Short-Term Safety of Allogeneic Adipose-Tissue Derived Mesenchymal Stem Cells in Acute Ischemic Stroke (AMASCIS): A Phase II, Randomised, Double-Blind, Placebo-Controlled, Single-Centre, Pilot Clinical Trial

Background: Pre-clinical studies on adipose tissue-derived mesenchymal stem cells (AD-MSC) suggest its efficacy and safety for ischemic stroke (IS). Our aim was to evaluate the safety of a single dose of AD-MSC administered intravenously in acute IS patients. Methods: A phase II, randomised, double-blind, placebo-controlled, single-center, pilot clinical trial. We included patients aged ≥ 60 years, with moderate to severe IS. Patients were randomly assigned (1:1 ratio) to receive either 1M cells/kg AD-MSC or placebo within the first two weeks after the onset of an IS. The primary outcome measure was safety (adverse events, neurological and systemic complications, and tumor developments). Secondary outcomes explored efficacy (modified Rankin Scale (mRS) and NIHSS). Here we report the preliminary results at 6 months of follow-up. EudraCT: 2011-003551-18; NCT01678534. Findings: Recruitment was stopped in December 2017 after including 19 out of the 20 planned patients. Six patients did not receive the study treatment (3 for technical reasons and 3 because they presented exclusion criteria after randomisation). The final sample was composed of 13 patients (4 in the AD-MSC and 9 in the placebo group). One patient from the placebo group died within the first 7 days due to sepsis. Serious adverse events at 6 months were reported in 5.1% of the AD-MSC group and in 6.6% in the placebo group. No injection-related adverse events or tumour developments were reported. After 6 months of follow-up there were no significant differences between the groups in median NIHSS scores [2.5 (IQR 1.75, 3.50) vs. 5 (IQR 4.0, 7.50)] and median mRS [3 (IQR 3.0, 3.25) vs. 4 (IQR 3.0, 4.0)]. Interpretation: Intravenous administration of AD-MSC within the first 2 weeks from IS onset seems to be safe at 6-months of follow-up and shows a trend toward improving neurological and functional recovery. Trial Registration: The study was registered at Clinicaltrials.gov, under the number NCT01678534. Funding Statement: Spanish Ministry of Health (EC2010/171). Declaration of Interests: B Fuentes reports grants from Spanish Ministry of Health and European Commission (Horizon2020 program), during the conduct of the study; other from Daichi-Sankyo, other from Bayer, other from BMS-Pfizer, other from Novonordisk, other from Novartis, outside the submitted work; M Gutierrez-Fernandez rports grants from Spanish Ministry of Health and European Commission (Horizon2020 program), during the conduct of the study; non-financial support from Cellerix/Tigenix, non-financial support from Histocell, outside the submitted work.AM Borobia reports grants from Instituto de Salud Carlos III, during the conduct of the study; personal fees from Mundipharma, personal fees from Menarini, outside the submitted work; and Principal Investigator in Clinical Trials for GSK and Daiichi Sankyo. E Diez-Tejedor reports grants from Spanish Ministry of Health and European Commission (Horizon2020 program), during the conduct of the study; non-financial support from Cellerix/Tigenix, non-financial support from Histocell, other from Daichi-Sankyo, other from Bayer, other from Sanofy Aventis, other from Novartis outside the submitted work. R Gutierrez-Zuniga, M Alonso de Lecinana, JC Martinez Avila, G Ruiz-Ares, MC Gomez-de Frutos, F Laso-Garcia and L Otero-Ortega report nothing to disclosure. Ethics Approval Statement: It was approved by the La Paz University Hospital Research Ethics Committee and by the Spanish Agency of Medicines and Health Products (EudraCT: 2011-003551-18).