Efficacy and tolerability of bevacizumab in patients with severe Covid-19

  1. Jiaojiao Pang
  2. Feng Xu
  3. Gianmarco Aondio
  4. Yu Li
  5. Alberto Fumagalli
  6. Ming Lu
  7. Giuseppe Valmadre
  8. Jie Wei
  9. Yuan Bian
  10. Margherita Canesi
  11. Giovanni Damiani
  12. Yuan Zhang
  13. Dexin Yu
  14. Jun Chen
  15. Xiang Ji
  16. Wenhai Sui
  17. Bailu Wang
  18. Shuo Wu
  19. Attila Kovacs
  20. Miriam Revera
  21. Hao Wang
  22. Xu Jing
  23. Ying Zhang
  24. Yuguo Chen
  25. Yihai Cao

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Abstract

On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O 2 ratio (PaO 2 /FiO 2 ) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO 2 /FiO 2 ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.

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  1. Version published to 10.1038/s41467-021-21085-8
  2. ScreenIT

    SciScore for 10.1101/2020.07.26.20159756: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementConsent: The following patients were excluded from the trial: 1) patients with severe hepatic dysfunction (Child-Pugh score ≥ C or aspartate aminotransferase level > 5 times the upper reference limit, URL); 2) patients with severe renal dysfunction (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m2) or who required continuous renal replacement therapy, haemodialysis, or peritoneal dialysis; 3) patients with uncontrolled hypertension (sitting systolic blood pressure > 160 mmHg or diastolic blood pressure >100 mmHg) or a history of hypertension crisis or hypertensive encephalopathy; 4) patients with poorly controlled heart diseases, such as New York Heart Association class II or higher cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, or supraventricular or ventricular arrhythmia needing treatment or intervention; 5) patients with hereditary bleeding tendency or coagulopathy, and patients who received full-dose anticoagulant or thrombolytic therapy within 10 days before enrollment, or non-steroidal anti-inflammatory drugs with platelet suppression within 10 days before enrolment (except those who used small doses of aspirin [≤ 325 mg/day] for preventive use); 6) patients with thrombosis within 6 months before enrollment, patients who had experienced arterial/venous thromboembolic events, such as ischemic stroke, transient ischemic attack, deep venous thrombosis, or pulmonary embolism within 1 year prior to trial enrollment, and patients with severe vascular diseases (including aneurysms or arterial thrombosis requiring surgery) within 6 months before trial enrollment; 7) patients with unhealed wounds, active gastric ulcers, or fractures; patients with gastrointestinal perforation, gastrointestinal fistula, abdominal abscess, or visceral fistula formation within 6 months before trial enrollment; 8) patients who had undergone major surgery (including preoperative chest biopsy) or received major trauma (such as a fracture) within 28 days before enrollment; patients who might need surgery during the trial; 9) patients with severe, active bleeding such as haemoptysis, gastrointestinal bleeding, central nervous system bleeding, and epistaxis within 1 month before trial enrollment; 10) patients with malignant tumours within 5 years before trial enrollment; 11) patients allergic to bevacizumab or its components; 12) patients with untreated active hepatitis or HIV-positive patients; pregnant and lactating women and those planning to get pregnant; 13) patients who participated in other clinical trials or not considered suitable for this trial by the researchers; or 14) patients who did not provide signed informed consent.
    IRB: The trial was approved by the ethics committees of Qilu Hospital of Shandong University, Renmin Hospital of Wuhan University, and Italia Hospital S.p.A. Ospedale Generale di Zona Moriggia - Pelascini, Gravedona ed Uniti (CO).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe following patients were excluded from the trial: 1) patients with severe hepatic dysfunction (Child-Pugh score ≥ C or aspartate aminotransferase level > 5 times the upper reference limit, URL); 2) patients with severe renal dysfunction (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m2) or who required continuous renal replacement therapy, haemodialysis, or peritoneal dialysis; 3) patients with uncontrolled hypertension (sitting systolic blood pressure > 160 mmHg or diastolic blood pressure >100 mmHg) or a history of hypertension crisis or hypertensive encephalopathy; 4) patients with poorly controlled heart diseases, such as New York Heart Association class II or higher cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, or supraventricular or ventricular arrhythmia needing treatment or