Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial
- The Ottawa Hospital, Canada
- The Ottawa Hospital Research Institute, Canada
- The University of Edinburgh, United Kingdom
- University of Calgary, Canada
- St. Michaels Hospital, The University of Toronto, Canada
- University of Ottawa, Canada
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) of in vivo sepsis models. Meta-analysis demonstrated that MSC treatment of preclinical sepsis significantly reduced mortality (odds ratio 0.27, 95% confidence interval 0.18-0.40, latest timepoint reported for each study) over a range of experimental conditions. 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.
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Funding
National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/L000970/1)
- David Moher
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Lalu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial
eLife 5:e17850.
https://doi.org/10.7554/eLife.17850
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