. 2025 Sep 22:e2515185.

doi: 10.1001/jama.2025.15185. Online ahead of print.

Levodopa Added to Stroke Rehabilitation: The ESTREL Randomized Clinical Trial

Stefan T Engelter^{1

2}, Josefin E Kaufmann^{1

2}, Annaelle Zietz^{1

2}, Andreas R Luft^{3

4}, Alexandros Polymeris^{2

5}, Valerian L Altersberger^{2

6}, Karin Wiesner¹, Martina Wiegert^{1

2}, Jeremia P O Held^{3

7}, Yannik Rottenberger³, Anne Schwarz^{3

8}, Friedrich Medlin⁹, Ettore A Accolla⁹, Sandrine Foucras⁹, Georg Kägi^{10

11}, Gian Marco De Marchis¹⁰, Svetlana Politz¹², Matthias Greulich^{13

14}, Alexander A Tarnutzer^{15

16}, Rolf Sturzenegger¹⁷, Mira Katan², Urs Fischer¹⁸, Krassen Nedeltchev¹⁹, Janine Schär²⁰, Katrien Van Den Keybus Deglon²¹, Pierre-André Rapin²², Alexander Salerno²³, David J Seiffge¹⁸, Elias Auer¹⁸, Julian Lippert¹⁸, Leo H Bonati^{2

24}, Corina Schuster-Amft^{24

25

26}, Szabina Gäumann²⁴, Joelle N Chabwine^{27

28}, Andrea Humm⁹, J Carsten Möller^{27

29}, Raoul Schweinfurther²⁹, Bartosz Bujan³⁰, Piotr Jedrysiak³⁰, Peter S Sandor³¹, Roman Gonzenbach³², Veit Mylius³², Dietmar Lutz³², Carmen Lienert³², Nils Peters²⁰, Patrik Michel²³, René M Müri^{11

33}, Sabine Schädelin³⁴, Lars G Hemkens^{34

35

36}, Gary A Ford³⁷, Philippe A Lyrer², Henrik Gensicke^{1

2}, Christopher Traenka^{1

2}; ESTREL Investigators

Collaborators, Affiliations

Collaborators

ESTREL Investigators:
Krassen Nedeltchev, Timo Kahles, Sandra Clarke, Catharina Fritz-Rochner, Alexander Tarnutzer, Loric Berney, Manuela Buehrer, Karin Diserens, Alexandra Dos Reis Moreira, Grégoire Eberle, Ashraf Eskandari, Melissa Esteves, Gaël Hafner, Errikos Maslias, Patrik Michel, Pierre-André Rapin, Suzette Remillard, Alexander Salerno, Davide Strambo, Guillaume Thevoz, 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, Boudewijn Drop, Julie Hanke, Eveline Kaufmann, Marianne Kormann, Martin Lange, Christina Leistner, Basel Maamari, Liselotte McEvoy, Madlaine Müller, René Müri, Janis Patricia Rauch, Jasmin Schlatter, Adrian Scutelnic, Bernhard Matthias Siepen, Norbert Silimon, Vasileios Tentolouris Piperas, Jan Vynckier, Johanna Weghorn, Valerian Altersberger, Nikolaos Symeon Avramiotis, Lea Barone, Lukas Boos, Eveline Brunner, Gian Marco De Marchis, Stefan Engelter, Fabina Engelter, Sophia Engelter, Sandro Fischer, Joachim Fladt, Henrik Gensicke, Jasmine Jost, Mira Katan, Josefin Kaufmann, Wilma Kamerbeek Verhagen, Martin Lucht, Philippe Lyrer, Yasmin Liechti, Marina Maurer, Louisa Meya, Daniela Minio, Lukas Nussbaum, Larissa Nussbaumer, Ines Piot, Alexandros Polymeris, Flavia Ravanelli, Mirjam Sauter, Iris Schneider, Christopher Tränka, Simon Trüssel, Benjamin Wagner, Martina Wiegert, Karin Wiesner, Céline Zbinden, Annaelle Zietz, Meret Branscheidt, Ioannis Georgiou, Christoph Globas, Marcellina Haeberlin, Jeremia Held, Eva Heusi-Thürlimann, Aurelia Lehmann, Andreas Luft, Theodor Pipping, Johannes Pohl, Todor Popov, Yannik Rottenberger, Anne Schwarz, Juliane Schweizer, Ursula Surbeck, Jannie van Duinen, Janne Veerbeek, Susanne Wegener, Rolf Sturzenegger, Sylvan Albert, Christa Caflisch, Markus Baumgaertner, Svetlana Politz, Ludwig Schelosky, Vjosa Iljazi, Georg Kägi, Anna Müller, Jochen Vehoff, Fabian Engelter, Matthias Frank, Claire Liniger, Vera Paltzer, Annick Voeste, Frank Behrendt, Leo Bonati, Heiner Brunnschweiler, Thierry Ettlin, Szabina Gäumann, Sarah Hermann, Corina Schuster-Amft, Zorica Suica, Niklaus Urscheler, Marco Eugster, Carmen Lienert, Roman Gonzenbach, Yuka Hasegawa, Manuela Marugg, Christine Meier Khan, Veit Mylius, Heike Rosemeyer

