Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicle Infusion for the Treatment of Respiratory Failure from COVID-19: A Randomized Placebo Controlled Dosing Clinical Trial

BACKGROUND: Bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (EVs), ExoFlo(TM), convey the immunomodulatory and regenerative properties of intact BM-MSC. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate-to-severe Acute Respiratory Distress Syndrome (ARDS) in patients with severe COVID-19. RESEARCH QUESTION: Does two doses of ExoFlo safely reduce mortality in COVID-19 associated moderate to severe ARDS as compared to placebo? STUDY DESIGN AND METHODS: A prospective phase 2 multicenter, double-blind, randomized, placebo-controlled dosing trial was conducted at five sites across the US with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on Day 1 and 4. Patients (102) with COVID-19 associated moderate-to-severe ARDS were enrolled and randomized. Adverse events were documented throughout. The primary outcome measure was all-cause 60-day mortality rate. Secondary outcomes included time to death (overall mortality), the incidence of treatment emergent serious adverse events, proportion of discharged patients at 7, 30, and 60 days, time to hospital discharge, and ventilation free days. RESULTS: No treatment-related adverse events were reported. Mortality (60-day) in the Intention-to-Treat (ITT) population was reduced in ExoFlo-15 compared to Placebo (not significant, Chi-square p=0.1343). For the post-hoc subgroup analyses, 60-day mortality was decreased in ExoFlo-15 compared to Placebo (Relative Risk=0.385; 95% confidence interval [CI]=0.159,0.931; p=0.0340; N=50). In ExoFlo-15 a Relative Risk of 0.423 (CI=0.173,1.032; p=0.0588; N=24) was determined for participants aged 18-65 with moderate to severe ARDS. Ventilation-free days (VFDs) improved in ExoFlo-15 (p=0.0455; N=50) for all participants aged 18-65. INTERPRETATION: ExoFlo (15 mL dose) is safe in patients with severe or critical COVID-19 respiratory failure. In participants aged 18 to 65, the risk reduction in 60-day mortality was further improved from all aged subjects in the ITT population after two doses of 15 mL of ExoFlo as compared to placebo.