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
Affiliations
Antoine Monsel
Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié–Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne University
Caroline Hauw-Berlemont
Intensive Care Unit, APHP-CUP, Hôpital Européen Georges-Pompidou, Université de Paris
Miryam Mebarki
APHP, Hôpital Saint-Louis, Unité de Thérapie Cellulaire, Centre d’Investigation Clinique en Biothérapies CBT501, INSERM, Université de Paris
Nicholas Heming
FHU SEPSIS, Department of Intensive Care, Hôpital Raymond-Poincaré (APHP), Laboratory of Infection & Inflammation–INSERM U1173, Simone Veil School of Medicine, University Versailles Saint Quentin–University Paris Saclay
Julien Mayaux
APHP, Groupe Hospitalier Universitaire–Sorbonne Université, site Pitié–Salpêtrière, Service de Médecine Intensive et Réanimation (Département R3S), and Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique
Intensive Care Unit, APHP-CUP, Hôpital Européen Georges-Pompidou, Université de Paris
Alexandre Demoule
APHP, Groupe Hospitalier Universitaire–Sorbonne Université, site Pitié–Salpêtrière, Service de Médecine Intensive et Réanimation (Département R3S), and Sorbonne Université, INSERM, UMRS1158 Neurophysiologie Respiratoire Expérimentale et Clinique
Djillali Annane
FHU SEPSIS, Department of Intensive Care, Hôpital Raymond-Poincaré (APHP), Laboratory of Infection & Inflammation–INSERM U1173, Simone Veil School of Medicine, University Versailles Saint Quentin–University Paris Saclay
Clémence Marois
Neurological Intensive Care Unit, Department of Neurology, La Pitié–Salpêtrière Hospital, APHP, Sorbonne University
Sophie Demeret
Neurological Intensive Care Unit, Department of Neurology, La Pitié–Salpêtrière Hospital, APHP, Sorbonne University
Emmanuel Weiss
Department of Anesthesiology and Critical Care, Beaujon Hospital, DMU PARABOL, APHP Nord
Guillaume Voiriot
Service de Médecine Intensive Réanimation, Hôpital Tenon, APHP, Sorbonne Université
Muriel Fartoukh
Service de Médecine Intensive Réanimation, Hôpital Tenon, APHP, Sorbonne Université
Jean-Michel Constantin
Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié–Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP) Sorbonne University
Bruno Mégarbane
Department of Medical and Toxicological Critical Care, Lariboisière Hospital, INSERM UMRS1144, University of Paris
Gaëtan Plantefève
Service de Réanimation Polyvalente, Centre Hospitalier Victor Dupouy
Stéphanie Malard-Castagnet
Immunology and HLA Laboratory, Hôpital Saint-Louis
Sonia Burrel
INSERM U1136, Institut Pierre-Louis d’Epidémiologie et de Santé Publique (iPLESP), APHP, Hôpital Pitié–Salpêtrière, Service de Virologie, Sorbonne Université
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://clinicaltrials.gov/ct2/history/NCT04333368 .
