title: Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  The National Heart, Lung, and Blood Institute.
authors.affiliation: Departments of Emergency Medicine and Anesthesia, University of California, San Francisco, CA, USA.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Hanjing
authors.initials: H
authors.lastname: Zhuo
authors.affiliation: Clinical Laboratories, Blood and Marrow Transplant Laboratory, University of California, San Francisco, CA, USA.
authors.forename: Lizette
authors.initials: L
authors.lastname: Caballero
authors.affiliation: Clinical Laboratories, Blood and Marrow Transplant Laboratory, University of California, San Francisco, CA, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: McMillan
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, MA, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Cosgrove
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Vojnik
authors.affiliation: Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.affiliation: Department of Anesthesia, University of California, San Francisco, CA, USA.
authors.forename: Jae-Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Rogers
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, CA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Levitt
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard University, Cambridge, MA, USA.
authors.forename: Jeanine
authors.initials: J
authors.lastname: Wiener-Kronish
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, MA, USA.
authors.forename: Ednan K
authors.initials: EK
authors.lastname: Bajwa
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leavitt
authors.affiliation: Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: David
authors.initials: D
authors.lastname: McKenna
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, MA, USA.
authors.forename: B Taylor
authors.initials: BT
authors.lastname: Thompson
authors.affiliation: Departments of Medicine and Anesthesia and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA. Electronic address: michael.matthay@ucsf.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods / Q000706:statistics & numerical data*; D008875:Middle Aged; D012128:Respiratory Distress Syndrome / Q000628:therapy*; D016896:Treatment Outcome