TY - JOUR
T1 - Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial)
T2 - A Multicentre, Randomised, Controlled Trial
AU - Gorman, Ellen A
AU - Rynne, Jennifer
AU - Gardiner, Hannah J
AU - Rostron, Anthony J
AU - Bannard-Smith, Jonathan
AU - Bentley, Andrew M
AU - Brealey, David
AU - Campbell, Christina
AU - Curley, Gerard
AU - Clarke, Mike
AU - Dushianthan, Ahilanadan
AU - Hopkins, Phillip
AU - Jackson, Colette
AU - Kefela, Kallirroi
AU - Krasnodembskaya, Anna
AU - Laffey, John G
AU - McDowell, Cliona
AU - McFarland, Margaret
AU - McFerran, Jamie
AU - McGuigan, Peter
AU - Perkins, Gavin D
AU - Silversides, Jonathan
AU - Smythe, Jon
AU - Thompson, Jacqui
AU - Tunnicliffe, William S
AU - Welters, Ingeborg Dm
AU - Amado-Rodríguez, Laura
AU - Albaiceta, Guillermo
AU - Williams, Barry
AU - Shankar-Hari, Manu
AU - McAuley, Daniel F
AU - O'Kane, Cecilia M
N1 - Funding Information:
Supported by the Wellcome Trust Health Innovation Challenge Fund (reference 106939/Z/15/Z) and the Northern Ireland Health and Social Care Research and Development Fund for needs-led research. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. Orbsen Therapeutics Ltd. has granted a nonexclusive, trial-specific license to the Cellular and Molecular Therapies Division of the National Health Service Blood and Transplant Service to manufacture ORBCEL-C to Good Manufacturing Practice standards for the REALIST trial. Orbsen Therapeutics Ltd. had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The authors acknowledge all patients who participated in the REALIST trial and their legal representatives; clinical research teams at each clinical site who participated in patient recruitment, data collection, and patient follow-up; clinical teams at each site who provided clinical care to patients involved in the study; pharmacy and cell therapy facility staff members at each clinical site for oversight and management of the study drugs; staff members at National Health Service Blood and Transplant involved in the manufacture and distribution of ORBCEL-C; staff members at Victoria Pharmaceuticals involved in the manufacture and distribution of placebo; staff members at the Northern Ireland Clinical Trials Unit for support in the conduct of the trial; staff members at Queen’s University Belfast who supported laboratory analysis; members of the data monitoring and ethics committee (Professor John Norrie, Professor Mervyn Singer, and Professor Sam Janes); and members of the trial steering committee (Professor Charles Hinds, Professor John Simpson, Professor Mike Grocott, Mr. Barry Williams, and Professor John Laffey). The authors acknowledge Dr. David Oliver Hamilton for his effort in recruiting patients at Liverpool Royal Infirmary.
Funding Information:
Supported by the Wellcome Trust Health Innovation Challenge Fund (reference 106939/Z/15/Z) and the Northern Ireland Health and Social Care Research and Development Fund for needs-led research. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. Orbsen Therapeutics Ltd. has granted a nonexclusive, trial-specific license to the Cellular and Molecular Therapies Division of the National Health Service Blood and Transplant Service to manufacture ORBCEL-C to Good Manufacturing Practice standards for the REALIST trial. Orbsen Therapeutics Ltd. had no role in the study design, data collection, data analysis, data interpretation, or writing of this report.
Funding Information:
REALIST-COVID (NCT 03042143) was a multicenter randomized, double-blind, allocation-concealed, placebo-controlled trial of ORBCEL-C MSCs in patients with ARDS due to COVID-19 in 12 ICUs across the United Kingdom. Full details of the study design have been published (37) and are available in the online supplement. The trial was sponsored by Belfast Health and Social Care Trust and approved by the North-East York research ethics committee (18/NE/ 0006) and the Medicines and Healthcare Products Regulatory Agency (European Union Drug Regulating Authorities Clinical Trials Database number 2017-000584-33). In brief, after informed consent was obtained, eligible patients who were mechanically ventilated within 72 hours of the onset of moderate to severe ARDS due to COVID-19 were randomized (1:1) to receive a single intravenous infusion of either ORBCEL-C (400 3 106 CD362-enriched umbilical cord–derived MSCs in 200 ml Plasma-Lyte 148; see theonlinesupplement for manufacturing details, including cell viability assessment) or placebo (Baxter Healthcare Ltd.) (200 ml Plasma-Lyte 148). All other aspects of carewereaccording to standard critical care guidelines (4).
Publisher Copyright:
Copyright © 2023 by the American Thoracic Society.
PY - 2023/5/8
Y1 - 2023/5/8
N2 - RATIONALE: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS).OBJECTIVES: We investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS.METHODS: This multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148).MEASUREMENTS: The primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit 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 day 0, 4 and 7.MAIN RESULTS: 60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome.CONCLUSION: ORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.CLINICALTRIALS: gov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
AB - RATIONALE: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS).OBJECTIVES: We investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS.METHODS: This multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148).MEASUREMENTS: The primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit 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 day 0, 4 and 7.MAIN RESULTS: 60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome.CONCLUSION: ORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.CLINICALTRIALS: gov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
U2 - 10.1164/rccm.202302-0297OC
DO - 10.1164/rccm.202302-0297OC
M3 - Article
C2 - 37154608
SN - 1073-449X
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
ER -