Affiliations

¹ Department of Rehabilitation and Neurology, University Department of Geriatric Medicine FELIX PLATTER, University of Basel, Basel, Switzerland.
² Department of Neurology and Stroke Center, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
³ Division of Vascular Neurology and Neurorehabilitation, Department of Neurology, University Hospital of Zurich and University of Zurich, Zurich, Switzerland.
⁴ cereneo Center for Neurology & Rehabilitation, Vitznau, Switzerland.
⁵ Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
⁶ Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
⁷ Bellevue Medical Group, Zurich, Switzerland.
⁸ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California.
⁹ Service of Neurology and Stroke Unit, HFR Fribourg-Cantonal Hospital, Fribourg, Switzerland.
¹⁰ University Teaching and Research Hospital, Neurology Department & Stroke Center, HOCH Health Ostschweiz, Kantonsspital St Gallen, St Gallen, Switzerland.
¹¹ Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
¹² Kantonsspital Münsterlingen, Münsterlingen, Switzerland.
¹³ Kantonsspital Winterthur, Winterthur, Switzerland.
¹⁴ NeuroPraxis Zurich GmbH, Zurich, Switzerland.
¹⁵ Neurology, Cantonal Hospital of Baden, Baden, Switzerland.
¹⁶ Faculty of Medicine, University of Zurich, Zurich, Switzerland.
¹⁷ Kantonsspital Graubünden, Departement Innere Medizin, Neurologie, Chur, Switzerland.
¹⁸ Department of Neurology, University Hospital Bern, University of Bern, Bern, Switzerland.
¹⁹ Cantonal Hospital of Aarau and Department of Neurology, University of Bern, Bern, Switzerland.
²⁰ Department of Neurology and Stroke Center, Klinik Hirslanden, Zurich, Switzerland.
²¹ Acute Neurorehabilitation Unit, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²² Lavigny Rehabilitation Institution, Lavigny, Switzerland.
²³ Stroke Center, Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁴ Research Department, Reha Rheinfelden, Rheinfelden, Switzerland.
²⁵ School of Engineering and Computer Science, Bern University of Applied Sciences, Biel, Switzerland.
²⁶ Department for Sport, Exercise and Health, University of Basel, Basel, Switzerland.
²⁷ Division of Neurorehabilitation, Fribourg Hospital, Meyriez-Murten, Switzerland.
²⁸ Laboratory for Neurorehabilitation Science, Medicine Section, University of Fribourg, Fribourg, Switzerland.
²⁹ Rehaklinik Zihlschlacht AG, Zihlschlacht-Sittendorf, Switzerland.
³⁰ Neurorehabilitation, Klinik Lengg Zurich, Zurich, Switzerland.
³¹ Research Department, Rehaklinik Bad Zurzach, ZURZACH Care Group, Bad Zurzach, Switzerland.
³² Kliniken Valens, St Gallen, Switzerland.
³³ Gerontechnology and Rehabilitation Group, University of Bern, Bern, Switzerland.
³⁴ Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
³⁵ Pragmatic Evidence Lab, Research Center for Clinical Neuroimmunology and Neuroscience Basel, (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland.
³⁶ Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California.
³⁷ Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

PMID: 40982270
PMCID: PMC12455486 (available on 2026-03-22)
DOI: 10.1001/jama.2025.15185

Levodopa Added to Stroke Rehabilitation: The ESTREL Randomized Clinical Trial

Stefan T Engelter et al. JAMA. 2025.

. 2025 Sep 22:e2515185.

doi: 10.1001/jama.2025.15185. Online ahead of print.