intervention; 5) patients with hereditary bleeding tendency or coagulopathy, and patients who received full-dose anticoagulant or thrombolytic therapy within 10 days before enrollment, or non-steroidal anti-inflammatory drugs with platelet suppression within 10 days before enrolment (except those who used small doses of aspirin [≤ 325 mg/day] for preventive use); 6) patients with thrombosis within 6 months before enrollment, patients who had experienced arterial/venous thromboembolic events, such as ischemic stroke, transient ischemic attack, deep venous thrombosis, or pulmonary embolism within 1 year prior to trial enrollment, and patients with severe vascular diseases (including aneurysms or arterial thrombosis requiring surgery) within 6 months before trial enrollment; 7) patients with unhealed wounds, active gastric ulcers, or fractures; patients with gastrointestinal perforation, gastrointestinal fistula, abdominal abscess, or visceral fistula formation within 6 months before trial enrollment; 8) patients who had undergone major surgery (including preoperative chest biopsy) or received major trauma (such as a fracture) within 28 days before enrollment; patients who might need surgery during the trial; 9) patients with severe, active bleeding such as haemoptysis, gastrointestinal bleeding, central nervous system bleeding, and epistaxis within 1 month before trial enrollment; 10) patients with malignant tumours within 5 years before trial enrollment; 11) patients allergic to bevacizumab or its components; 12) patients with untreated active hepatitis or HIV-positive patients; pregnant and lactating women and those planning to get pregnant; 13) patients who participated in other clinical trials or not considered suitable for this trial by the researchers; or 14) patients who did not provide signed informed consent.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    All analyses were conducted with SAS software, version 9.4 (SAS Institute, USA).
    SAS
    suggested: (SASqPCR, RRID:SCR_003056)
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    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:
    Owing to the following reasons, we did not measure plasma VEGF levels: 1) the Covid-19 pandemic-associated limitation of feasibility; 2) plasma VEGF levels may not reflect local VEGF production in pulmonary tissues; and 3) most VEGF isoforms binds to heparin and may be sequestered the tissues where they produce. The limitation of these results is the small size of the cohort. However, significant improvements of multiple clinical parameters in bevacizumab-treated patients suggest that anti-VEGF might benefit for treating patients with Covid-19. In particular, it is worthy to design future trials by combining bevacizumab with other therapeutic modalities such as anti-viral and anti-inflammatory drugs. Given the limited medical supply and available facility in most medical centers, a single injection of bevacizumab might immediately relieve clinical symptoms and early discharge of patients with severe Covid-19. The therapeutic benefits of bevacizumab monotherapy and combination therapy warrant future validation in patients with severe Covid-19 by randomized and placebo-controlled trials.

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

    IdentifierStatusTitle
    NCT04275414CompletedBevacizumab in Severe or Critical Patients With COVID-19 Pne…

    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. ScreenIT

    SciScore for 10.1101/2020.07.26.20159756: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementThe informed consent was waived.RandomizationClinical efficacy of bevacizumab warrants double blind, randomized, placebo-controlled trials.BlindingClinical efficacy of bevacizumab warrants double blind, randomized, placebo-controlled trials.Power Analysisnot detected.Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Thus, we employed bevacizumab, a humanized antiVEGF monoclonal antibody, for treating patients with severe Covid-19.
    antiVEGF
    suggested: None
    Software and Algorithms
    SentencesResources
    All analyses were conducted with SAS software, version 9.4 (SAS Institute, USA)
    SAS
    suggested: (SASqPCR, SCR_003056)
          <div style="margin-bottom:8px">
        <div><b>SAS Institute</b></div>
        <div>suggested: (Statistical Analysis System, <a href="https://scicrunch.org/resources/Any/search?q=SCR_008567">SCR_008567</a>)</div>
      </div>
    </td></tr></table>

    Data from additional tools added to each annotation on a weekly basis.

    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 is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  4. Version published to 10.1101/2020.07.26.20159756v1 on medRxiv