Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial) A Multicenter, Randomized, Controlled Clinical Trial

Copyright \ua9 2023 by the American Thoracic Society. Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in coronavirus disease (COVID-19)–related acute respiratory distress syndrome (ARDS). Objectives: We investigated the safety and efficacy of ORBCEL-C (CD362 [cluster of differentiation 362]–enriched, umbilical cord–derived MSCs) in COVID-19–related ARDS. Methods: In this multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial (NCT 03042143), patients with moderate to severe COVID-19–related ARDS were randomized to receive ORBCEL-C (400 million cells) or placebo (Plasma-Lyte 148). The primary safety and efficacy outcomes were the incidence of serious adverse events and oxygenation index at Day 7, respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2:FIO2 ratio, and Sequential Organ Failure Assessment score. Clinical outcomes relating to duration of ventilation, lengths of ICU and hospital stays, and mortality were collected. Long-term follow-up included diagnosis of interstitial lung disease at 1 year and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at Days 0, 4, and 7. Measurements and Main Results: Sixty participants were recruited (final analysis: n = 30 received ORBCEL-C, n = 29 received placebo; 1 participant in the placebo group withdrew consent). Six serious adverse events occurred in the ORBCEL-C group and three in the placebo group (risk ratio, 2.9 [95% confidence interval, 0.6–13.2]; P = 0.25). Day 7 mean (SD) oxygenation index did not differ (ORBCEL-C, 98.3 [57.2] cm H2O/kPa; placebo, 96.6 [67.3] cm H2O/kPa). There were no differences in secondary surrogate outcomes or in mortality at Day 28, Day 90, 1 year, or 2 years. There was no difference in the prevalence of interstitial lung disease at 1 year or significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in subjects with moderate to severe COVID-19–related ARDS but did not improve surrogates of pulmonary organ dysfunction

S44 Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID trial): 1 year follow up for safety and pulmonary dysfunction

Introduction and Objectives REALIST-COVID was a UK multicentre, double-blind randomised, allocation concealed, placebo-controlled phase 2 trial, investigating a novel mesenchymal stromal cell (MSC) product (ORBCEL-C cryopreserved, allogeneic, umbilical cord-derived CD362 enriched MSCs) in patients with ARDS due to COVID-19. Here we report follow up of the REALIST-COVID cohort at 1 year, with the aim of further evaluation of ORBCEL-C MSC safety.Methods 1-year mortality status was recorded from GP and hospital records where possible. Survivors at 1 year were followed up for significant medical events (SMEs) via telephone interview, medical record review, or contact with GP. Interstitial lung disease (ILD) and pulmonary dysfunction on clinically indicated thoracic computerised tomography (CT) and pulmonary function tests (PFTs) was recorded.Results Mortality at 1-year was 29% (n=8/28) in the ORBCEL-C group and 28% (n=8/29) in the placebo group. One patient in the ORBCEL-C group died between day 90 and 1 year. 41 survivors were followed up at 1 year (20 in ORBCEL-C, 21 in placebo). Significant medical events in survivors were similar in both groups (7 events in 6 patients in the ORBCEL-C group and 11 events in 9 patients in the placebo group). Classification of SMEs is summarised in table 1.Thoracic CTs were available for 12 participants (ORBCEL-C n=5/20, placebo n=8/21). Median time to CT and results are summarised in table 1). Evidence of ILD was similar in each group.PFTs were available for 18 participants (ORBCEL-C n=10/20, placebo n=8/21). Median time to PFTs and results are summarised in table 1. FEV1, FVC, FEV1/FVC ratio and TLCO were similar between groups. There was a high rate of impairment of transfer factor (TLCO<80% predicted) in participants from both groups