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. 2025 Nov 29.
doi: 10.1002/mds.70120. Online ahead of print.

Effect on Dyskinesia of the Early Combination of Amantadine to Levodopa-Therapy in Parkinson's Disease: A Randomized, Placebo-Controlled Study (PREMANDYSK)

Olivier Rascol  1   2 , Fabienne Ory-Magne  1   2 , Wassilios G Meissner  1   3   4 , David Maltête  1   5 , Luc Defebvre  1   6 , Jean-Philippe Azulay  1   7 , Stéphane Thobois  1   8   9 , Jean-Luc Houeto  1   10 , Claire Thalamas  2 , Agnès Sommet  2 , Christian Geny  1   11 , Philippe Damier  1   12 , Mathieu Anheim  1   13   14 , Ana Marquès  1   15 , François Viallet  1   16 , Maurice Giroud  1   17 , Romain Lefaucheur  1   18 , Guillaume Costentin  1   18 , Umberto Spampinato  1   3   19 , Alexandra Samier-Foubert  1   3 , Nicolas Carrière  1   6 , Eugénie Mutez  1   6 , Louise-Laure Mariani  1   20 , Alexandre Eusebio  1   7 , Stéphane Prange  1   8 , Isabelle Benatru  1   21 , Mahmoud Charif  1   11 , Christine Brefel-Courbon  1   2 , Margherita Fabbri  1   2 , Monique Galitzky  2 , Vanessa Rousseau  2 , Amandine Saubion  2 , Hélène Catala  2 , Joaquim J Ferreira  22 , David J Burn  23 , Jean-Christophe Corvol  1   20 ; PREMANDYSK Study Group
Collaborators, Affiliations

Effect on Dyskinesia of the Early Combination of Amantadine to Levodopa-Therapy in Parkinson's Disease: A Randomized, Placebo-Controlled Study (PREMANDYSK)

Olivier Rascol et al. Mov Disord. .

Abstract

Objective: Investigate the efficacy of immediate-release (IR) amantadine in reducing the risk of peak-dose dyskinesia in early Parkinson's disease (PD) as add-on to levodopa.

Background: While the use of amantadine to manage dyskinesia in PD is well supported by controlled clinical trials, data on its efficacy in patients without motor complications remain limited.

Methods: This 22-month, multicenter, randomized, placebo-controlled trial (NCT01538329) enrolled early PD patients on stable levodopa (≥150 mg/day for ≤1 year) without motor complications. The study included three double-blind phases: an 18-month treatment phase with adjunct amantadine-IR (200 mg/day) or placebo (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; secondary outcomes included dyskinesia rates at the end of Periods 2 and 3 to assess potential long-lasting mechanisms of the drug. Exploratory outcomes investigated the potential effects of amantadine-IR on motor and non-motor symptoms and quality of life.

Results: A total of 207 patients were randomized to amantadine-IR (N = 99) or placebo (N = 108). Significantly fewer patients in the amantadine-IR group developed dyskinesia versus placebo during Period 1 (11% vs. 22%, P = 0.025), while the mean daily dose of levodopa (95% CI) increased by 70 (21-119) mg less (P = 0.005). The proportion of patients with dyskinesia was less in the amantadine-IR group versus placebo at the end of Periods 2 and 3, but the difference was not statistically significant (12% vs. 20%, P = 0.13 and 16% vs. 22%, P = 0.23, respectively). Mild but significant positive effects on freezing of gait, fatigue, and quality of life were observed during Period 1. The safety profile of amantadine-IR was in line with previous reports.

Conclusions: Adjunctive amantadine-IR in early PD halved dyskinesia incidence over 18 months. Long-lasting mechanisms could not be demonstrated and merit further investigation. Exploratory positive findings on the potential benefit of amantadine-IR on symptoms like freezing of gait and fatigue also call for further investigation. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; amantadine; dyskinesia; levodopa.

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References

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