Adjunct zonisamide to levodopa for DLB parkinsonism

Abstract

ObjectiveTo investigate the efficacy and safety of zonisamide as an adjunct to levodopa therapy for parkinsonism in patients with dementia with Lewy bodies (DLB).MethodsThis 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.ResultsOverall, 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.ConclusionZonisamide (adjunctive to levodopa) improved parkinsonism accompanying DLB without worsening cognitive function or psychiatric symptoms.Clinical trial registrationJapicCTI-122040.Classification of evidenceThis study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB.

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

“…Our previous phase 2 trial of zonisamide for the treatment of parkinsonism in patients with DLB showed a significant change in UPDRS part III total score at Week 12 compared with placebo for the 50-mg dose but not the 25-mg dose [16]. Here, we report that both doses of zonisamide were superior to placebo, with a significant improvement in UPDRS part III total score observed in both groups at Week 12.…”

“…MMSE total score at Week 12 decreased significantly (−0.8) from baseline in the 50-mg group, suggesting a negative effect of zonisamide 50 mg/day on cognitive function. In our previous phase 2 trial [16], however, MMSE total score increased (+0.5) in the 50-mg group, indicating a between-trial variability of 1.3. The mean change in the placebo group ranged from −0.4 to 0.0 points in the present trial and the phase 2 trial; in other previously reported randomized clinical trials in patients with DLB [21,22], the change ranged from −0.4 to 0.6 points in the placebo groups.…”

“…For the baseline levodopa/decarboxylase inhibitor treatment in this trial, dose reduction was permitted during the trial only if AEs, such as psychiatric symptoms, occurred; dose reescalation was prohibited. Other inclusion/exclusion criteria and prohibited and restricted concomitant medications were the same as reported previously in the associated phase 2 trial [16].…”

“…Given that DLB and PD are considered to lie within the same disease spectrum as Lewy body disease, zonisamide is considered likely to be effective for the treatment of parkinsonism in patients with DLB. Therefore, we previously conducted an exploratory phase 2 trial to evaluate the efficacy and safety of zonisamide in this patient population [16]. We found a significant improvement in motor dysfunction in the 50-mg/day group compared with placebo.…”

Evaluation of Medicinal Effects of Isoxazole Ring Isosteres on Zonisamide for Autism Treatment by Binding to Potassium Voltage-Gated Channel Subfamily D Member 2 (Kv 4.2)

“…Zonisamide later received its FDA approval as an adjuvant treatment for partial seizures in 2000. Over the years, the ameliorative effect of this drug in both partial and generalized seizures [2][3][4][5][6][7] as well as several other neurological disorders namely, psychotic conditions [8], Parkinson disease [9][10][11][12][13], neuropathic pain [14] and essential tremor [15] have been investigated. Although the precise mechanism of Zonisamide has not yet fully understood, blockage of voltagegated sodium channels and T-type calcium channels seems to be the principle route of action.…”