Loïc Legris ¹ Anaick Moisan ² Assia Jaillard ³ Louise Bonnet ⁴ Thierry Moulin ⁴ Igor Sibon ⁵ Emmanuel Touzé ⁶ Isabelle Favre-Wiki ⁷ Charlotte Cordonnier ⁸ Lucie Dellaschiava ⁸ Mikael Mazighi ⁹ Charlotte Rosso ¹⁰ Sonia Alamowitch ¹¹ David Calvet ¹² Marianne Barbieux-Guillot ¹³ Stephan Roux ¹⁴ Alain-Ali Mojallal ¹⁵ Fabien Boucher ¹⁵ Antoine Thuriot ⁷ Julie Soulard ⁷ Bernadette Naegele ⁷ Dominic Perennou ¹⁶ Matthieu Roustit ¹⁷ Zaza Putkaradze ¹⁷ Marc Hommel ¹⁸ Audrey Lehmann ¹⁹ Julien Colombat ²⁰ Fatima Chorfa ²¹ Delphine Maucort-Boulch ²¹ Laurent Lamalle ²² Sylvie Grand ²³ Alexandre Krainik ²⁴ Olivier Detante ^1*

• ¹ Univ. Grenoble Alpes, Inserm, U1216, Stroke Unit, Department of Neurology, CHU Grenoble Alpes, Grenoble Institut Neurosciences, 38043 Grenoble, France, Grenoble, France
• ² Cell Therapy and Engineering Unit, EFS Rhône Alpes, 38330 Saint Ismier, France, Saint Ismier, France
• ³ Univ. Grenoble Alpes, AGEIS EA 7407. Research 3T-MRI, IRMaGe, CHU Grenoble Alpes, 38043 Grenoble, France, Grenoble, France
• ⁴ University of Franche-Comté, UFR Santé, Department of Neurology, CHU Besançon, 25000 Besançon, France, Besançon, France
• ⁵ Department of Neurology, Stroke Unit, CHU Bordeaux, 33000 Bordeaux, France, Bordeaux, France
• ⁶ Department of Neurology, Stroke Unit, CHU Caen, Medical University of Caen, Normandy, Caen, 14000, France, Caen, France
• ⁷ Univ. Grenoble Alpes, Department of Neurology, Stroke Unit, CHU Grenoble Alpes, 38043 Grenoble, France, Grenoble, France
• ⁸ University of Lille, Inserm, CHU Lille, U1172 – LiINCog – Lille Neuroscience and Cognition, 59000, Lille, France, Lille, France
• ⁹ Department of Neurology, APHP Nord, Interventional Neuroradiology Department, Rothschild Foundation Hospital, University of Paris City, FHU Neurovasc, INSERM 1144, 75000 Paris, France, Paris, France
• ¹⁰ Inserm U 1127, CNRS UMR 7225, Sorbonne Université, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, APHP Stroke Unit, Pitié Salpêtrière Hospital 75013, Paris, France, Paris, France
• ¹¹ AP-HP, Urgences Cérébro-Vasculaires, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France ; STARE team, iCRIN, Institut du Cerveau, INSERM U1266, Paris, France., Paris, France
• ¹² Department of Neurology, Stroke Unit, GHU-Paris Psychiatry and Neurosciences, Sainte Anne Hospital, University of Paris City, Inserm, U1266, 75000 Paris, France, Paris, France
• ¹³ Department of Neurology, Stroke Unit, CHU Toulouse, 31000 Toulouse, France, Toulouse, France
• ¹⁴ Cell Therapy and Engineering Unit, EFS Bourgogne Franche Comté, 25000 Besançon, France, Besançon, France
• ¹⁵ Department of Plastic Surgery, Croix Rousse Hospital, HCL, 69004 Lyon, France, Lyon, France
• ¹⁶ Univ. Grenoble Alpes, Department of neurorehabilitation, CHU Grenoble Alpes, LPNC, 38000 Grenoble, France, Grenoble, France
• ¹⁷ Univ. Grenoble Alpes, Inserm, Clinical Investigation Center CIC, CHU Grenoble Alpes, 38000 Grenoble, France, Grenoble, France
• ¹⁸ Univ. Grenoble Alpes, AGEIS EA 7407, 38000 Grenoble, France, Grenoble, France
• ¹⁹ Univ. Grenoble Alpes, Department of Pharmacy, CHU Grenoble Alpes, 38000 Grenoble, France, Grenoble, France
• ²⁰ Department of Research and Innovation, CHU Grenoble Alpes, 38000 Grenoble, France, Grenoble, France
• ²¹ Hospices Civils de Lyon, Service de Biostatistique et Bioinformatique, Lyon F-69003; Université Lyon 1, CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Lyon, France
• ²² Univ. Grenoble Alpes, Inserm, CHU Grenoble Alpes, CNRS, IRMaGe, 38000, Grenoble, France, Grenoble, France
• ²³ Univ. Grenoble Alpes, Inserm, U1216, Department of Neuroradiology, CHU Grenoble Alpes, Grenoble Institut Neurosciences, 38043 Grenoble, France, Grenoble, France
• ²⁴ Univ. Grenoble Alpes, Inserm, U1216, Research 3T-MRI, IRMaGe, Department of Neuroradiology, CHU Grenoble Alpes, Grenoble Institut Neurosciences, 38043 Grenoble, France, Grenoble, France

Introduction: Encouraging the activation of brain repair mechanisms and fostering spontaneous functional recovery in stroke patients holds great promise for alleviating the global burden of this condition, allowing an extended therapeutic time window. Cell-based regenerative therapy (with mesenchymal stem/stromal cells, such as Adipose Derived Stem Cells, ADSCs) is particularly attractive considering an excellent safety profile, low immunogenicity after allogeneic application and well-established functional benefits on stroke recovery in animal models. The aim of this study is to assess efficacy and safety effects of intravenous (IV) infusion of fresh cultured allogeneic ADSCs on recovery after ischemic stroke. Population and Methods: RESSTORE is a multicentric, randomized 1:1, controlled, double-blind clinical trial (RCT). Eighty patients will be enrolled in 9 French stroke centers. Main inclusion criteria are: ≥ 18-year-old, acute hemispheric ischemic stroke, NIHSS ≥ 7 including motor score ≥ 3. According to the previous dose-escalation safety trial data, the maximum tolerated dose of 3 million ADSCs /kg was selected. IV infusion is performed within 10 days following stroke onset, with a follow-up over 2 years. Outcomes: The primary endpoint is the motor NIHSS subscore, computed as the sum of upper limb, lower limb and hand scores, measured 6 months after stroke onset to assess motor recovery. The secondary outcomes are the occurrence of death / serious adverse events, clinical scores (detailed NIHSS, MoCA, mRS, Aphasia Handicap Score, Depression Intensity Scale Circles, Fatigue Scale…), immunomonitoring (for 30 first patients) and multimodal biomarkers derived from diffusion and functional MRI. Discussion: This study may provide some evidence for the effects of fresh cultured allogenic ADSCs IV infusion in subacute stroke that may help to design a larger international RCT.