title: Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial.
abstract: Evaluation of preclinical evidence prior to initiating early-phase clinical studies has typically been performed by selecting individual studies in a non-systematic process that may introduce bias. Thus, in preparation for a first-in-human trial of mesenchymal stromal cells (MSCs) for septic shock, we applied systematic review methodology to evaluate all published preclinical evidence. We identified 20 controlled comparison experiments (980 animals from 18 publications) ofin vivosepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality over a range of experimental conditions (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study). Risk of bias was unclear as few studies described elements such as randomization and no studies included an appropriately calculated sample size. Moreover, the presence of publication bias resulted in a ~30% overestimate of effect and threats to validity limit the strength of our conclusions. This novel prospective application of systematic review methodology serves as a template to evaluate preclinical evidence prior to initiating first-in-human clinical studies.
authors.affiliation: Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Canada.|Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.|Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Manoj M
authors.identifier: 0000-0002-0322-382X
authors.initials: MM
authors.lastname: Lalu
authors.affiliation: Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Sullivan
authors.affiliation: Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Shirley Hj
authors.initials: SH
authors.lastname: Mei
authors.affiliation: Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.|School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Moher
authors.affiliation: Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Straus
authors.affiliation: Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fergusson
authors.affiliation: Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Cell and Molecular Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Duncan J
authors.identifier: 0000-0002-9113-8691
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.|Faculty of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Mazen
authors.initials: M
authors.lastname: Jazi
authors.affiliation: Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacLeod
authors.affiliation: Department of Critical Care Medicine, University of Calgary, Calgary, Canada.
authors.forename: Brent
authors.initials: B
authors.lastname: Winston
authors.affiliation: Departments of Surgery and Critical Care Medicine, Keenan Research Centre of the Li KaShing Knowledge Institute, St. Michaels Hospital, The University of Toronto, Toronto, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.affiliation: Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Hutton
authors.affiliation: Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.affiliation: Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada.|Department of Medicine, University of Ottawa, Ottawa, Canada.
authors.forename: Lauralyn
authors.identifier: 0000-0001-7421-1407
authors.initials: L
authors.lastname: McIntyre
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D018805:Sepsis / Q000473:pathology / Q000628:therapy*
keywords: epidemiology; global health; human biology; medicine; mouse; preclinical; rat; sepsis; stem cells; systematic review; translation