Amantadine Immediate Release Lowers Dyskinesia Risk in Early Parkinson Disease, Study Shows

A 22-month, multicenter, randomized, placebo-controlled, phase 2 trial (NCT01538329) evaluating immediate-release (IR) amantadine as an add-on to levodopa in patients with early Parkinson Disease (PD) found that adjunctive amantadine-IR reduced peak-dose dyskinesia incidence by 50% over 18 months in treated patients. Despite the benefit, there remained questions about the long-lasting mechanisms of amantadine-IR, and thus, investigators concluded more testing is needed.¹

Led by Olivier Rascol, MD, PhD, professor of pharmacology at Toulouse University in France, the trial enrolled 207 early PD patients on stable levodopa (≥150 mg/day for ≤1 year) who had not yet experienced motor complications. The study included 3 double-blind phases: an 18-month treatment phase with adjunct amantadine-IR (200 mg/day; n = 99) or placebo (n = 108; Period 1), a 3-month delayed-start phase where all participants received amantadine-IR (Period 2), and a 1-month washout with placebo (Period 3).

The primary outcome was dyskinesia incidence at month 18 while secondary outcomes included dyskinesia rates at the end of Periods 2 and 3 to assess potential long-lasting mechanisms. Exploratory outcomes investigated the potential effects of amantadine-IR on motor and non-motor symptoms and the quality of life.

Published in Movement Disorders, the trial found significantly fewer patients in the amantadine-IR group developed dyskinesia versus placebo during Period 1 (11% vs. 22%, P = 0.025). Throughout the study, the mean daily dose of levodopa increased 70 mg less in the amantadine-IR group compared with placebo (95% CI 21–119 mg; P = 0.005). At the end of Periods 2 and 3, dyskinesia rates remained lower in the amantadine-IR group, but differences were not statistically significant (Period 2: 12% vs 20%, P = 0.13; Period 3: 16% vs 22%, P = 0.23). Notably, mild but significant improvements in freezing of gait, fatigue, and quality of life were also observed during Period 1, and the safety profile of amantadine-IR was consistent with previous reports.

“The PREMANDYSK trial provides novel data that encourage further studies on amantadine-IR in the early stage of PD as a strategy to delay the onset of Levodopa-induced peak-dose dyskinesias (LID),” the study authors noted.¹ “If confirmed, such a strategy would offer an alternative to the early use of dopamine agonist monotherapy, an approach which has been steadily losing favor. Our findings also support the concept that the effects of amantadine-IR on PD symptoms poorly responding to dopaminergic medications, such as fatigue and freezing of gait, may deserve further investigation.”

Watch More: Recent Advancements in Parkinson Disease Treatment Options

Although fewer participants experiencing LID at the end of each period in the group on amantadine-IR from the beginning of the trial, secondary outcomes of period 2 and 3 indicated there were no significant differences between the groups (amantadine-IR vs. placebo) in the proportion of participants who experienced LID at the end of Period 2 (P = 0.13) or Period 3 (P = 0.23).

There were no differences in the rates of AEs, serious AEs, or treatment-related AEs between treatment groups during Period 1, with most participants (92% on amantadine-IR and 89% on placebo) reporting at least 1 AE. Treatment-related AEs of dry mouth (9% vs. 1%), hallucinations (12% vs. 6%), and livedo reticularis (4% vs. 1%) were more common on amantadine-IR. No serious AEs occurred in at least 1 amantadine-IR-treated participant and no participants died during the study. The only serious AE considered related to amantadine-IR treatment was persecutory delusion.

Interest in amantadine IR is continuing to grow following these phase 2 trial results. This follows the success of the delayed-release/extended-release (DR/ER) formulation, which is the only FDA-approved therapy for both dyskinesia and “off” time in PD. Taken at bedtime, the DR/ER version uses delayed-release pellets to avoid sleep disruption, maintaining therapeutic levels throughout the day while gradually declining toward the evening, sustaining efficacy.

A recently launched NeurologyLive segment highlighted how the DR/ER formulation influences clinical decision-making, particularly in patients with both dyskinesia and “off” time. The discussion focused on a 54-year-old woman with PD and dyskinesia who had a favorable profile; younger age, good cognitive function, and no hallucinations, psychosis, or impulse control disorders. For patients with minimal “off” time, clinicians may first reduce medication, whereas those with significant “off” time require strategies that address both dyskinesia and “off” periods simultaneously.

REFERENCES
1. Rascol, O., Ory-Magne, F., Meissner, W.G., et al. Effect on Dyskinesia of the Early Combination of Amantadine to Levodopa-Therapy in Parkinson's Disease: A Randomized, Placebo-Controlled Study (PREMANDYSK). Mov Disord. 2025; Doi: 10.1002/mds.70120