Authors

Collaborators

ESTREL Investigators:
Krassen Nedeltchev, Timo Kahles, Sandra Clarke, Catharina Fritz-Rochner, Alexander Tarnutzer, Loric Berney, Manuela Buehrer, Karin Diserens, Alexandra Dos Reis Moreira, Grégoire Eberle, Ashraf Eskandari, Melissa Esteves, Gaël Hafner, Errikos Maslias, Patrik Michel, Pierre-André Rapin, Suzette Remillard, Alexander Salerno, Davide Strambo, Guillaume Thevoz, 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, Boudewijn Drop, Julie Hanke, Eveline Kaufmann, Marianne Kormann, Martin Lange, Christina Leistner, Basel Maamari, Liselotte McEvoy, Madlaine Müller, René Müri, Janis Patricia Rauch, Jasmin Schlatter, Adrian Scutelnic, Bernhard Matthias Siepen, Norbert Silimon, Vasileios Tentolouris Piperas, Jan Vynckier, Johanna Weghorn, Valerian Altersberger, Nikolaos Symeon Avramiotis, Lea Barone, Lukas Boos, Eveline Brunner, Gian Marco De Marchis, Stefan Engelter, Fabina Engelter, Sophia Engelter, Sandro Fischer, Joachim Fladt, Henrik Gensicke, Jasmine Jost, Mira Katan, Josefin Kaufmann, Wilma Kamerbeek Verhagen, Martin Lucht, Philippe Lyrer, Yasmin Liechti, Marina Maurer, Louisa Meya, Daniela Minio, Lukas Nussbaum, Larissa Nussbaumer, Ines Piot, Alexandros Polymeris, Flavia Ravanelli, Mirjam Sauter, Iris Schneider, Christopher Tränka, Simon Trüssel, Benjamin Wagner, Martina Wiegert, Karin Wiesner, Céline Zbinden, Annaelle Zietz, Meret Branscheidt, Ioannis Georgiou, Christoph Globas, Marcellina Haeberlin, Jeremia Held, Eva Heusi-Thürlimann, Aurelia Lehmann, Andreas Luft, Theodor Pipping, Johannes Pohl, Todor Popov, Yannik Rottenberger, Anne Schwarz, Juliane Schweizer, Ursula Surbeck, Jannie van Duinen, Janne Veerbeek, Susanne Wegener, Rolf Sturzenegger, Sylvan Albert, Christa Caflisch, Markus Baumgaertner, Svetlana Politz, Ludwig Schelosky, Vjosa Iljazi, Georg Kägi, Anna Müller, Jochen Vehoff, Fabian Engelter, Matthias Frank, Claire Liniger, Vera Paltzer, Annick Voeste, Frank Behrendt, Leo Bonati, Heiner Brunnschweiler, Thierry Ettlin, Szabina Gäumann, Sarah Hermann, Corina Schuster-Amft, Zorica Suica, Niklaus Urscheler, Marco Eugster, Carmen Lienert, Roman Gonzenbach, Yuka Hasegawa, Manuela Marugg, Christine Meier Khan, Veit Mylius, Heike Rosemeyer

