Effect on Dyskinesia of the Early Combination of Amantadine to Levodopa‐Therapy in Parkinson's Disease: A Randomized, Placebo‐Controlled Study ( PREMANDYSK )
2 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
3 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
4 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
5 University of Otago [Dunedin, Nouvelle-Zélande]
6 NorDic - Neuroendocrine, Endocrine and Germinal Differentiation Communication
7 CHU Rouen
8 LilNCog - Lille Neurosciences & Cognition - U 1172
9 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
10 INT - Institut de Neurosciences de la Timone
11 TIMONE - Hôpital de la Timone [CHU - APHM]
12 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
13 Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]
14 EpiMaCT - Epidémiologie des Maladies Chroniques en zone tropicale
15 CHU Limoges
16 Service Pharmacologie Clinique [CHU Toulouse]
17 CIC Montpellier
18 CHU Montpellier = Montpellier University Hospital
19 CIC Nantes - Centre d’Investigation Clinique de Nantes
20 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
21 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
22 HUS - Hôpitaux Universitaires de Strasbourg
23 CHU Clermont-Ferrand
24 IP - Institut Pascal
25 CHIAP - Centre Hospitalier d'Aix en Provence [Aix-en-Provence]
26 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
27 INCIA - Institut de Neurosciences cognitives et intégratives d'Aquitaine
28 ICM - Institut du Cerveau = Paris Brain Institute
29 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
30 Université de Lyon
31 CIC 1402 - CIC de Poitiers – Centre d'investigation clinique de Poitiers (CIC 1402)
32 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
33 ULISBOA - Universidade de Lisboa = University of Lisbon = Université de Lisbonne [Lisboa]
34 Newcastle University [Newcastle]
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Résumé
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.
