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

Abstract

Bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (ExoFlo) convey the immunomodulatory and regenerative properties of intact BM-MSCs. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate to severe ARDS in patients with severe COVID-19. Do two doses of ExoFlo safely reduce mortality in COVID-19-associated moderate to severe ARDS compared with placebo? A prospective phase 2 multicenter double-anonymized randomized placebo-controlled dosing trial was conducted at five sites across the United States with infusions of placebo, 10mL of ExoFlo, or 15mL of ExoFlo on days 1 and 4. Patients (N= 102) with COVID-19-associated moderate to severe ARDS were enrolled and randomized to treatment. Adverse events were documented throughout the study. 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 60days; time to hospital discharge; and ventilation-free days. No treatment-related adverse events were reported. Mortality (60-day) in the intention-to-treat population was reduced with 15mL ExoFlo mixed with 85mL normal saline (ExoFlo-15) compared with placebo (not significant, χ2, P= .1343). For the post hoc subgroup analyses, 60-day mortality was decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95%CI, 0.159-0.931; P= .0340; n= 50). With ExoFlo-15, a relative risk of 0.423 (95%CI, 0.173-1.032; P= .0588; n= 24) was determined for participants aged 18 to 65 years with moderate to severe ARDS. Ventilation-free days improved with ExoFlo-15 (P= .0455; n= 50) for all participants aged 18 to 65 years. The 15mL dose of ExoFlo was found to be safe in patients with severe or critical COVID-19-associated respiratory failure. In participants aged 18 to 65 years, the risk reduction in 60-day mortality was further improved from subjects of all ages in the intention-to-treat population after two doses of 15mL of ExoFlo compared with placebo. ClinicalTrials.gov; No.: NCT04493242; URL: www. gov.