Potential utility of amantadine DR/ER in persons with Parkinson's disease meeting 5-2-1 criteria for device aided therapy

Abstract

Background: The 5-2-1 criteria (≥5 levodopa doses/day, ≥2 h OFF/day, and ≥ 1-hour dyskinesia/day) propose to identify people with Parkinson's disease (PD) who are poorly controlled on oral therapies and who may therefore benefit from device-aided therapies. Amantadine-DR/ER is the only medication FDA-approved for both dyskinesia and OFF episodes in levodopa-treated patients. In this post-hoc analysis of phase 3 clinical trials, we evaluated the efficacy and safety of amantadine-DR/ER in patients meeting 5-2-1 criteria.

Methods: Week-12 treatment differences (Amantadine-DR/ER - placebo) in the Unified Dyskinesia Rating Scale (UDysRS) and PD motor states (patient diaries) were evaluated in pooled, phase-3, double-blind trial participants meeting 5-2-1 criteria at baseline. This 5-2-1 cohort was followed into a 2-year open-label trial, where Movement Disorder Society - Unified Parkinson's Disease Rate Scale (MDS-UPDRS) Part IV scores were assessed relative to double-blind baseline.

Results: Of 198 enrolled participants in the phase 3 trials, 65 (33%; n = 29 placebo; n = 36 amantadine-DR/ER) comprised the 5-2-1 cohort. At Week-12 endpoint, amantadine-DR/ER significantly improved UDysRS scores (treatment difference of 9.57 ± 3.15 points, p = 0.004) and ON time without troublesome dyskinesia ('good ON', treatment difference of 2.9 ± 0.90 h/day, p = 0.002). Improvements in good ON time resulted from significant reductions in both troublesome dyskinesia and OFF time. Treatment benefit on MDS-UPDRS-Part IV was sustained through open-label, follow-up. The most common adverse events in patients who met 5-2-1 criteria and were treated with amantadine-DR/ER included falls and peripheral edema.

Conclusions: Findings suggest Amantadine-DR/ER should be considered as an option for people with PD who meet 5-2-1 criteria.

Keywords: 5-2-1 criteria; Amantadine; Dyskinesia; OFF time; ON time; Parkinson’s disease; Treatment.

Fig. 1

LS Mean Change from baseline in efficacy parameters during double-blind treatment for patients meeting all three 5–2-1 criteria (a) Unified Dyskinesia Rating Scale (UDysRS), (b) Changes good ON time versus OFF time + ON time with troublesome dyskinesia, based on PD diaries (c) Clinician’s Global Impression of Change (CGI-C) in overall Parkinson’s disease symptoms ratings by Treatment Group. *p < 0.05, **p < 0.01 versus placebo, analysed using MMRM for UDysRS and PD Diary measures and CMH for CGI-C. Good ON is defined as ON time without troublesome dyskinesia. AMT DR/ER: amantadine DR/ER. ONTD: ON with troublesome dyskinesia.