DISCUSSION
parkinsonism, DLB, PDD, Lewy body disease, delusions, visual hallucinations, PD, motor dysfunction, mood improvements, BPSD, depression, drooling, apathy
PARKINSONISM, LEWY BODY DISEASE, RECRUITMENT, DYSFUNCTION, SECONDARY
This study aimed to demonstrate whether the efficacy of a zonisamide add-on dose of 25 mg/day on motor dysfunction was non-inferior to a 100 mg/day levodopa dose increase for 24 weeks in patients with DLB with a history of visual hallucinations or delusions who were receiving ≤300 mg/day of levodopa for parkinsonism. Although the target sample size was 130 patients, the analysis was conducted using data from 61 patients because of impaired recruitment as a result of the COVID-19 pandemic. In this study, the non-inferiority margin for the primary endpoint, adjusted mean change from baseline in the MDS-UPDRS Part III total score at 24 weeks, was reached in the zonisamide add-on group. There were no statistically significant differences between the two groups in the total scores of the secondary endpoints. Patients in the zonisamide add-on group showed significant improvement in specific MDS-UPDRS Part II sub-items, including saliva and drooling, dressing, and eating tasks at 24 weeks compared with the levodopa increase group. No worsening of MMSE, NPI-12 scores, cognitive function, or BPSD was observed in either group. Additionally, no notable differences were observed in the incidences of AEs between the two groups. The number of ADRs, serious ADRs, and ADRs leading to discontinuation in the zonisamide add-on group tended to be smaller than in the levodopa increase group.The adjusted mean difference between the two groups of the MDS-UPDRS Part III total score at 24 weeks in the PP population was –6.4, and the upper limit of the 95% CI (0.7) was lower than the non-inferiority margin of 3.0. Based on this result, the zonisamide add-on dose was non-inferior to the levodopa dose increase. The adjusted mean changes from the baseline MDS-UPDRS Part III total score at 16 and 24 weeks in the zonisamide add-on group (–6.3 and –4.4) were similar to previous reports, with a decrease in treatment effect from 16 to 24 weeks [No appropriate studies have compared levodopa escalation with another adjunctive antiparkinsonian drug or placebo; thus, historical comparisons with previous studies are limited because of differences in study design and patient population. The response rate to an increased dose of 100 mg/day levodopa for motor symptoms was similar to previous studies [There have been no reports on the minimal clinically important difference (MCID) for changes in parkinsonism in patients with DLB. However, a study of 653 patients with PD reported that the estimated minimal, moderate, and large clinically relevant differences in UPDRS Part III total score (MDS-UPDRS Part III total score equivalent) were –2.5, –5.2, and –10.8, respectively [Comparing this study with previous studies of zonisamide in patients with DLB developing parkinsonism [In patients with Lewy body disease (PDD and DLB), it has been reported that the total MMSE score changed by –1.3, the total NPI-12 score remained unchanged, and the UPDRS Part III total score (MDS-UPDRS equivalent) increased by 3.2 (3.8) during 6-month follow-up [It can be difficult to interpret speech results in MDS-UPDRS Part II and Part III, as there are discrepancies between them. Interestingly, speech in MDS-UPDRS Part III was improved in the zonisamide add-on group, whereas speech in MDS-UPDRS Part II was improved in the levodopa increase group. The reason for this difference is unclear. It is worth noting that the levodopa group had greater reductions in NPI depression and apathy scores compared with the zonisamide group. This suggests that mood improvements might play a role in the improvement in speech seen in the levodopa group in MDS-UPDRS Part II. Another possible explanation is that a type 1 error is likely to occur because no correction for repeated comparisons was made due to the exploratory analysis.Another highly important finding was that zonisamide significantly improved the MDS-UPDRS Part II sub-items of saliva and drooling (The zonisamide add-on group showed a numerical improvement in motor dysfunction, and the non-inferiority of zonisamide add-on to the levodopa dose increase was demonstrated by statistical testing. However, the levodopa increase group did not significantly reduce the MDS-UPDRS Part III total score at 24 weeks as expected. Therefore, the analytical sensitivity of the non-inferiority test (the ability to identify the test drug’s efficacy) was insufficient. There is another concern that an increase 100 mg/day of levodopa may have been too small to evaluate the equivalence/superiority of zonisamide. Further studies are required to verify non-inferiority or superiority.This study has some limitations that should be considered when interpreting the findings. First, although a third party unaware of the study conducted the evaluations, it is impossible to completely rule out measurement bias because this was not a double-blind comparative study. Second, because of the COVID-19 pandemic, the planned number of subjects could not be enrolled, and hence the study was underpowered to detect the desired between-group differences. Finally, the efficacy of the levodopa increase could not be confirmed because the increase of levodopa as a control drug dose was limited to100 mg/day.In conclusion, in patients with parkinsonism in DLB with a history of visual hallucinations or delusions treated with ≤300 mg/day of levodopa, a zonisamide add-on dose of 25 mg/day may be useful when the levodopa effect is insufficient. However, it cannot be clearly stated that effectiveness is verifiable from these results alone; a large, double-blind, comparative trial will be needed to verify the efficacy of this treatment approach.