Levodopa Added to Stroke Rehabilitation
Stefan T. Engelter, Josefin E. Kaufmann, Annaelle Zietz, Andreas R. Luft, Alexandros A. Polymeris, Valerian Altersberger, Karin Wiesner, Martina Wiegert, Jeremia P. O. Held, Yannik Rottenberger, Anne Schwarz, Friedrich Medlin, Ettore Accolla, Sandrine Foucras, Georg Kägi, Gian Marco De Marchis, Svetlana Politz, Matthias Greulich, Alexander A. Tarnutzer, Rolf Sturzenegger, Mira Katan, Urs Fischer, Krassen Nedeltchev, Janine Schär, Katrien Van Den Keybus Deglon, Pierre-André Rapin, Alexander Salerno, David J. Seiffge, Elias Auer, Julian Lippert, Leo H. Bonati, Corina Schuster‐Amft, Szabina Gäumann, Joëlle Nsimire Chabwine, Andrea M. Humm, Jens Carsten Möller, Raoul Schweinfurther, Bartosz Bujan, Piotr Jedrysiak, Peter S. Sándor, Roman Gonzenbach, Veit Mylius, Dietmar Lutz, Carmen Lienert, Nils Peters, Patrik Michel, René M. Müri, Sabine Schädelin, Lars G. Hemkens, Gary A. Ford, Philippe Lyrer, Henrik Gensicke, Christopher Traenka, ESTREL Investigators, Krassen Nedeltchev, Timo Kahles, Sandra Clarke, Catharina Fritz-Rochner, Alexander A. Tarnutzer, Loric Berney, Manuela Buehrer, Karin Diserens, Alexandra Dos Reis Moreira, Grégoire Eberle, Ashraf Eskandari, Melissa Esteves, G. Hafner, Errikos Maslias, Patrik Michel, Pierre-André Rapin, Suzette Rémillard, Alexander Salerno, Davide Strambo, Guillaume Thévoz, Katrien Van Den Keybus Deglon, Elodie Cottier, Aline Duc, Sandrine Foucras, Friedrich Medlin, Martine Rime, Romain Stohr, Sabine Spring, Barbara Bleuler, Marion Huser, Joelle Keller, Fabienne Maibach, Maja Müller, Nils Peters, Steven Rieger, Janine Schär, Shadi Taheri, Carina Wehrli, Sereina Zwissler, Marcel Arnold, Elias Auer, Morin Beyeler, Anna Boronylo, Yvonne Brückner, Christine Brülisauer, Leander Clénin
Abstract
Importance: Levodopa enhances dopaminergic signaling and may stimulate neuroplasticity, which could potentially enhance motor recovery after stroke. Levodopa is used in stroke rehabilitation despite mixed evidence for its effectiveness. Objective: To determine whether levodopa compared with placebo, administered in addition to standardized rehabilitation based on active task-oriented training, is associated with enhanced motor recovery in patients with acute stroke. Design, Setting, and Participants: A double-blind, placebo-controlled randomized clinical trial at 13 stroke units and centers and 11 collaborating rehabilitation centers in Switzerland. Between June 14, 2019 (first patient, first visit), and August 27, 2024 (last patient, last visit), 610 patients with acute ischemic or hemorrhagic stroke with clinically meaningful hemiparesis (ie, a total score of ≥3 points on the following National Institutes of Health Stroke Scale items: motor arm, motor leg, or limb ataxia) were randomized 1:1 to receive levodopa or placebo. Statistical analyses were conducted from November 2024 to August 2025. Intervention: Patients received levodopa/carbidopa (100 mg/25 mg; n = 307) or placebo (n = 303) 3 times daily for 39 days, alongside standardized rehabilitation therapy based on active task-oriented training. Main Outcomes and Measures: The primary outcome was the adjusted mean between-group difference in the Fugl-Meyer Assessment (FMA) total score (range, 0-100 points; fewer points indicate worse motor function; 6-point difference considered patient-relevant) at 3 months. Results: Among the 610 participants (median [IQR] age, 73 [64-82] years; 252 [41.3%] female; median baseline FMA total score, 34 [14-54]), 28 participants died by 3 months, leaving 582 (95.4%) participants eligible for the primary analysis. At 3 months, the median (IQR) FMA total score was 68 (42-85) points in the levodopa group and 64 (44-83) points in the placebo group. The mean difference in the FMA total score between the levodopa and placebo groups was -0.90 points (95% CI, -3.78 to 1.98; P = .54). There were 126 serious adverse events in the levodopa group and 129 in the placebo group; the most common was infection (levodopa, n = 55; placebo, n = 44). Conclusions and Relevance: In this randomized clinical trial, among patients receiving inpatient rehabilitation for acute stroke, levodopa added to standardized rehabilitation did not significantly improve motor function at 3 months compared with placebo plus standardized rehabilitation. These results do not support the use of levodopa as an adjunct to rehabilitation therapy for enhancing motor recovery after acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03735901.