Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial

Ellen A Gorman; Jennifer Rynne; Hannah J Gardiner; Anthony J Rostron; Jonathan Bannard-Smith; Andrew M Bentley; David Brealey; Christina Campbell; Gerard Curley; Mike Clarke; Ahilanadan Dushianthan; Phillip Hopkins; Colette Jackson; Kallirroi Kefela; Anna Krasnodembskaya; John G. Laffey; Cliona McDowell; Margaret McFarland; Jamie McFerran; Peter McGuigan; Gavin D Perkins; Jonathan Silversides; Jon Smythe; Jacqui Thompson; William S Tunnicliffe; Ingeborg DM Welters; Laura Amado-Rodríguez; Guillermo Albaiceta; Barry Williams; Manu Shankar-Hari; Daniel F. McAuley; Cecilia M. O'Kane

doi:10.1164/rccm.202302-0297oc

Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial

Ellen A Gorman, Jennifer Rynne, Hannah J Gardiner, Anthony J Rostron, Jonathan Bannard-Smith, Andrew M Bentley, David Brealey, Christina Campbell, Gerard Curley, Mike Clarke, Ahilanadan Dushianthan, Phillip Hopkins, Colette Jackson, Kallirroi Kefela, Anna Krasnodembskaya, John G. Laffey, Cliona McDowell, Margaret McFarland, Jamie McFerran, Peter McGuiganGavin D Perkins, Jonathan Silversides, Jon Smythe, Jacqui Thompson, William S Tunnicliffe, Ingeborg DM Welters, Laura Amado-Rodríguez, Guillermo Albaiceta, Barry Williams, Manu Shankar-Hari, Daniel F. McAuley, Cecilia M. O'Kane

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Abstract

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 98.357.2], placebo 96.667.3). 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.

Original language	English
Pages (from-to)	256-269
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	208
Issue number	3
Early online date	08 May 2023
DOIs	https://doi.org/10.1164/rccm.202302-0297oc
Publication status	Published - 01 Aug 2023

Keywords

Critical Care and Intensive Care Medicine
Pulmonary and Respiratory Medicine

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10.1164/rccm.202302-0297ocLicence: CC BY

Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial
Copyright 2023 the authors. This is an open access article published under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 1.94 MBLicence: CC BY-NC-ND

Role of active deresuscitation after resuscitation
Silversides, J. (Author), McAuley, D. (Supervisor) & Blackwood, B. (Supervisor), Dec 2019
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Gorman, E. A., Rynne, J., Gardiner, H. J., Rostron, A. J., Bannard-Smith, J., Bentley, A. M., Brealey, D., Campbell, C., Curley, G., Clarke, M., Dushianthan, A., Hopkins, P., Jackson, C., Kefela, K., Krasnodembskaya, A., Laffey, J. G., McDowell, C., McFarland, M., McFerran, J., ... O'Kane, C. M. (2023). Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial. American Journal of Respiratory and Critical Care Medicine, 208(3), 256-269. https://doi.org/10.1164/rccm.202302-0297oc

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title = "Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial",

abstract = "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 98.357.2], placebo 96.667.3). 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.",

keywords = "Critical Care and Intensive Care Medicine, Pulmonary and Respiratory Medicine",

author = "Gorman, {Ellen A} and Jennifer Rynne and Gardiner, {Hannah J} and Rostron, {Anthony J} and Jonathan Bannard-Smith and Bentley, {Andrew M} and David Brealey and Christina Campbell and Gerard Curley and Mike Clarke and Ahilanadan Dushianthan and Phillip Hopkins and Colette Jackson and Kallirroi Kefela and Anna Krasnodembskaya and Laffey, {John G.} and Cliona McDowell and Margaret McFarland and Jamie McFerran and Peter McGuigan and Perkins, {Gavin D} and Jonathan Silversides and Jon Smythe and Jacqui Thompson and Tunnicliffe, {William S} and Welters, {Ingeborg DM} and Laura Amado-Rodr{\'i}guez and Guillermo Albaiceta and Barry Williams and Manu Shankar-Hari and McAuley, {Daniel F.} and O'Kane, {Cecilia M.}",

year = "2023",

month = aug,

day = "1",

doi = "10.1164/rccm.202302-0297oc",

language = "English",

volume = "208",

pages = "256--269",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "3",

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Gorman, EA, Rynne, J, Gardiner, HJ, Rostron, AJ, Bannard-Smith, J, Bentley, AM, Brealey, D, Campbell, C, Curley, G, Clarke, M, Dushianthan, A, Hopkins, P, Jackson, C, Kefela, K, Krasnodembskaya, A, Laffey, JG, McDowell, C, McFarland, M, McFerran, J, McGuigan, P, Perkins, GD, Silversides, J, Smythe, J, Thompson, J, Tunnicliffe, WS, Welters, IDM, Amado-Rodríguez, L, Albaiceta, G, Williams, B, Shankar-Hari, M, McAuley, DF & O'Kane, CM 2023, 'Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial', American Journal of Respiratory and Critical Care Medicine, vol. 208, no. 3, pp. 256-269. https://doi.org/10.1164/rccm.202302-0297oc

Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial. / Gorman, Ellen A; Rynne, Jennifer; Gardiner, Hannah J et al.
In: American Journal of Respiratory and Critical Care Medicine, Vol. 208, No. 3, 01.08.2023, p. 256-269.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): 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.

PY - 2023/8/1

Y1 - 2023/8/1

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 98.357.2], placebo 96.667.3). 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.

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 98.357.2], placebo 96.667.3). 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.

KW - Critical Care and Intensive Care Medicine

KW - Pulmonary and Respiratory Medicine

U2 - 10.1164/rccm.202302-0297oc

DO - 10.1164/rccm.202302-0297oc

M3 - Article

C2 - 37154608

SN - 1073-449X

VL - 208

SP - 256

EP - 269

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 3

ER -

Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicentre, randomised, controlled trial

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Role of active deresuscitation after resuscitation

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