Background: Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS. Methods: We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ≥8 cm H2O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 106/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641. Findings: From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5–15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 ), minute ventilation (11·1 [3·2] vs 9·6 [2·4] L/min), and PEEP (12·4 [3·7] vs 10·8 [2·6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40–5·12, p=0·58). Viability of MSCs ranged from 36% to 85%. Interpretation: One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved. Funding: National Heart, Lung, and Blood Institute.
Bibliographical noteFunding Information:
MAM has received grants from Bayer Pharmaceuticals and GlaxoSmithKline, personal fees from Boehringer Ingelheim, Cerus Therapeutics, CSL Berhing, Quark Pharmaceuticals, Roche-Genentec, and Thesan Pharmaceuticals. CSC has received grants and personal fees from Bayer and GlaxoSmithKline, personal fees from Boehringer Ingelheim, CSL Behring, Prometic, and Roche/Genentech. EKB has received personal fees from Merck. BJM has received grants from Bayer Pharmaceuticals and personal fees from Vapotherm. KDL has received personal fees from Achaogen, Durect, Potrero Medical, Quark, Theravance, and Z S Pharma, and other funding or awards from Amgen. The other authors declare no competing interests.
This work was funded by the National Heart, Lung, and Blood Institute Production Assistance for Cellular Therapies Program (U01 HL108713 and HHSN26820100008C). We thank the clinical coordinators and bone-marrow transplant staff at the medical centres: Faye Pais, Brian Daniel, Annika Belzer (coordinators), and Xiaohui Fang (laboratory investigator), University of California San Francisco; Sarah F Rapport (coordinator) and Misty DeRiggi (bone-marrow-transplantation laboratory lead technician), University of Pittsburgh Medical Center; Emily Robart, Luke Herren (coordinators), Beth Besecker (co-investigator), Hillary Bradbury, and Beth Daneault (bone-marrow-transplantation laboratory), Ohio State University Medical Center; Rosemary Vojnik (coordinator) and Mary McLeod (bone-marrow-transplantation laboratory), Stanford University; Kelsey Brait (coordinator), Massachusetts General Hospital; and Diane Kadidlo, (technical supervisor) and Darin Sumstad (technical specialist), University of Minnesota Program Assisted Cellular Therapeutics and Translational Development Team of the Cell Therapy Laboratory of University of Minnesota Medical Center.
© 2019 Elsevier Ltd