measured by change from baseline at week 12 in UPDRS part III total score (A), individual motor symptom scores (B), and proportion of responders at week 12 (LOCF) (C). LS means (SE) and p-values for change from baseline in UPDRS scores were calculated using an MMRM with treatment group, visit, trial, and treatment-by-visit interaction as fixed effects, and baseline score as a covariate. An unstructured covariance matrix was assumed and the degree of freedom was estimated using Kenward–Roger’s approximation. Heterogeneity between the trials was evaluated using p-value for trial-by-treatment-by-visit interaction, which was added to the original MMRM model. p-values for the proportion of responders were calculated using logistic regression analysis with Firth’s penalized likelihood approach, with treatment group and trial as fixed effects and baseline score as a covariate. Responder: UPDRS part III total score change from baseline ≥ 10%, ≥ 20%, or ≥ 30%. LS mean, least-squares mean; LOCF, last observation carried forward; MMRM, mixed-effect model for repeated measures; PIGD, postural instability/gait disturbance; SE, standard error; UPDRS, Unified Parkinson’s Disease Rating Scale; ZNS, zonisamide.

Fig. 3

Effect of zonisamide on cognitive function as measured by change from baseline at week 12 in MMSE total score (A), and on BPSD as measured by change from baseline at week 12 in NPI-10 total score (B). LS means (SE) and p-values for change from baseline were calculated using an ANCOVA model with treatment group and trial as fixed effects, and baseline score as covariate. Heterogeneity between the trials was evaluated using p-value for trial-by-treatment interaction, which was added to the original ANCOVA model. ANCOVA, analysis of covariance; BPSD, behavioral and psychological symptoms of dementia; LS mean, least-squares mean; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; SE, standard error; ZNS, zonisamide.