Safinamide as an adjunct to levodopa monotherapy in Asian patients with Parkinson's disease experiencing early wearing-off: a pooled analysis of the J-SILVER and KEEP studies

Abstract

Background: Limited trials are evaluating the efficacy of monoamine oxidase B inhibitors as an adjunct to levodopa monotherapy for early wearing-off in Parkinson's disease (PD). We evaluated the efficacy and safety of safinamide in patients with fluctuating PD treated with levodopa monotherapy.

Methods: This pooled analysis used data from the J-SILVER and KEEP studies and targeted patients with PD experiencing wearing-off who received safinamide as adjunct to levodopa monotherapy. Efficacy endpoints were mean changes in 39-item Parkinson's Disease Questionnaire (PDQ-39), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts III and IV, and daily OFF time at 18 weeks of treatment.

Results: Of 54 patients (J-SILVER, N = 24; KEEP, N = 30), 41 completed the studies. Although not statistically significant, the change in PDQ-39 Summary Index exceeded the minimal clinical important difference (mean [standard deviation (SD)]: -2.2 [7.5], p = 0.094) at Week 18. Significant improvements in MDS-UPDRS Parts III and IV scores and daily OFF time were observed at Week 18 from baseline (mean [SD]: -2.8 [8.5]; p = 0.043, -1.3 [2.7]; p = 0.004, and -1.2 [3.5] hours; p = 0.041, respectively). Adverse events occurred in 24 patients (43.6%) and adverse drug reactions (ADRs) occurred in 12 patients (21.8%). ADRs with an incidence ≥5% were dyskinesia (3 events, 5.5%). In subgroup analyses, improvements in PDQ-39 Summary Index and MDS-UPDRS Parts III and IV were significant in patients aged ≥75 years (p = 0.039, p = 0.029, and p = 0.025, respectively).

Conclusion: Safinamide as an adjunct to levodopa monotherapy was effective for early wearing-off without any new tolerability concerns. Safinamide was particularly beneficial in elderly patients.

Keywords: MAO-B inhibitor; Parkinson’s disease; early wearing-off; elderly; safinamide; sodium channel blocker.

Figure 1

Effect of patient characteristics on change from baseline at Week 18 for (A) PDQ-39 Summary Index, (B) MDS-UPDRS Part III, (C) MDS-UPDRS Part IV, and (D) daily OFF time. Plots show means and error bars show 95% confidence intervals. The leftward trend indicates improvement. CI, confidence interval; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; PDQ-39, 39-item Parkinson’s Disease Questionnaire.

Figure 2

Radar plots evaluating the effect of patient characteristics on PDQ-39 Summary Index items. The mean change from baseline at Week 18 is plotted. A vertex in the orange area indicates improvement. The outward direction indicates greater improvement. (A) Age, (B) sex, (C) disease duration, and (D) daily levodopa dose at baseline. ADL, activities of daily living; PDQ-39, 39-item Parkinson’s Disease Questionnaire. *p < 0.05 compared with baseline.

Figure 3

Path analysis investigating the relationship between variables at baseline and changes in the PDQ-39 Summary Index, MDS-UPDRS Part III and Part IV, and KPPS total score at Week 18. The number above the arrow represents the standardized path coefficient, which represents the effect of the variables at the start of the arrow on the variables at the end of the arrow. (A) Path analysis of variables at baseline (CFI = 1, RMSEA [90% CI] = 0 [0, 0]); (B) path analysis of variable change at baseline and at 18 weeks (CFI = 0.889, RMSEA [90% CI] = 0.083 [0.022, 0.177]). *p < 0.05, **p < 0.01. CI, confidence interval; CFI comparative fit index; KPPS, King’s Parkinson’s Pain Scale; MDS-UPDRS, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; PDQ-39, 39-item Parkinson’s Disease Questionnaire; RMSEA, root mean square error of approximation.