Adjunct zonisamide to levodopa for DLB parkinsonism: A randomized double-blind phase 2 study

Abstract

Objective: To investigate the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with dementia with Lewy bodies (DLB).

Methods: This phase 2, placebo-controlled, randomized, double-blind study consisted of run-in (placebo, 4 weeks) and treatment (placebo or zonisamide 25 or 50 mg once daily, 12 weeks) periods. Outpatients diagnosed with probable DLB were eligible for inclusion. The primary endpoint was the change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) part 3 total score at week 12. Cognitive function, behavioral and psychological symptoms of dementia (BPSD), caregiver burden, other UPDRS parts as secondary endpoints, and safety were also assessed.

Results: Overall, 158 patients with DLB received the study drug; 21 discontinued during treatment and 137 completed treatment. Improvement in UPDRS part 3 total score at week 12 was significantly greater in the zonisamide 50 mg group compared with placebo (between-group difference -4.1; 95% confidence interval -6.8 to -1.4; p = 0.003). Zonisamide did not worsen cognitive function, BPSD, or caregiver burden. The overall incidence of adverse events was higher in the zonisamide 50 mg than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%, respectively); similar rates of serious adverse events were observed among all groups.

Conclusion: Zonisamide (adjunctive to levodopa) improved parkinsonism accompanying DLB without worsening cognitive function or psychiatric symptoms.

Clinical trial registration: JapicCTI-122040.

Classification of evidence: This study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB.

Figure 1. Patient disposition

*An adverse event occurred in the run-in period in 1 of 3 patients (excluded from table 2). mITT = modified intention-to-treat; PP = per protocol.

Figure 2. Change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) part 3 total score at week 12 (last observation carried forward [LOCF])

Results are presented as least squares mean ± SEM with LOCF. Statistical analysis was performed by analysis of covariance with Fisher least significant difference method for multiplicity adjustment (p < 0.05: statistically significant vs placebo).

Figure 3. Time course of change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) part 3 total score

Results are the least squares mean ± SEM. Statistical analysis at weeks 4, 8, and 12 was performed by analysis of covariance. *p < 0.05; **p < 0.001 (vs placebo).