A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19

Abstract

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

Keywords: SARS-CoV-2; clinical trial; mechanical ventilation; stem cells; survival.

Figure 1.

CONSORT (Consolidated Standards of Reporting Trials) diagram. *The most common reasons for not meeting inclusion/exclusion criteria included not having moderate and/or severe acute respiratory distress syndrome or requiring mechanical ventilator support (n = 533) and intubation greater than 72 hours (n = 208). ^†Three subjects discontinued intervention because of death (MSC = 1 and placebo = 2). ^‡Discontinued intervention means the second infusion was not administered. LAR = legally authorized representative; MSC = mesenchymal stromal cell.

Figure 2.

Survival and key secondary endpoint. (A) Depicts survival by randomization group. The tick marks show the censoring of data. (B) Depicts the distributions of rank by randomization group from the rank-based assessment of the key secondary endpoint, days alive, and free of mechanical ventilation at Day 60. Higher ranks correspond to better outcomes (i.e., fewer d on mechanical ventilation), and deaths were assigned the worst ranks in order of time of death. (C) Depicts the proportion of patients alive and off mechanical ventilation, alive on mechanical ventilation, alive with unknown ventilation status, withdrawn, or died, by randomization group over each study day from randomization through Day 60. CI = confidence interval; IQR = interquartile range; MSC = mesenchymal stromal cell.

Figure 3.

Subgroup analyses of the primary endpoint. Subgroup analyses of the primary endpoint in key clinical subgroups were prespecified. Per protocol, strata in which the number of patients assigned to a specific group is less than 20 were not considered. ARDS = acute respiratory distress syndrome; BMI = body mass index; CI = confidence interval; DM = diabetes mellitus; MSC = mesenchymal stromal cell.