Affiliations

¹ Department of Rehabilitation and Neurology, University Department of Geriatric Medicine FELIX PLATTER, University of Basel, Basel, Switzerland.
² Department of Neurology and Stroke Center, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
³ Division of Vascular Neurology and Neurorehabilitation, Department of Neurology, University Hospital of Zurich and University of Zurich, Zurich, Switzerland.
⁴ cereneo Center for Neurology & Rehabilitation, Vitznau, Switzerland.
⁵ Stroke Division, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
⁶ Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia.
⁷ Bellevue Medical Group, Zurich, Switzerland.
⁸ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California.
⁹ Service of Neurology and Stroke Unit, HFR Fribourg-Cantonal Hospital, Fribourg, Switzerland.
¹⁰ University Teaching and Research Hospital, Neurology Department & Stroke Center, HOCH Health Ostschweiz, Kantonsspital St Gallen, St Gallen, Switzerland.
¹¹ Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
¹² Kantonsspital Münsterlingen, Münsterlingen, Switzerland.
¹³ Kantonsspital Winterthur, Winterthur, Switzerland.
¹⁴ NeuroPraxis Zurich GmbH, Zurich, Switzerland.
¹⁵ Neurology, Cantonal Hospital of Baden, Baden, Switzerland.
¹⁶ Faculty of Medicine, University of Zurich, Zurich, Switzerland.
¹⁷ Kantonsspital Graubünden, Departement Innere Medizin, Neurologie, Chur, Switzerland.
¹⁸ Department of Neurology, University Hospital Bern, University of Bern, Bern, Switzerland.
¹⁹ Cantonal Hospital of Aarau and Department of Neurology, University of Bern, Bern, Switzerland.
²⁰ Department of Neurology and Stroke Center, Klinik Hirslanden, Zurich, Switzerland.
²¹ Acute Neurorehabilitation Unit, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²² Lavigny Rehabilitation Institution, Lavigny, Switzerland.
²³ Stroke Center, Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁴ Research Department, Reha Rheinfelden, Rheinfelden, Switzerland.
²⁵ School of Engineering and Computer Science, Bern University of Applied Sciences, Biel, Switzerland.
²⁶ Department for Sport, Exercise and Health, University of Basel, Basel, Switzerland.
²⁷ Division of Neurorehabilitation, Fribourg Hospital, Meyriez-Murten, Switzerland.
²⁸ Laboratory for Neurorehabilitation Science, Medicine Section, University of Fribourg, Fribourg, Switzerland.
²⁹ Rehaklinik Zihlschlacht AG, Zihlschlacht-Sittendorf, Switzerland.
³⁰ Neurorehabilitation, Klinik Lengg Zurich, Zurich, Switzerland.
³¹ Research Department, Rehaklinik Bad Zurzach, ZURZACH Care Group, Bad Zurzach, Switzerland.
³² Kliniken Valens, St Gallen, Switzerland.
³³ Gerontechnology and Rehabilitation Group, University of Bern, Bern, Switzerland.
³⁴ Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
³⁵ Pragmatic Evidence Lab, Research Center for Clinical Neuroimmunology and Neuroscience Basel, (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland.
³⁶ Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California.
³⁷ Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

PMID: 40982270
PMCID: PMC12455486 (available on 2026-03-22)
DOI: 10.1001/jama.2025.15185

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Engelter reported receiving an investigator-initiated research grant to their institution from Swiss National Science Foundation (SNSF) during the conduct of the study. Ms Wiegert reported receiving grants from SNSF during the conduct of the study. Dr Greulich reported receiving personal fees from Novartis, Pfizer AG, and Lundbeck AG outside the submitted work. Dr Katan reported receiving grants from SNSF and Swiss Heart Foundation; and personal fees for serving on the advisory boards of Bristol Myers Squibb, Janssen, AstraZeneca, and Medtronic outside the submitted work. Dr Fischer reported receiving consulting fees to their institution from AbbVie, AstraZeneca, Bayer, Biogen, Boehringer Ingelheim, CSL, and Siemens outside the submitted work; and being the president of the European Stroke Organization, president-elect of Swiss Federation of Clinical Neuro-Societies, and president of the Advanced Training in Neuro-subjects task force at Swiss Neurological Society. Dr Seiffge reported receiving consulting and advisory fees paid to their institution from AstraZeneca; and grants from Swiss Heart Foundation, SNSF, and AstraZeneca outside the submitted work. Dr Bonati reported receiving grants from SNSF outside the submitted work. Dr Humm reported receiving reimbursement from University of Basel for patient recruitment and follow-up during the conduct of the study. Dr Sandor reported serving as a board member of Swiss Neurological Society, Swiss Society for Neurorehabilitation, and SW!SS REHA. Dr Michel reported receiving grants from SNSF, Swiss Heart Foundation, Faculty of Biology and Medicine of the University of Lausanne, and Porphyrogenis Foundation outside the submitted work. Dr Hemkens reported receiving grants from SNSF (179667) during the conduct of the study; working for Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University of Basel and University Hospital Basel, which is supported by Foundation of Clinical Neuroimmunology and Neuroscience Basel; and RC2NB having a contract with Roche for Dr Hemkens’ steering committee participation outside the submitted work. Dr Gensicke reported receiving grants from SNSF during the conduct of the study; grants from AbbVie, Merz, and Ipsen; and personal fees from AbbVie outside the submitted work. Dr Traenka reported receiving grants from Swiss Heart Foundation; honoraria from Reha Rheinfelden for lectures during the conduct of the study; and grants from Swiss Heart Foundation outside the submitted work. No other disclosures were reported.

References

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Levodopa Added to Stroke Rehabilitation: The ESTREL Randomized Clinical Trial

Collaborators

Affiliations

Levodopa Added to Stroke Rehabilitation: The ESTREL Randomized Clinical Trial

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Associated data

LinkOut - more resources

Full Text Sources

Medical