Human mesenchymal stem cells treatment for severe COVID-19: 1-year follow-up results of a randomized, double-blind, placebo-controlled trial

Abstract

Background: The long-term consequences of human umbilical cord-derived mesenchymal stem cell (UC-MSC) treatment for COVID-19 patients are yet to be reported. This study assessed the 1-year outcomes in patients with severe COVID-19, who were recruited in our previous UC-MSC clinical trial.

Methods: In this prospective, longitudinal, cohort study, 100 patients enrolled in our phase 2 trial were prospectively followed up at 3-month intervals for 1 year to evaluate the long-term safety and effectiveness of UC-MSC treatment. The primary endpoint was an altered proportion of whole-lung lesion volumes measured by high-resolution CT. Other imaging outcomes, 6 min walking distance (6-MWD), lung function, plasma biomarkers, and adverse events were also recorded and analyzed. This trial was registered with ClinicalTrials.gov (NCT04288102).

Findings: MSC administration improved in whole-lung lesion volume compared with the placebo with a difference of -10.8% (95% CI: -20.7%, -1.5%, p = 0.030) on day 10. MSC also reduced the proportion of solid component lesion volume compared with the placebo at each follow-up point. More interestingly, 17.9% (10/56) of patients in the MSC group had normal CT images at month 12, but none in the placebo group (p = 0.013). The incidence of symptoms was lower in the MSC group than in the placebo group at each follow-up time. Neutralizing antibodies were all positive, with a similar median inhibition rate (61.6% vs. 67.6%) in both groups at month 12. No difference in adverse events at the 1-year follow-up and tumor markers at month 12 were observed between the two groups.

Interpretation: UC-MSC administration achieves a long-term benefit in the recovery of lung lesions and symptoms in COVID-19 patients.

Funding: The National Key R&D Program of China, the Innovation Groups of the National Natural Science Foundation of China, and the National Science and Technology Major Project.

Keywords: 1-year follow-up results; COVID-19; Mesenchymal stem cells treatment; RCT.

Conflict of interest statement

Declaration of interests YZ is a current employee of Vcanbio Cell & Gene Engineering Co., Ltd. All authors declare no competing interests.

Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Figure 1

Trial profile.

Figure 2

The effect of human umbilical cord-mesenchymal stem cells (UC‑MSCs) on the lung damage in patients with severe COVID-19. (a, b: total lesion; c, d: solid component lesion). (a) shows the between-group median difference in the change in total lesion proportion (%) of the whole lung volume from baseline to month 3. I bars indicate the Q1(the first quartile),Q3(the third quartile). (b) shows the mean absolute change from baseline to month 3 in the total lesion proportion (%) of the whole lung volume. I bars indicate the standard error. (c) shows the between-group median difference in the change in solid component lesion proportion (%) of the whole lung volume from baseline to month 12. I bars indicate the Q1(the first quartile),Q3(the third quartile). (d) shows the mean absolute change from baseline to month 12 in solid component lesion proportion (%) of the whole lung volume. I bars indicate the standard error. Group difference assessed by Wilcoxon rank sum test. The 95% CI calculated by Hodges–Lehmann estimation.

Figure 3

Comparison of UC‑MSCs on long-term follow-up 6MWD in patients with severe COVID-19. (a) and (b) show temporal changes in 6-MWD in the MSC and placebo groups at 3, 6, 9, and 12 months after enrollment. (a): absolute 6MWD. I bars indicate Q1(denotes the first quartile), Q3(the third quartile), and points indicate the median. (b): normalized to predicted values(%). Data are presented as median (interquartile range). I bars indicate Q1(denotes the first quartile), Q3(the third quartile), and points indicate the median. 6MWD=6 min walking distance.

Figure 4

Inhibition rate (IR) of neutralizing antibodies. The inhibition rate (IR) of neutralizing antibodies decreased gradually from baseline to the 1-year follow-up. However, the IR were all positive (over 20%) with a similar median (61.6% vs. 67.55%) in either the MSC group or placebo group at 12 months, which was higher than that in healthy people. The bars indicate the minimum and maximum values.