Use of mesenchymal stromal cells (MSCs) in patients with moderate to severe COVID-19-related acute respiratory distress syndrome (ARDS) is safe but is not associated with improvement in oxygenation index after 7 days or other pulmonary outcomes compared with placebo, according to study findings reported in the American Journal of Respiratory and Critical Care Medicine.
It is uncertain whether MSCs, which have pleiotropic immunomodulatory and reparative properties, might be used as a potential therapy for COVID-19-related ARDS. Investigators therefore conducted the randomized, double-blind, placebo-controlled, phase 2 REALIST-COVID trial (ClinicalTrials.gov Identifier: NCT03042143) to evaluate ORBCEL-C MSCs (ie, CD362-enriched MSCs derived from the umbilical cord) in patients with ARDS due to COVID-19 in 12 intensive care units in the United Kingdom. According to investigators, the REALIST phase 1 trial, a dose-finding trial that determined the dose-limiting toxicity of ORBEL-C in patients with ARDS unrelated to COVID-19, was the first investigation of ORBEL-C in humans.
The phase 2 REALIST-COVID trial included 60 participants, recruited between April and December 2020, who were mechanically ventilated within 72 hours of onset of moderate to severe ARDS due to COVID-19. These participants were randomly assigned 1:1 to receive a single intravenous infusion of ORBCEL-C (400 × 106 CD362 enriched umbilical cord-derived MSCs in 200 mL Plasma-Lyte 148), or placebo (200 mL Plasma-Lyte 148 only).
The primary safety outcome was the incidence of serious adverse events through 90 days. The primary efficacy outcome was oxygenation index at day 7. Primary outcome findings were available for 59 patients, 30 patients in the ORBCEL-C group (mean [SD] age, 58.4 [9.2] years; 80% male) and 29 in the placebo group (mean age, 58.4 (12.5) years; 69% male).
[A] single dose of 400×106 ORBCEL-C was safe and well tolerated in the population of patients with COVID-ARDS. However, there were no differences in the primary efficacy outcome of oxygenation index at day 7, or in other secondary surrogate outcomes of systemic and pulmonary organ function at day 4, 7 and 14.
The investigators found that the ORBCEL-C group had 6 serious adverse events vs 3 such events in the placebo group (risk ratio 2.9; 95% CI, 0.6-13.2; P =.25). The study drug was well-tolerated with no significant difference occurring between the 2 groups in postinfusion (up to 5 hours) hemodynamics, arterial blood gases, positive end-expiratory pressure, plateau pressure, or temperature. The groups had a comparable incidence of adverse events, and no serious adverse events were related to the study drug.
In the primary unadjusted analysis for the primary efficacy outcome, no difference was observed in oxygenation index at day 7 in the ORBCEL-C group (mean [SD], 98.3 [57.2]) and the placebo group (mean 96.6 [67.3]; mean difference 1.8; 95% CI, 30.7-34.4; P =.91). Notably, the result was not affected when the analysis was adjusted for baseline age, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), severity of disease as measured by the Acute Physiology and Chronic Health Evaluation II (APACHE II), vasopressor use, and site. No important differences were observed between the ORBCEL-C and placebo groups for secondary surrogate outcomes of pulmonary and nonpulmonary organ function.
An increase in ventilation duration occurred in the ORBCEL-C group (19 days; interquartile range [IQR] 13-30]) vs the placebo group (12 days [IQR 7-20]; hazard ratio 0.5; 95% CI, 0.3-0.9; P = .017). Mortality at day 28 or 90 was comparable in the 2 groups (28-day mortality: ORBCEL-C, n=5 [16.7%]; placebo, n=6 [20.7%]; risk ratio 0.8; 95% CI, 0.3-2.4; P =.69; 90-day mortality: ORBCEL-C, n=7 [23.3%], placebo, n=8 [27.6%]; risk ratio 0.8; 95% CI, 0.4-2.0; P =.71).
In the ORBCEL-C group, pulmonary function test reports were available for 11/20 patients vs 9/21 in the placebo group. Diffusing capacity for carbon monoxide decreased in the 2 groups, with a median percentage predicted value of 62% (IQR, 57%-71.5%) in the placebo group vs 76% (IQR, 74%-91.5%) in the ORBCEL-C group.
A study limitation is that data for the primary efficacy outcome of oxygenation index at day 7 were not available for all participants owing to extubation, death, and mode of ventilation.
“The key finding of this study is that a single dose of 400×106 ORBCEL-C was safe and well tolerated in the population of patients with COVID-ARDS. However, there were no differences in the primary efficacy outcome of oxygenation index at day 7, or in other secondary surrogate outcomes of systemic and pulmonary organ function at day 4, 7 and 14,” the investigators concluded.
Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.