A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19

Michael E. Bowdish; Christina E. Barkauskas; Jessica R. Overbey; Robert L. Gottlieb; Keren Osman; Abhijit Duggal; Mary E. Marks; Jonathan Hupf; Eustace Fernandes; Bradley G. Leshnower; Jonathan L. Golob; Alexander Iribarne; Athos J. Rassias; Ellen G. Moquete; Karen O'Sullivan; Helena L. Chang; Judson B. Williams; Sam Parnia; Nirav C. Patel; Nimesh D. Desai; Andrew M. Vekstein; Beth A. Hollister; Tammie Possemato; Christian Romero; Peter C. Hou; Elizabeth Burke; Jack Hayes; Fred Grossman; Silviu Itescu; Marc Gillinov; Francis D. Pagani; Patrick T. O'Gara; Michael J. Mack; Peter K. Smith; Emilia Bagiella; Alan J. Moskowitz; Annetine C. Gelijns

doi:10.1164/rccm.202201-0157OC

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19

Michael E. Bowdish, Christina E. Barkauskas, Jessica R. Overbey, Robert L. Gottlieb, Keren Osman, Abhijit Duggal, Mary E. Marks, Jonathan Hupf, Eustace Fernandes, Bradley G. Leshnower, Jonathan L. Golob, Alexander Iribarne, Athos J. Rassias, Ellen G. Moquete, Karen O'Sullivan, Helena L. Chang, Judson B. Williams, Sam Parnia, Nirav C. Patel, Nimesh D. DesaiAndrew M. Vekstein, Beth A. Hollister, Tammie Possemato, Christian Romero, Peter C. Hou, Elizabeth Burke, Jack Hayes, Fred Grossman, Silviu Itescu, Marc Gillinov, Francis D. Pagani, Patrick T. O'Gara, Michael J. Mack, Peter K. Smith, Emilia Bagiella, Alan J. Moskowitz, Annetine C. Gelijns

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

1 Scopus citations

Abstract

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P= 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

Original language	English
Pages (from-to)	261-270
Number of pages	10
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	207
Issue number	3
DOIs	https://doi.org/10.1164/rccm.202201-0157OC
State	Published - 1 Feb 2023

Keywords

SARS-CoV-2
clinical trial
mechanical ventilation
stem cells
survival

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10.1164/rccm.202201-0157OC

Cite this

Bowdish, M. E., Barkauskas, C. E., Overbey, J. R., Gottlieb, R. L., Osman, K., Duggal, A., Marks, M. E., Hupf, J., Fernandes, E., Leshnower, B. G., Golob, J. L., Iribarne, A., Rassias, A. J., Moquete, E. G., O'Sullivan, K., Chang, H. L., Williams, J. B., Parnia, S., Patel, N. C., ... Gelijns, A. C. (2023). A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19. American Journal of Respiratory and Critical Care Medicine, 207(3), 261-270. https://doi.org/10.1164/rccm.202201-0157OC

@article{75602845b61540cf81a957467dfceb76,

title = "A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19",

abstract = "Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P= 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.",

keywords = "SARS-CoV-2, clinical trial, mechanical ventilation, stem cells, survival",

author = "Bowdish, {Michael E.} and Barkauskas, {Christina E.} and Overbey, {Jessica R.} and Gottlieb, {Robert L.} and Keren Osman and Abhijit Duggal and Marks, {Mary E.} and Jonathan Hupf and Eustace Fernandes and Leshnower, {Bradley G.} and Golob, {Jonathan L.} and Alexander Iribarne and Rassias, {Athos J.} and Moquete, {Ellen G.} and Karen O'Sullivan and Chang, {Helena L.} and Williams, {Judson B.} and Sam Parnia and Patel, {Nirav C.} and Desai, {Nimesh D.} and Vekstein, {Andrew M.} and Hollister, {Beth A.} and Tammie Possemato and Christian Romero and Hou, {Peter C.} and Elizabeth Burke and Jack Hayes and Fred Grossman and Silviu Itescu and Marc Gillinov and Pagani, {Francis D.} and O'Gara, {Patrick T.} and Mack, {Michael J.} and Smith, {Peter K.} and Emilia Bagiella and Moskowitz, {Alan J.} and Gelijns, {Annetine C.}",

