Effect of zonisamide on parkinsonism in patients with dementia with Lewy bodies: A phase 3 randomized clinical trial

Abstract

Introduction: Zonisamide is approved in Japan for treating motor dysfunction in Parkinson's disease, and might also be effective for parkinsonism in patients with dementia with Lewy bodies (DLB). Our study evaluated the safety and efficacy of zonisamide for treating parkinsonism in patients with DLB. Methods: This multicenter, randomized, double-blind, phase 3 trial was conducted in Japan between April 2015 and November 2017. Following a 4-week run-in period, outpatients diagnosed with probable DLB who had developed parkinsonism were randomized to receive oral zonisamide (25 or 50 mg/day) or placebo for 12 weeks, followed by a 40-week open-label extension. The primary endpoint was the change in Unified Parkinson's Disease Rating Scale (UPDRS) part III total score at Week 12. Results: Of 351 patients randomized, 346 (mean age, 77.2 years; 188 males) were included in the modified intention-to-treat population. At Week 12, the group difference (least squares mean ± SEM) for changes from baseline (vs placebo) in UPDRS part III total score was −2.7 ± 0.9 (95% confidence interval [CI]: −4.4, −0.9, P = 0.005) in the zonisamide 25-mg group and −2.6 ± 0.9 (95% CI: −4.4, −0.8, P = 0.005) in the zonisamide 50-mg group. Adverse events were reported in 47.1%, 48.7%, and 54.5% of patients in the placebo and zonisamide 25-and 50-mg groups, and led to treatment discontinuation in 5.0%, 4.3%, and 9.8% of patients, respectively. Conclusion: Daily administration of 25-or 50-mg zonisamide significantly improved motor function compared with placebo; both doses were safe and well tolerated in patients with DLB.

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

“…With respect to the effect of zonisamide on cognitive function, no significant difference was observed between zonisamide (either dose) and placebo on the change in MMSE score. This finding differed from the outcome observed in the phase III trial, where zonisamide 50 mg significantly decreased the MMSE score compared with placebo [30]. Furthermore, in the analysis of the MMSE items and the subgroup analysis among patients with severe cognitive impairment, no differences in MMSE score change were observed between the zonisamide 25 mg or 50 mg groups and the placebo group (Supplementary Figures 1 and 2).…”

“…To reduce inter-/intra-rater variability, training was conducted prior to the trial start. A more detailed analysis of the effects of zonisamide on the following four motor symptoms [31] was also performed: tremor (items 20, 21), rigidity (item 22), bradykinesia (items [23][24][25][26]31), and postural instability/gait disturbance (PIGD) (items 29,30). For each individual motor symptom, patients with zero or missing values throughout the trial were excluded from the analysis.…”

“…Data were pooled from the phase II (JapicCTI-122040) and phase III (JapicCTI-152839) trials of zonisamide in patients with DLB conducted in Japan [29,30]; both trials were conducted in accord with the Declaration of Helsinki, Good Clinical Practice Ordinance and relevant regulations. Efficacy analyses were performed on the modified intention-to-treat populations from the two trials, which included all randomized patients who received at least one dose of the investigational product and had both baseline and at least one post-baseline UPDRS part III total scores (efficacy set).…”

“…The clear similarities between PD and DLB [5] and the results of an initial series of cases [28] have indicated that zonisamide might be effective for the treatment of DLB patients with parkinsonism. In phase II [29] and III [30] clinical trials within this patient population, zonisamide was shown to improve parkinsonism, assessed by Unified Parkinson's Disease Rating Scale (UPDRS) part III total score, with a clear benefit on motor function compared with placebo. Furthermore, no notable differences in the incidence of psychiatric adverse events (AEs) were observed between the zonisamide and placebo groups.…”

“…The differences observed between the above two trials may be attributable to insufficient statistical power to detect changes in some of the parameters. Therefore, we performed a post hoc analysis of pooled data from the phase II and III trials [29,30] to further examine the efficacy and safety of zonisamide in DLB patients with parkinsonism using a larger sample size. Specifically, regarding efficacy, we aimed to determine whether zonisamide improves symptoms of parkinsonism, particularly, which motor symptoms improve with zonisamide, and whether zonisamide affects cognitive function.…”