Mesenchymal stromal cell-based therapy in the COVID-19 pandemic: results from an academic phase I/II double-blind, randomized, placebo-controlled clinical trial and reflections for the field

BACKGROUND: During the COVID-19 pandemic, Mesenchymal Stromal Cells (MSCs) were rapidly proposed as a therapeutic option for Acute Respiratory Distress Syndrome (ARDS) based on their immunomodulatory properties. We report the results of COVIDMES, a multicenter trial initiated within a public blood and tissue bank infrastructure during unprecedented period of volatility and scientific uncertainty of the first pandemic waves. AIMS: To evaluate the safety, feasibility and exploratory efficacy of Wharton's Jelly-derived MSCs (WJ-MSCs) in hospitalized patients with moderate-to-severe COVID-19 associated ARDS. METHODS: This was a multicenter, prospective, double-blind, randomized, placebo-controlled Phase I/II pilot trial. The primary endpoint was all-cause 28-day mortality. Secondary endpoints included duration of mechanical ventilation, length of intensive care unit (ICU) stay, and longitudinal inflammatory biomarker kinetics. RESULTS: viable WJ-MSCs/kg (n = 13) or placebo (n = 12) on days 1 and 3. WJ-MSC administration was safe and well tolerated, with no treatment-related serious adverse events. No statistically significant differences were observed between groups in 28-day mortality (no deaths in the treatment group versus 2 in the placebo group, P = 0.18), duration of mechanical ventilation (18.3 versus 10.6 days; P = 0.08), or ICU stay (17.1 versus 11.9 days; P = 0.11). Ferritin levels showed a significantly different temporal evolution, with more pronounced reduction over time in the WJ-MSC group (P < 0.0001 from baseline; P = 0.0057 for group-time interactions), however this biological effect was not associated with clinical improvement. CONCLUSIONS: In this exploratory pilot study, WJ-MSCs demonstrated a favorable safety profile and evidence of biochemical immunomodulation but no clinical efficacy in moderate-to-severe COVID-19 associated ARDS. These findings highlight the challenges of evaluating advanced therapy medicinal products within a rapidly evolving standard of care and support the need for biomarker-guided patient stratification and optimized dosing strategies in future MSC trials. The successful execution of this trial also validates the resilience of academic "donor-to-patient" networks in global health emergencies.