Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19

  1. Mingxing Huang
  2. Man Li
  3. Fei Xiao
  4. Pengfei Pang
  5. Jiabi Liang
  6. Tiantian Tang
  7. Shaoxuan Liu
  8. Binghui Chen
  9. Jingxian Shu
  10. Yingying You
  11. Yang Li
  12. Meiwen Tang
  13. Jianhui Zhou
  14. Guanmin Jiang
  15. Jingfen Xiang
  16. Wenxin Hong
  17. Songmei He
  18. Zhaoqin Wang
  19. Jianhua Feng
  20. Changqing Lin
  21. Yinong Ye
  22. Zhilong Wu
  23. Yaocai Li
  24. Bei Zhong
  25. Ruilin Sun
  26. Zhongsi Hong
  27. Jing Liu
  28. Huili Chen
  29. Xiaohua Wang
  30. Zhonghe Li
  31. Duanqing Pei
  32. Lin Tian
  33. Jinyu Xia
  34. Shanping Jiang
  35. Nanshan Zhong
  36. Hong Shan

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Abstract

Effective therapies are urgently needed for the SARS-CoV-2 pandemic. Chloroquine has been proved to have antiviral effect against coronavirus in vitro. In this study, we aimed to assess the efficacy and safety of chloroquine with different doses in COVID-19. In this multicenter prospective observational study, we enrolled patients older than 18 years old with confirmed SARS-CoV-2 infection excluding critical cases from 12 hospitals in Guangdong and Hubei Provinces. Eligible patients received chloroquine phosphate 500 mg, orally, once (half dose) or twice (full dose) daily. Patients treated with non-chloroquine therapy were included as historical controls. The primary endpoint is the time to undetectable viral RNA. Secondary outcomes include the proportion of patients with undetectable viral RNA by day 10 and 14, hospitalization time, duration of fever, and adverse events. A total of 197 patients completed chloroquine treatment, and 176 patients were included as historical controls. The median time to achieve an undetectable viral RNA was shorter in chloroquine than in non-chloroquine (absolute difference in medians −6.0 days; 95% CI −6.0 to −4.0). The duration of fever is shorter in chloroquine (geometric mean ratio 0.6; 95% CI 0.5 to 0.8). No serious adverse events were observed in the chloroquine group. Patients treated with half dose experienced lower rate of adverse events than with full dose. Although randomized trials are needed for further evaluation, this study provides evidence for safety and efficacy of chloroquine in COVID-19 and suggests that chloroquine can be a cost-effective therapy for combating the COVID-19 pandemic.

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    SciScore for 10.1101/2020.04.26.20081059: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The study protocol was approved by the ethics committee of Fifth Affiliated Hospital of Sun Yat-sen University (SYSU5), located in Zhuhai, Guangdong Province, and registered at Chinese Clinical Trial Registry (ChiCTR2000029609).
    Consent: Written informed consent was obtained from all patients or their legal guardians.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablePatients were ineligible if he/she met any of the following criteria: pregnant women, with known allergies to 4-aminoquinoline compounds, blood system diseases, chronic liver or kidney diseases in end-stage, arrhythmia or second/third degree heart block, with known to have retinopathy, hypoacusis or hearing loss, mental disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, had received digitalis drugs within the 7 days preceding enrollment, or is classified as critical case according to China’s Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (4th Edition).

    Table 2: Resources

    No key resources detected.

    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:
    We recognize that our study has several limitations. This study was carried out under the COVID-19 public health emergency. Due to the limited medical capacity and urgent clinical situation, we were unable to conduct a standard randomised controlled study to formally evaluate efficacy and safety of chloroquine versus placebo. As an observational study, we have to note that several factors may influence the interpretation of the result. It is reasonable to suspect that the dramatic improvement in the primary outcome in chloroquine could be due to the later treatment initiation since symptom onset. Firstly, gaining experience in treatment management and attenuation of the virus during the course of the epidemic could contribute to the improved outcomes. Secondly, we cannot rule out the possibility that among those with longer interval time between symptom onset and treatment, some may already have been on the course of recovery. Nevertheless, post hoc analysis dividing subgroups according to the interval time did not change the conclusion that the chloroquine group had a better outcome than the non-chloroquine group. Notably, some of the strata were incomparable due to small sample size. Thirdly, although it is impossible to dissect the influence from other antiviral therapies used before chloroquine, it is a plausible assumption that chloroquine is the first antiviral therapy used in the group of patients treated within 3 days since symptom onset. In this stratum, chloroquine ...

    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.
    • Thank you for including a protocol registration statement.

    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. ScreenIT

    SciScore for 10.1101/2020.04.26.20081059: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementThe study protocol was approved by the ethics committee of Fifth 331 Affiliated Hospital of Sun Yat-sen University ( SYSU5) , located in Zhuhai , 332 Guangdong Province , and registered at Chinese Clinical Trial Registry 333 ( ChiCTR2000029609) .Randomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablePatients were ineligible if he/she met any 346 of the following criteria: pregnant women , with known allergies to 4- 347 aminoquinoline compounds , blood system diseases , chronic liver or kidney 348 diseases in end-stage , arrhythmia or second/third degree heart block , with 349 known to have retinopathy , hypoacusis or hearing loss , mental disease , 350 glucose-6-phosphate dehydrogenase ( G6PD ) deficiency , had received 351 digitalis drugs within the 7 days preceding enrollment , or is classified as 352 critical case according to China’s Novel Coronavirus Pneumonia Diagnosis 353 and Treatment Plan ( 4th Edition) .

    Table 2: Resources

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

    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.

  3. Version published to 10.1093/nsr/nwaa113
  4. Version published to 10.1101/2020.04.26.20081059v1 on medRxiv