Background: No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed 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 multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [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 prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774. Findings: No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, 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 before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related. Interpretation: A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints. Funding: The National Heart, Lung, and Blood Institute.
Bibliographical noteFunding Information:
This trial was supported by NHLBI U01 HL10871301 , an NIH/NCRR UCSF-CTSI Grant RR024131 (T1 Catalyst Award), and the NIH-supported Production Assistance for Cellular Therapies group (Molecular and Cellular Therapeutics, University of Minnesota), Contract # HHSN268201000008C. The authors also appreciate the support of the intensive care nursing at UCSF, Stanford Medical Center, and the Massachusetts General Hospital. We appreciate the work of Jason Abbott who did the biological measurements, and Brian Daniel, who assisted with adherence to the ARDS Network lung protective ventilation protocol. The authors also thank the Data Safety Monitoring Board (Gordon Bernard, Chair; Herbert Wiedemann, and Kevin Delucchi), and the Medical Monitor (Marc Moss).
All authors report receiving grant support from the National Heart, Lung, and Blood Institute for their work on this project. Additionally, AJR reports receiving grant support from the Parker B Francis Foundation. DM reports additional grants from the National Heart, Lung, and Blood Institute (PACT programme). KDL reports receiving grant support from the National Institute of Kidney and Digestive Diseases and financial and non-financial interests in Astute (adjudicator of clinical events), Abbvie (advisory board member), Complexa (scientific advisory board member), Amgen (stockholder), Cytopheryx (Data and Safety Monitoring Board), Chemocentryx (consultant), and Abbott (receives assay reagents). CSC reports grant support from GlaxoSmithKline and consulting work with GlaxoSmithKline and Cerus. BTT reports consulting work with GlaxoSmithKline. MAM reports grant support from the National Institute of Allergy and Infectious Diseases, GlaxoSmithKline, as well as consulting work with GlaxoSmithKline, Cerus, and Roche-Genentech (Chair of Data and Safety Monitoring Board). All other authors declare no competing interests.
© 2015 Elsevier Ltd.