Registered clinical trials investigating treatment with cell-derived extracellular vesicles: a scoping review

Interest in cell-based therapy using extracellular vesicles (EVs) is intensifying, building upon promising preclinical research and a handful of published clinical studies. Registered clinical trials remain small, heterogeneous in design and underpowered to determine safety and efficacy on their own. A scoping review of registered studies can identify opportunities to pool data and perform meta-analysis. Registered trials were identified by searching clinical trial databases (Clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry) on June 10, 2022. Seventy-three trials were identified and included for analysis. Mesenchymal stromal cells (MSCs) were the most common cell type from which EVs were derived (49 studies, 67%). Among the 49 identified MSC-EV studies, 25 were controlled trials (51%) with a combined total of 3094 participants anticipated to receive MSC-derived EVs (2225 in controlled studies). Although EVs are being administered to treat a broad range of conditions, trials treating patients with coronavirus disease-2019 and/or acute respiratory distress syndrome were observed most commonly. Despite heterogeneity between studies, we anticipate that at least some of the studies could be combined in meaningful meta-analysis and that a combined sample size of 1000 patients would provide the ability to detect a ≥5% difference in mortality with MSC-EVs compared to controls and could be achieved by December 2023. This scoping review identifies potential barriers that may stall clinical translation of EV-based treatment, and our analysis calls for more standardized product characterization, use of quantifiable product quality attributes and consistent outcome reporting in future clinical trials.