Updated Living Systematic Review and Meta-analysis of Controlled Trials of Mesenchymal Stromal Cells to Treat COVID-19: A Framework for Accelerated Synthesis of Trial Evidence for Rapid Approval-FASTER Approval

Aidan M Kirkham; Adrian J M Bailey; Madeline Monaghan; Risa Shorr; Manoj M Lalu; Dean A Fergusson; David S Allan

doi:10.1093/stcltm/szac038

Updated Living Systematic Review and Meta-analysis of Controlled Trials of Mesenchymal Stromal Cells to Treat COVID-19: A Framework for Accelerated Synthesis of Trial Evidence for Rapid Approval-FASTER Approval

Stem Cells Transl Med. 2022 Jul 20;11(7):675-687. doi: 10.1093/stcltm/szac038.

Authors

Aidan M Kirkham^{1

2}, Adrian J M Bailey², Madeline Monaghan², Risa Shorr³, Manoj M Lalu^{4

5

6

7}, Dean A Fergusson^{2

8

9

10}, David S Allan^{1

2

8

6

10}

Affiliations

¹ Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
² Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
³ Medical Information and Learning Services, The Ottawa Hospital, Ottawa, ON, Canada.
⁴ Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
⁵ Department of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, ON, Canada.
⁶ Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
⁷ Department of Anesthesia, The Ottawa Hospital, Ottawa, ON, Canada.
⁸ Department of Medicine, University of Ottawa, Ottawa, ON, Canada.
⁹ Department of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
¹⁰ Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada.

Abstract

Background: Mesenchymal stromal cells (MSCs) may reduce mortality in patients with COVID-19; however, early evidence is based on few studies with marked interstudy heterogeneity. The second iteration of our living systematic review and meta-analysis evaluates a framework needed for synthesizing evidence from high-quality studies to accelerate consideration for approval.

Methods: A systematic search of the literature was conducted on November 15, 2021, to identify all English-language, full-text, and controlled clinical studies examining MSCs to treat COVID-19 (PROSPERO: CRD42021225431).

Findings: Eleven studies were identified (403 patients with severe and/or critical COVID-19, including 207 given MSCs and 196 controls). All 11 studies reported mortality and were pooled through random-effects meta-analysis. MSCs decreased relative risk of death at study endpoint (RR: 0.50 [95% CI, 0.34-0.75]) and RR of death at 28 days after treatment (0.19 [95% CI], 0.05-0.78) compared to controls. MSCs also decreased length of hospital stay (mean difference (MD: -3.97 days [95% CI, -6.09 to -1.85], n = 5 studies) and increased oxygenation levels at study endpoint compared to controls (MD: 105.62 mmHg O2 [95% CI, 73.9-137.3,], n = 3 studies). Only 2 of 11 studies reported on all International Society for Cellular Therapy (ISCT) criteria for MSC characterization. Included randomized controlled trials were found to have some concerns (n = 2) to low (n = 4) risk of bias (RoB), while all non-randomized studies were found to have moderate (n = 5) RoB.

Interpretation: Our updated living systematic review concludes that MSCs can likely reduce mortality in patients with severe or critical COVID-19. A master protocol based on our Faster Approval framework appears necessary to facilitate the more accelerated accumulation of high-quality evidence that would reduce RoB, improve consistency in product characterization, and standardize outcome reporting.

Keywords: ARDS; COVID-19; MSC-EVs exosomes; SARS-CoV-2; acute respiratory distress syndrome; coronavirus disease 2019; extracellular vesicles; mesenchymal stem cells; mesenchymal stromal cells; microvesicles; pneumonia; sepsis; severe acute respiratory syndrome coronavirus 2.

Publication types

Meta-Analysis
Systematic Review
Research Support, Non-U.S. Gov't

MeSH terms

Bias
COVID-19* / therapy
Humans
Lung
Mesenchymal Stem Cells*
Randomized Controlled Trials as Topic