Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial

  1. Lei Shi
  2. Hai Huang
  3. Xuechun Lu
  4. Xiaoyan Yan
  5. Xiaojing Jiang
  6. Ruonan Xu
  7. Siyu Wang
  8. Chao Zhang
  9. Xin Yuan
  10. Zhe Xu
  11. Lei Huang
  12. Jun-Liang Fu
  13. Yuanyuan Li
  14. Yu Zhang
  15. Wei-Qi Yao
  16. Tianyi Liu
  17. Jinwen Song
  18. Liangliang Sun
  19. Fan Yang
  20. Xin Zhang
  21. Bo Zhang
  22. Ming Shi
  23. Fanping Meng
  24. Yanning Song
  25. Yongpei Yu
  26. Jiqiu Wen
  27. Qi Li
  28. Qing Mao
  29. Markus Maeurer
  30. Alimuddin Zumla
  31. Chen Yao
  32. Wei-Fen Xie
  33. Fu-Sheng Wang

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Abstract

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 10 7 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs ( n  = 65) or placebo ( n  = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was −13.31%, 95% CI −29.14%, 2.13%, P  = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: −15.45%; 95% CI −30.82%, −0.39%; P  = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P  = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.15.20213553: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethical approval was obtained from the institutional review boards of each participating hospital.
    Consent: Written informed consent was obtained from all the enrolled patients or their legal representatives if they were unable to provide consent.
    RandomizationDesign: We conducted a randomized, placebo-controlled, double-blind phase 2 trial (ClinicalTrials.gov: NCT04288102).
    BlindingPatients, investigators, and outcome assessors (independent central imaging reviewers) were all blinded to the treatment allocation.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical analyses were performed using SAS software, version 9.4 (Cary, NC, USA).
    SAS
    suggested: (SASqPCR, RRID:SCR_003056)
    The figures were generated using GraphPad Prism 7 software (GraphPad Inc., La Jolla, CA, USA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    There were several operational limitations to our study. A larger sample size could have improved efficacy analyses. According to management guidelines issued by the Chinese National Health Commission (7th edition),21 patients with COVID-19 require further centralized isolation for 14 days after discharge. In this setting, some of the patients missed the follow-up data at day 28, but they did receive a follow-up check around 7–10 days after the 28-day follow-up window. Importantly, our PP population analysis also revealed similar results compared with mITT population analysis. Whether the cell dosage, interval duration, and cycles of UC-MSC medication were the best regimen for patients with severe COVID-19 were not fully investigated in this study. To the best of our knowledge, this is the first randomized, double-blind, placebo-controlled trial evaluating the safety and preliminary efficacy of UC-MSCs as a potential treatment for patients with COVID-19 with lung damage, even at the convalescent stage. UC-MSC administration was safe and accelerated resolution of lung solid component lesions and improvement in the integrated reserve capability after UC-MSC administration. UC-MSCs treatment offers a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to further evaluate effects on preventing long-term pulmonary disability, reducing mortality and determining the underlying mechanisms of UC-MSC treatment for COVI...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04288102CompletedTreatment With Human Umbilical Cord-derived Mesenchymal Stem…
    NCT04252118RecruitingMesenchymal Stem Cell Treatment for Pneumonia Patients Infec…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1038/s41392-021-00488-5
  3. Version published to 10.1101/2020.10.15.20213553v2 on medRxiv
  4. Version published to 10.1101/2020.10.15.20213553v1 on medRxiv