Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial

  1. Manoj M Lalu
  2. Katrina J Sullivan
  3. Shirley HJ Mei
  4. David Moher
  5. Alexander Straus
  6. Dean A Fergusson
  7. Duncan J Stewart
  8. Mazen Jazi
  9. Malcolm MacLeod
  10. Brent Winston
  11. John Marshall
  12. Brian Hutton
  13. Keith R Walley
  14. Lauralyn McIntyre  Is a corresponding author
  15. on behalf of the Canadian Critical Care Translational Biology Group
  1. The Ottawa Hospital, Canada
  2. The Ottawa Hospital Research Institute, Canada
  3. The University of Edinburgh, United Kingdom
  4. University of Calgary, Canada
  5. St. Michaels Hospital, The University of Toronto, Canada
  6. 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.

Article and author information

Author details

  1. Manoj M Lalu

    Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0322-382X
  2. Katrina J Sullivan

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Shirley HJ Mei

    Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. David Moher

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Alexander Straus

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Dean A Fergusson

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Duncan J Stewart

    Regenerative Medicine Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9113-8691
  8. Mazen Jazi

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Malcolm MacLeod

    Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Brent Winston

    Department of Critical Care Medicine, University of Calgary, Calgary, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. John Marshall

    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
    Competing interests
    The authors declare that no competing interests exist.
  12. Brian Hutton

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Keith R Walley

    Department of Medicine, University of Ottawa, Ottawa, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Lauralyn McIntyre

    Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, Canada
    For correspondence
    lmcintyre@ohri.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7421-1407

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.

Reviewing Editor

  1. M Dawn Teare, University of Sheffield, United Kingdom

Version history

  1. Received: May 15, 2016
  2. Accepted: November 2, 2016
  3. Accepted Manuscript published: November 17, 2016 (version 1)
  4. Version of Record published: December 12, 2016 (version 2)

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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  1. Manoj M Lalu
  2. Katrina J Sullivan
  3. Shirley HJ Mei
  4. David Moher
  5. Alexander Straus
  6. Dean A Fergusson
  7. Duncan J Stewart
  8. Mazen Jazi
  9. Malcolm MacLeod
  10. Brent Winston
  11. John Marshall
  12. Brian Hutton
  13. Keith R Walley
  14. Lauralyn McIntyre
  15. on behalf of the Canadian Critical Care Translational Biology Group
(2016)
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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https://doi.org/10.7554/eLife.17850