. 2024 Dec;9(4):1093-1102.

doi: 10.1177/23969873241255867. Epub 2024 Jun 9.

Enhancement of STroke REhabilitation with Levodopa (ESTREL): Rationale and design of a randomized placebo-controlled, double blind superiority trial

Annaelle Zietz^{1

2}, Josefin E Kaufmann^{1

2}, Karin Wiesner^{1

2}, Sandro Kevin Fischer^{1

2}, Martina Wiegert^{1

2}, Wilma Dj Verhagen-Kamerbeek^{1

2}, Yannik Rottenberger³, Anne Schwarz³, Nils Peters^{1

2

4}, Henrik Gensicke^{1

2}, Friedrich Medlin⁵, Jens Carsten Möller⁶, Bartosz Bujan⁷, Leo H Bonati^{2

8}, Marcel Arnold⁹, Sabine Schaedelin¹⁰, René M Müri⁹, Lars G Hemkens^{10

11

12

13}, Patrik Michel¹⁴, Philippe A Lyrer², Jeremia P Held^{3

15}, Gary A Ford¹⁶, Andreas R Luft^{3

17}, Christopher Traenka^{1

2}, Stefan T Engelter^{1

2}

Affiliations

¹ Neurology and Neurorehabilitation, 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 Department of Neurology, University and University Hospital of Zurich, Zurich, Switzerland.
⁴ Stroke Center, Klinik Hirslanden, Zürich, Switzerland.
⁵ Stroke Unit, Cantonal Hospital Fribourg, Fribourg, Switzerland.
⁶ Center for Neurological Rehabilitation, Zihlschlacht, Switzerland.
⁷ Neurorehabilitation, Klinik Lengg Zürich, Zurich, Switzerland.
⁸ Research Department, Rheinfelden Rehabilitation Clinic, Switzerland.
⁹ Department of Neurology, University Hospital Inselspital, Bern, Switzerland.
¹⁰ Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
¹¹ Pragmatic Evidence Lab, Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland.
¹² Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA.
¹³ Meta-Research Innovation Center Berlin (METRIC-B), Berlin Institute of Health, Berlin, Germany.
¹⁴ Stroke Center, Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁵ Rehabilitation Triemli Zurich, Valens Clinics, Zurich, Switzerland.
¹⁶ Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK.
¹⁷ Cereneo, Center for Neurology and Rehabilitation, Vitznau, Switzerland.

PMID: 38853524
PMCID: PMC11569567
DOI: 10.1177/23969873241255867

Enhancement of STroke REhabilitation with Levodopa (ESTREL): Rationale and design of a randomized placebo-controlled, double blind superiority trial

Annaelle Zietz et al. Eur Stroke J. 2024 Dec.

. 2024 Dec;9(4):1093-1102.

doi: 10.1177/23969873241255867. Epub 2024 Jun 9.

Authors

Affiliations

¹ Neurology and Neurorehabilitation, 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 Department of Neurology, University and University Hospital of Zurich, Zurich, Switzerland.
⁴ Stroke Center, Klinik Hirslanden, Zürich, Switzerland.
⁵ Stroke Unit, Cantonal Hospital Fribourg, Fribourg, Switzerland.
⁶ Center for Neurological Rehabilitation, Zihlschlacht, Switzerland.
⁷ Neurorehabilitation, Klinik Lengg Zürich, Zurich, Switzerland.
⁸ Research Department, Rheinfelden Rehabilitation Clinic, Switzerland.
⁹ Department of Neurology, University Hospital Inselspital, Bern, Switzerland.
¹⁰ Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.
¹¹ Pragmatic Evidence Lab, Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland.
¹² Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, California, USA.
¹³ Meta-Research Innovation Center Berlin (METRIC-B), Berlin Institute of Health, Berlin, Germany.
¹⁴ Stroke Center, Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁵ Rehabilitation Triemli Zurich, Valens Clinics, Zurich, Switzerland.
¹⁶ Oxford University Hospitals NHS Foundation Trust, University of Oxford, Oxford, UK.
¹⁷ Cereneo, Center for Neurology and Rehabilitation, Vitznau, Switzerland.

PMID: 38853524
PMCID: PMC11569567
DOI: 10.1177/23969873241255867

Abstract

Rationale: Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a neurotransmitter involved in motor learning, reward, and brain plasticity. Its prodrug levodopa is a promising agent for stroke recovery.

Aim and hypothesis: To investigate the hypothesis that levodopa, in addition to standardized rehabilitation therapy based on active task training, results in an enhancement of functional recovery in acute ischemic or hemorrhagic stroke patients compared to placebo.

Design: ESTREL (Enhancement of Stroke REhabilitation with Levodopa) is a randomized (ratio 1:1), multicenter, placebo-controlled, double-blind, parallel-group superiority trial.

Participants: 610 participants (according to sample size calculation) with a clinically meaningful hemiparesis will be enrolled ⩽7 days after stroke onset. Key eligibility criteria include (i) in-hospital-rehabilitation required, (ii) capability to participate in rehabilitation, (iii) previous independence in daily living.

Intervention: Levodopa 100 mg/carbidopa 25 mg three times daily, administered for 5 weeks in addition to standardized rehabilitation. The study intervention will be initiated within 7 days after stroke onset.

Comparison: Matching placebo plus standardized rehabilitation.

Outcomes: The primary outcome is the between-group difference of the Fugl-Meyer-Motor Assessment (FMMA) total score measured 3 months after randomization. Secondary outcomes include patient-reported health and wellbeing (PROMIS 10 and 29), patient-reported assessment of improvement, Rivermead Mobility Index, modified Rankin Scale, National Institutes of Health Stroke Scale (NIHSS), and as measures of harm: mortality, recurrent stroke, and serious adverse events.

Conclusion: The ESTREL trial will provide evidence of whether the use of Levodopa in addition to standardized rehabilitation in stroke patients leads to better functional recovery compared to rehabilitation alone.

Keywords: Fugl-Meyer-motor assessment; levodopa; motor recovery; neurorehabilitation; protocol; randomized controlled trial; stroke rehabilitation.

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Conflict of interest statement

Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AZ, JK, KW, SKF, MW, WVK, AS, YR, HG, FM, RMM, PL, JCM, BB, LB, MA, SS, JH, GF, AL, and NP report no conflict of interest, via their institutions STE and CT received funding for ESTREL from the Swiss National Science Foundation (IICT 33IC30_179667) the Swiss Heart Foundation and the Science Funds Rehabilitation of the University Geriatric Medicine FELIX PLATTER, University of Basel, Switzerland.LGH’s institution (RC2NB; Research Center for Clinical Neuroimmunology and Neuroscience Basel) is supported by the Foundation Clinical Neuroimmunology and Neuroscience Basel.PM received funding outside this trial from the Swiss National Science Foundation, the Swiss Heart Foundation, and Faculty of Biology and Medicine of the Lausanne University.

Figures

**Figure 1.**
Meta-analysis based on a systematic review dated from August 17^th, 2017.

**Figure 2.**
Detailed study schedule of the ESTREL trial.

**Figure 3.**
Study flow chart of the ESTREL trial.

See this image and copyright information in PMC

References

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Enhancement of STroke REhabilitation with Levodopa (ESTREL): Rationale and design of a randomized placebo-controlled, double blind superiority trial

Affiliations

Enhancement of STroke REhabilitation with Levodopa (ESTREL): Rationale and design of a randomized placebo-controlled, double blind superiority trial

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources