Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: a multicenter randomized double-blind trial

Antoine Monsel, Caroline Hauw-Berlemont, Miryam Mebarki, Nicholas Heming, Julien Mayaux, Otriv Nguekap Tchoumba, Jean-Luc Diehl, Alexandre Demoule, Djillali Annane, Clémence Marois, Sophie Demeret, Emmanuel Weiss, Guillaume Voiriot, Muriel Fartoukh, Jean-Michel Constantin, Bruno Mégarbane, Gaëtan Plantefève, Stéphanie Malard-Castagnet, Sonia Burrel, Michelle Rosenzwajg, Nicolas Tchitchek, Hélène Boucher-Pillet, Guillaume Churlaud, Audrey Cras, Camille Maheux, Chloé Pezzana, Mamadou Hassimiou Diallo, Jacques Ropers, Philippe Menasché, Jérôme Larghero, APHP STROMA–CoV-2 Collaborative Research Group, Déborah Benchetrit, Harold Bonvallot, Fanny Charbonnier-Beaupel, Meriem Dhib-Charfi, Pierre Romain Delmotte, Assitan Kone, Marine Le Corre, Anne-Geneviève Marcelin, Carole Metz, Louis Puybasset, Joe-Elie Salem, Corinne Vezinet, Antoine Monsel, Caroline Hauw-Berlemont, Miryam Mebarki, Nicholas Heming, Julien Mayaux, Otriv Nguekap Tchoumba, Jean-Luc Diehl, Alexandre Demoule, Djillali Annane, Clémence Marois, Sophie Demeret, Emmanuel Weiss, Guillaume Voiriot, Muriel Fartoukh, Jean-Michel Constantin, Bruno Mégarbane, Gaëtan Plantefève, Stéphanie Malard-Castagnet, Sonia Burrel, Michelle Rosenzwajg, Nicolas Tchitchek, Hélène Boucher-Pillet, Guillaume Churlaud, Audrey Cras, Camille Maheux, Chloé Pezzana, Mamadou Hassimiou Diallo, Jacques Ropers, Philippe Menasché, Jérôme Larghero, APHP STROMA–CoV-2 Collaborative Research Group, Déborah Benchetrit, Harold Bonvallot, Fanny Charbonnier-Beaupel, Meriem Dhib-Charfi, Pierre Romain Delmotte, Assitan Kone, Marine Le Corre, Anne-Geneviève Marcelin, Carole Metz, Louis Puybasset, Joe-Elie Salem, Corinne Vezinet

Abstract

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced acute respiratory distress syndrome (ARDS) causes high mortality. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have potentially relevant immune-modulatory properties, whose place in ARDS treatment is not established. This phase 2b trial was undertaken to assess the efficacy of UC-MSCs in patients with SARS-CoV-2-induced ARDS.

Methods: This multicentre, double-blind, randomized, placebo-controlled trial (STROMA-CoV-2) recruited adults (≥ 18 years) with SARS-CoV-2-induced early (< 96 h) mild-to-severe ARDS in 10 French centres. Patients were randomly assigned to receive three intravenous infusions of 106 UC-MSCs/kg or placebo (0.9% NaCl) over 5 days after recruitment. For the modified intention-to-treat population, the primary endpoint was the partial pressure of oxygen to fractional inspired oxygen (PaO2/FiO2)-ratio change between baseline (day (D) 0) and D7.

Results: Among the 107 patients screened for eligibility from April 6, 2020, to October 29, 2020, 45 were enrolled, randomized and analyzed. PaO2/FiO2 changes between D0 and D7 did not differ significantly between the UC-MSCs and placebo groups (medians [IQR] 54.3 [- 15.5 to 93.3] vs 25.3 [- 33.3 to 104.6], respectively; ANCOVA estimated treatment effect 7.4, 95% CI - 44.7 to 59.7; P = 0.77). Six (28.6%) of the 21 UC-MSCs recipients and six of 24 (25%) placebo-group patients experienced serious adverse events, none of which were related to UC-MSCs treatment.

Conclusions: D0-to-D7 PaO2/FiO2 changes for intravenous UC-MSCs-versus placebo-treated adults with SARS-CoV-2-induced ARDS did not differ significantly. Repeated UC-MSCs infusions were not associated with any serious adverse events during treatment or thereafter (until D28). Larger trials enrolling patients earlier during the course of their ARDS are needed to further assess UC-MSCs efficacy in this context.

Trial registration: NCT04333368. Registered 01 April 2020, https://ichgcp.net/clinical-trials-registry/NCT04333368 .

Keywords: Acute respiratory distress syndrome; Good-manufacturing practice; Severe acute respiratory syndrome coronavirus-2; Umbilical cord-derived mesenchymal stromal cells.

Conflict of interest statement

AD declared grants or contracts from Philips, Fisher & Paykel; French Ministry of Health; Respinor; Lungspacer; consulting fees from Lungspacer, Respinor; payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Fisher & Paykel, Getinge, Lungspacer, Gilead, Lowenstein, Astra; support for attending meetings and/or travel from Fisher & Paykel, Lungspacer; received equipment, materials, drugs, medical writing, gifts or other services from Lungspacer, Respinor. MF declared grants or contracts from BioMérieux and MSD; French Ministry of Health; consulting fees from Pfizer; payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events from Fisher & Paykel and Biomérieux; participation on a data safety monitoring board or advisory board. ONT received grants or contracts from the French National Society of Internal Medicine (SNFMI). No conflict of interests is reported for other authors.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart of the trial. ARDS acute respiratory distress syndrome. ATMP advanced therapeutic medicinal product. D day. ELS extracorporeal life support. ICU intensive care unit. UC-MSCs umbilical cord-derived mesenchymal stromal cells
Fig. 2
Fig. 2
Primary endpoint: PaO2/FiO2 values and their changes between days 0 and 7. A Baseline (D0) and D7 PaO2/FiO2 ratios were similar for the two groups. Box plots of PaO2/FiO2 ratios: internal horizontal lines are the medians; lower and upper box limits are the 25th–75th interquartile range, respectively; and vertical bars represent the 10th and 90th percentiles. B PaO2/FiO2 ratios increased significantly from D0 to D7 in the UC-MSC group (respectively, 156.2 ± 68.2 vs 188.3 ± 74.2; Wilcoxon signed-rank exact test). The placebo group’s PaO2/FiO2 ratios on D0 and D7 were comparable (respectively, 171.2 ± 72.9 vs 169.8 ± 85.6, Wilcoxon signed-rank exact test). UC-MSCs group in red; placebo group in blue. D day. PaO2/FiO2 ratio of partial pressure of oxygen to fractional inspired oxygen. UC-MSCs umbilical cord-derived mesenchymal stromal cells

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