Efficacy and Safety of Leflunomide for Refractory COVID-19: A Pilot Study

  1. Qiang Wang
  2. Haipeng Guo
  3. Yu Li
  4. Xiangdong Jian
  5. Xinguo Hou
  6. Ning Zhong
  7. Jianchun Fei
  8. Dezhen Su
  9. Zhouyan Bian
  10. Yi Zhang
  11. Yingying Hu
  12. Yan Sun
  13. Xueyuan Yu
  14. Yuan Li
  15. Bei Jiang
  16. Yan Li
  17. Fengping Qin
  18. Yingying Wu
  19. Yanxia Gao
  20. Zhao Hu

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Abstract

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may persist in patients with coronavirus disease 2019 (COVID-19) despite receiving standard care.

Methods: In this pilot study of hospitalized adult patients (≥18 years of age), with radiologically confirmed pneumonia who were SARS-CoV-2 positive for more than 28 days despite standard care, were assigned to receive standard of care (SOC, grp I) or leflunomide + SOC (grp 2). After 2 weeks, grp 1 and grp 2 patients who continued to be SARS-CoV-2-positive received leflunomide for 14 days while continuing SOC. The primary outcomes were the rate of and time to SARS-CoV-2 clearance and the 14-day and 30-day hospital discharge rate.

Results: 12 patients were enrolled in grp 1 and 15 patients were in grp 2. The 14 days SARS-CoV-2 viral clearance rate was 80.0% (12/15) for grp 2 patients receiving leflunomide vs. 16.7% for grp 1 patients (2/12) ( p = 0.002). By day 14, the median time to SARS-CoV-2 clearance was 6.0 days (range 1–12, IQR 1–12) for grp 2 patients. In grp 1, two patients converted to viral negative on days 1 and 6 ( p = 0.002). The 14-day discharge rate was 73.3% (11/15) for the grp 2 vs. 8.3% (1/12) for grp 1 ( p = 0.001). The 30 days discharge rate was 100% (15/15) for the grp 2 vs. 66.7% (8/12) for grp 1. No severe adverse events or deaths were reported.

Conclusion: Leflunomide may improve the SARS-CoV-2 clearance rate and discharge rate in patients with refractory COVID-19. The tolerability of the 14–28 days course of treatment with leflunomide is acceptable. These preliminary observations need to be verified by a large sample size and randomized controlled trial.

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  1. Version published to 10.3389/fphar.2021.581833
  2. ScreenIT

    SciScore for 10.1101/2020.05.29.20114223: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: All patients provided written informed consent to the study.
    RandomizationStudy Design: This open-label study of leflunomide as adjunctive therapy to SOC was designed as a pilot study in anticipation for a randomized controlled trial (ChiCTR2000030058) and enrolled hospitalized adult patients (≥ 18 years of age) with radiologically confirmed COVID-19 pneumonia who were reverse transcriptase-polymerase chain reaction (RT-PCR)-positive for SARS-CoV-2 for more than 28 days despite standard care.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were conducted with SPSS software, version 25 (IBM Corp.). P<0.05 indicated a statistically significant difference.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    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:
    Limitations of this study: Despite the demonstration of promising efficacy of leflunomiude, this study has several limitations. This pilot study was not randomized, the sample size of refractory COVID-19 patients was small, and all patients came from a single center. The RT-PCR assay utilized was semi-quantitative, and no plasma was saved to assay for serum teriflunomide levels.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    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.

  3. Version published to 10.1101/2020.05.29.20114223 on medRxiv