Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial

Abstract

Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 10⁶ UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.

Keywords: cell transplantation; cellular therapy; clinical trials; mesenchymal stem cells; respiratory tract; transplantation; umbilical cord.

FIGURE 1

Enrollment and randomization. UC‐MSC, umbilical cord mesenchymal stem cell

FIGURE 2

Kaplan‐Meier curves. A, Survival. At 31 days after the first infusion (corresponding to 28 days after the last infusion), patient survival was 91% vs 42% in the UC‐MSC and control group, respectively (P = .015). The difference between the groups was statistically significant. B, SAE‐free survival. SAE‐free survival was significantly improved in the UC‐MSC treatment group compared with the control group (P = .008). SAEs affected two vs eight patients in the UC‐MSC and control group, respectively. C, Time to recovery. Time to recovery was significantly shorter in the UC‐MSC treatment group compared with the control group (P = .031). Censoring was limited to dropout from study, and the event of interest was recovery. In the case of death, the patient's time to recovery was considered censored at the end of study observation; thus the patient conservatively remained in the risk set for all Kaplan‐Meier estimation throughout the study period. CI, confidence interval; HR, hazard ratio; SAE, serious adverse event; UC‐MSC, umbilical cord mesenchymal stem cell

FIGURE 3

Analysis of inflammatory cytokines, chemokines, and growth factors in plasma of randomized subjects. In the comparison between groups at day 6 and in the longitudinal analysis from day 0 to day 6, inflammatory cytokine concentrations showed marked and statistically significant decreases from day 0 to day 6 only in the UC‐MSC treatment group. The overall “signature” of the response in the UC‐MSC treatment group is characterized by a reduction of the levels of key inflammatory molecules involved in the COVID‐19 “cytokine storm,” including IFNg, IL‐6, and TNFa cytokines and RANTES chemokine. GM‐CSF and PDGF‐BB also decreased significantly only in the UC‐MSC treatment group. ns, not significant; UC‐MSC, umbilical cord mesenchymal stem cell