note = "Funding Information: Supported by Mesoblast, Inc. Biospecimen collection for the purposes of enabling mechanistic studies was supported by a cooperative agreement (U01 HL088942) funded by the National Heart, Lung, and Blood Institute. Mesoblast, Inc. was not involved in data collection and data analysis. Mesoblast reviewed the data and final manuscript, but the academic authors retained editorial control. Publisher Copyright: {\textcopyright} 2023 by the American Thoracic Society.",

year = "2023",

month = feb,

day = "1",

doi = "10.1164/rccm.202201-0157OC",

language = "English",

volume = "207",

pages = "261--270",

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

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "3",

}

Bowdish, ME, Barkauskas, CE, Overbey, JR, Gottlieb, RL, Osman, K, Duggal, A, Marks, ME, Hupf, J, Fernandes, E, Leshnower, BG, Golob, JL, Iribarne, A, Rassias, AJ, Moquete, EG, O'Sullivan, K, Chang, HL, Williams, JB, Parnia, S, Patel, NC, Desai, ND, Vekstein, AM, Hollister, BA, Possemato, T, Romero, C, Hou, PC, Burke, E, Hayes, J, Grossman, F, Itescu, S, Gillinov, M, Pagani, FD, O'Gara, PT, Mack, MJ, Smith, PK, Bagiella, E, Moskowitz, AJ & Gelijns, AC 2023, 'A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19', American Journal of Respiratory and Critical Care Medicine, vol. 207, no. 3, pp. 261-270. https://doi.org/10.1164/rccm.202201-0157OC

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19. / Bowdish, Michael E.; Barkauskas, Christina E.; Overbey, Jessica R. et al.
In: American Journal of Respiratory and Critical Care Medicine, Vol. 207, No. 3, 01.02.2023, p. 261-270.

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

TY - JOUR

T1 - A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19

AU - Bowdish, Michael E.

AU - Barkauskas, Christina E.

AU - Overbey, Jessica R.

AU - Gottlieb, Robert L.

AU - Osman, Keren

AU - Duggal, Abhijit

AU - Marks, Mary E.

AU - Hupf, Jonathan

AU - Fernandes, Eustace

AU - Leshnower, Bradley G.

AU - Golob, Jonathan L.

AU - Iribarne, Alexander

AU - Rassias, Athos J.

AU - Moquete, Ellen G.

AU - O'Sullivan, Karen

AU - Chang, Helena L.

AU - Williams, Judson B.

AU - Parnia, Sam

AU - Patel, Nirav C.

AU - Desai, Nimesh D.

AU - Vekstein, Andrew M.

AU - Hollister, Beth A.

AU - Possemato, Tammie

AU - Romero, Christian

AU - Hou, Peter C.

AU - Burke, Elizabeth

AU - Hayes, Jack

AU - Grossman, Fred

AU - Itescu, Silviu

AU - Gillinov, Marc

AU - Pagani, Francis D.

AU - O'Gara, Patrick T.

AU - Mack, Michael J.

AU - Smith, Peter K.

AU - Bagiella, Emilia

AU - Moskowitz, Alan J.

AU - Gelijns, Annetine C.

N1 - Funding Information: Supported by Mesoblast, Inc. Biospecimen collection for the purposes of enabling mechanistic studies was supported by a cooperative agreement (U01 HL088942) funded by the National Heart, Lung, and Blood Institute. Mesoblast, Inc. was not involved in data collection and data analysis. Mesoblast reviewed the data and final manuscript, but the academic authors retained editorial control. Publisher Copyright: © 2023 by the American Thoracic Society.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P= 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

AB - Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P= 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.

KW - SARS-CoV-2

KW - clinical trial

KW - mechanical ventilation

KW - stem cells

KW - survival

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U2 - 10.1164/rccm.202201-0157OC

DO - 10.1164/rccm.202201-0157OC

M3 - Article

C2 - 36099435

AN - SCOPUS:85147234533

SN - 1073-449X

VL - 207

SP - 261

EP - 270

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 3

ER -

A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19

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