Objective: To assess amantadine effects on dyskinesia and other PD symptoms when adjunct to L-DOPA in early PD.

Background: Amantadine is efficacious on L-DOPA-induced dyskinesia in advanced PD, but its effect on motor and non-motor symptoms/complications remains poorly known when used at earlier stages.

Method: The effects of amantadine (200 mg/d adjunct within the first year of L-DOPA-therapy in patients with early PD free of motor complications) was tested in a double-blind 18-month placebo-controlled randomised trial (Phase 1), followed by a 3-month delayed-start (Phase 2) and a 1-month wash-out (Phase 3) design. Primary outcome was the proportion of dyskinetic patients at month-18. Secondary outcomes were the proportion of dyskinetic patients at the end of Phases 2 and 3 to assess putative symptomatic or disease modifying effects. Exploratory outcomes included the occurrence of motor fluctuations and changes from baseline to 18-month in L-DOPA dose and motor/non-motor symptoms.

Results: 207 patients were randomised to amantadine (n=99) or placebo (n=108) [age=62 yrs; 3 yrs from PD diagnosis; 8 months on L-DOPA (305 mg/d); MDS-UPDRS 3=15]. At month-18, the proportion of dyskinetic patients (primary outcome) was significantly lower on amantadine than placebo (11% vs 22%, p=0.02). Proportions remained lower (although non-significantly) at the end of Phase 2 (11% vs 20%, p=0.14) and 3 (16% vs 22%, p=0.20). At month-18, mean L-DOPA dose had increased more on placebo than amantadine (+95±177mg/d vs +41±158, p=0.005). At the same time, freezing of gait (Giladi et al, 2000), fatigue (Brown et al, 2005) and quality of life (PDQ-8) scores had increased less on amantadine (p=0.002; p=0.027; p=0.013 respectively). There was no difference at month-18 in the proportion of patients with motor fluctuations and in changes from baseline in MDS-UPDRS, cognitive and behavioural scores. The safety profile of amantadine was in line with previous reports in PD.

Conclusion: Combining amantadine to L-DOPA in early PD reduced by 50% the occurrence of dyskinesia after 18 months of follow-up. A long-term “disease-modifying” effect was not demonstrated but could not be ruled out. At month-18, freezing of gait, fatigue and quality of life outcomes had deteriorated significantly less on amantadine while L-DOPA daily dose had increased more on placebo.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/decreased-occurrence-of-dyskinesia-when-combining-amantadine-to-l-dopa-in-early-parkinson-disease-pd-the-premandysk-trial/