Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial

Abstract

Background There is no effective pharmacotherapy for the acute respiratory distress syndrome (ARDS), and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. The aim of this phase one clinical trial was to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS. Methods The STem cells for ARDS Treatment (START) trial was a multi-center, open-label, dose-escalation phase one clinical trial of a single dose of intravenous MSCs in patients with moderate-to-severe ARDS. The trial is registered with clinicaltrials.gov number [NCT01775774]. The first three patients were treated with low dose MSCs (1million cells/kg predicted body weight (PBW)); the next three patients received intermediate dose MSCs (5 million cells/kg PBW); and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of pre-specified infusion associated events and serious adverse events. Secondary outcomes included standard respiratory and systemic endpoints, 28- and 60-day mortality, and measurement of biologic markers of inflammation and endothelial and epithelial injury. The trial completed enrollment in January 2014. Findings There were no pre-specified infusion associated events or treatment-related adverse events in any of the nine patients in this trial. Serious adverse events (SAEs) were subsequently observed in three patients during in the weeks following the infusion: two patients expired >seven days after the MSC infusion, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate but thought to have occurred prior the MSC infusion based on MRI results. None of these SAEs were thought to be MSC-related. Interpretation A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in 9 patients with moderate to severe ARDS. Based on this phase one experience, we have proceeded to phase two testing of MSCs for moderate to severe ARDS. Funding The trial was funded by the National Heart, Lung and Blood Institute (NHLBI U01HL10871301).