Amantadine delayed release/extended release capsules significantly reduce OFF time in Parkinson's disease

Abstract

Maintaining consistent levodopa benefits while simultaneously controlling dyskinesia can be difficult. Recently, an amantadine delayed release/extended release (DR/ER) formulation (Gocovri^®) indicated for dyskinesia received additional FDA approval as an adjunct to levodopa for the treatment of OFF episodes. We evaluated OFF time reductions with amantadine-DR/ER in a pooled analysis of two phase III amantadine-DR/ER trials (NCT02136914, NCT02274766) followed by a 2-year open-label extension trial (NCT02202551). OFF outcomes were analyzed for the mITT population, as well as stratified by baseline OFF time of ≥2.5 h/day or <2.5 h/day. At Week 12, mean placebo-subtracted treatment difference in OFF time was -1.00 [-1.57, -0.44] h in the mITT population (n = 196), -1.2 [-2.08, -0.32] h in the ≥2.5 h subgroup (n = 102) and -0.77 [-1.49, -0.06] in the <2.5 h subgroup (n = 94). Amantadine-DR/ER-treated participants showed reduced MDS-UPDRS Part IV motor fluctuation subscores by week 2 that were maintained below baseline to Week 100.

Fig. 1. Patient disposition.

*Completed double-blind trial or were active in EASE LID which was stopped early by the sponsor to accelerate data submission to the US Food and Drug Administration. All randomized patients had the opportunity to complete their week 12 trial visit (time of primary efficacy assessment). **An additional 78 patients (not included in the analyses) were enrolled, n = 17 who participated in a phase II dose-finding trial and later enrolled in EASE LID 2 after a gap in amantadine-DR/ER therapy, and n = 61 who had DBS and did not participate in double-blind trials. *** Seven participants (n = 3 who received placebo and n = 4 who received amantadine-DR/ER in double-blind pivotal trials experienced a gap in treatment before entering the open-label trial. For purposes of these analyses we have included them with their original double-blind treatment groups.

Fig. 2. LS Mean (SE) Change from Baseline to Week 12 in OFF time.

Data are for the mITT population and stratified by baseline OFF time (≥2.5 h and < 2.5 h subgroups). P-values are based on comparisons between amantadine DR/ER versus placebo from an MMRM model with change from baseline as the dependent variable and baseline values as a covariate. The model includes categorical effects for treatment group, study, and visit (weeks 2, 8, and 12), and the interaction between treatment group and visit.

Fig. 3. MDS UPDRS Part 4 Motor Fluctuations Subscores through the double-blind and open-label trials for (a) mITT population and (b) ≥ 2.5 h subgroup.

Motor Fluctuations Subscore = MDS-UPDRS items 4.3 (time spent in OFF state) +4.4 (functional impact of fluctuations) + 4.5 (complexity of motor fluctuations) +4.6 (OFF state dystonia). For double-blind weeks 2, 8, and 12, P-values are based on the comparison between amantadine DR/ER vs. placebo from the MMRM model (n = 196 for mITT and n = 102 for ≥ 2.5 h subgroup) with change from baseline as the dependent variable and baseline as a covariate, with categorical effects for treatment group, study, and visit (Weeks 2, 8, and 12), and the interaction between treatment group and visit. L = Last on study visit.