Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial

Abstract

While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) promote recovery, few randomized controlled trials (RCT) have assessed cell therapy in humans. In this RCT, we assessed the safety, feasibility, and efficacy of intravenous autologous bone marrow-derived MSCs in subacute stroke. ISIS-HERMES was a single-center, open-label RCT, with a 2-year follow-up. We enrolled patients aged 18–70 years less than 2 weeks following moderate-severe ischemic carotid stroke. Patients were randomized 2:1 to receive intravenous MSCs or not. Primary outcomes assessed feasibility and safety. Secondary outcomes assessed global and motor recovery. Passive wrist movement functional MRI (fMRI) activity in primary motor cortex (MI) was employed as a motor recovery biomarker. We compared “treated” and “control” groups using as-treated analyses. Of 31 enrolled patients, 16 patients received MSCs. Treatment feasibility was 80%, and there were 10 and 16 adverse events in treated patients, and 12 and 24 in controls at 6-month and 2-year follow-up, respectively. Using mixed modeling analyses, we observed no treatment effects on the Barthel Index, NIHSS, and modified-Rankin scores, but significant improvements in motor-NIHSS (p = 0.004), motor-Fugl-Meyer scores (p = 0.028), and task-related fMRI activity in MI-4a (p = 0.031) and MI-4p (p = 0.002). Intravenous autologous MSC treatment following stroke was safe and feasible. Motor performance and task-related MI activity results suggest that MSCs improve motor recovery through sensorimotor neuroplasticity.

ClinicalTrials.gov Identifier NCT 00875654.

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Acknowledgments

We thank the other members of the ISIS-HERMES Study group (listed in alphabetical order): S. Achard, P. Antoine, E. L. Barbier C.E. Bulabois, L. Carey, A. Chrispin, M. Cucherat, P. Davoine, F. de Fraipont, C. Delon-Martin, C. Dubray, H. Egelhofer, M.C. Favrot, K. Garambois, P. Garnier, J. Gere, N. Gonnet, I Goundous, F.F. Hannanu, O. Heck, A.V. Jaillard, A. Krainik, J.F. Le Bas, S. Miguel, A. B. Naegele, A. Paris, D. Perennou, P. Pernot, C. Remy, F. Renard, M.J. Richard, G. Rodier, E. Schir A. Thuriot, I. Tropres, and J. Warnking.

Trial Registration

ClinicalTrials.gov, number NCT00875654. https://clinicaltrials.gov/ct2/show/NCT00875654?term=ISIS+stroke+stem+cells&rank=1

Protocols

French ISIS RCT and satellite MRI HERMES protocols are available on demand.

Funding

This trial was funded by an academic grant from the French Health Ministry: PHRCI Grant numbers: ISIS-2007PHR04 and HERMES-2007-A00853-50. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. MRI data acquisition was performed at the IRMaGe MRI platform, which gratefully acknowledge financial support from France Life Imaging network through the grant “ANR-11-INBS-0006.” Data monitoring was performed by the Clinical Investigation Center (CIC) INSERM UMS 002 CHU Grenoble Alpes. Data analysis was partly supported by RESSTORE project (www.resstore.eu) funded by the European Commission under the H2020 program (Grant Number 681044).

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Contributions

Dr. Jaillard had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the analysis. Concept and design: A. Jaillard, M. Hommel, and O. Detante. Acquisition of data. Recruitment and/or clinical follow-up: O. Detante, I. Favre-Wiki, M. Barbieux-Guillot, W. Vadot, and S. Marcel. MRI data acquisition: A. Jaillard, M. Hommel, L. Lamalle, and S. Grand. Analysis or interpretation of data: A. Jaillard, M. Hommel, T. A. Zeffiro, and O. Detante. Drafting of the manuscript: A. Jaillard, O. Detante, M. Hommel, T.A. Zeffiro, and A. Moisan. Critical revision of the manuscript for important intellectual content: A. Jaillard, T.A. Zeffiro, M. Hommel, and O. Detante. Statistical analysis: A. Jaillard and M. Hommel. Obtaining funding: A. Jaillard and O. Detante. Administrative, technical, or material support: A. Jaillard, M. Hommel, O. Detante, L. Lamalle (MRI calibration), and A. Moisan (Autologous mesenchymal stem cell preparation). Study supervision: O. Detante (ISIS) and A. Jaillard (HERMES).

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Correspondence to Assia Jaillard.

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The authors declare that they have no conflict of interest.

Ethical Approval

All patients gave written informed consent. The trial and the amendments were approved by the local ethics committee (“Comité de Protection des Personnes”). ISIS was monitored by an independent data and safety monitoring board (DSMB).

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Jaillard, A., Hommel, M., Moisan, A. et al. Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial. Transl. Stroke Res. (2020). https://doi.org/10.1007/s12975-020-00787-z

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Keywords

  • Stroke
  • Mesenchymal stem cell
  • Motor recovery
  • fMRI
  • Biomarker
  • Cell therapy
  • Neuroimaging
  • Motor
  • Recovery
  • Motor activation