Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cell Administration (REALIST-COVID) Phase 2 Randomised Controlled Trial

Gorman, E., McAuley, D.F., Rostron, A.J., Shankar-Hari, M., Bannard-Smith, J., Bentley, A.M., Brealey, D., Campbell, C., Curley, G., Clarke, M., Dushianthan, A., Hopkins, P., Jackson, C., Kefala, K., Krasnodembskaya, A., Laffey, J.G., McDowell, C., McFarland, M., McFerran, J., McGuigan, P., Perkins, G.D., Silversides, J., Smythe, J., Thompson, J., Tunnicliffe, W.S., Welters, I.D.M., Williams, B. and O'Kane, C.M. (2022) Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cell Administration (REALIST-COVID) Phase 2 Randomised Controlled Trial. All That is COVID-19 - Mini Symposium, , San Francisco, United States. 18 May 2022. (doi:10.1164/ajrccm-conference.2022.205.1_meetingabstracts.a5285).

Abstract

RATIONALE Mesenchymal stromal cells (MSCs) have immunomodulatory and reparative effects which may be of benefit in acute respiratory distress syndrome (ARDS). The REALIST phase 1 study demonstrated safety of ORBCEL-C MSCs in patients with ARDS.1 The REALIST COVID phase 2 study investigated the safety and efficacy of ORBCEL-C MSCs in patients with ARDS due to COVID-19. METHODS This was a multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial in mechanically ventilated patients with moderate to severe ARDS, due to COVID-19. Participants were randomised (1:1) to receive either ORBCEL-C (CD362 enriched umbilical cord-derived MSCs, 400x106 cells) or placebo (Plasma-Lyte-148). The primary safety outcome was the incidence of serious adverse events (SAEs). The primary efficacy outcome was oxygenation index (OI) at day 7. Secondary surrogate outcomes included OI at day 4 and day 7, respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score on days 4, 7, and 14. Clinical outcomes (including duration of ventilation and mortality) are reported. Patients were followed up at 1 year for mortality and significant medical events. Trial registration NCT03042143. RESULTS 60 participants were recruited from 2nd April until 4th December 2020 (the final analysis included n=30 in ORBCEL-C and n=29 in placebo groups as n=1 in placebo group withdrew consent). Groups were balanced at baseline. There were 6 SAEs in the ORBCEL-C and 3 in the placebo group, risk ratio (RR) 2.9(95% confidence interval (CI) 0.6-13.2, p=0.25). There was no difference in OI at day 7 between the ORBCEL-C (mean(SD) 98.3(57.2)) and placebo groups (mean(SD) 96.6(67.3): mean difference 1.8(95% CI 30.7-34.4, p=0.91). There were no differences between groups in surrogate secondary outcomes (Figure 1). Clinical outcomes were underpowered, however there was no difference in mortality (28-day mortality ORBCEL-C 16.7% (n=5), placebo 20.7%(n=6); RR 0.8(95% CI 0.3-2.4), p=0.69) and an increased duration of ventilation in the ORBCEL-C group compared to placebo (ORBCEL-C 19 days (IQR 13-30), placebo 12 days (IQR 7-20); hazard ratio 0.5(95% CI 0.3-0.9), p=0.017). CONCLUSIONS This phase 2 trial supports the safety of ORBCEL-C in patients with moderate to severe ARDS due to COVID- 19 but did not demonstrate efficacy, and does not support routine administration of ORBCEL-C MSCs in this population. FUNDING Wellcome Trust Health Innovation Challenge Fund (reference 106939/Z/15/Z) and the Northern Ireland Health and Social Care Research and Development Fund. 1.Gorman E et al. Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) trial: A phase 1 trial.

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Contributors

Author: A. Dushianthan

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