Rapid systematic review on clinical evidence of chloroquine and hydroxychloroquine in COVID-19: critical assessment and recommendation for future clinical trials

  1. Yitong Wang
  2. Shuyao Liang
  3. Tingting Qiu
  4. Ru Han
  5. Monique Dabbous
  6. Anna Nowotarska
  7. Mondher Toumi

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Abstract

Purpose

This study aims to critically assess the published studies of Chloroquine (CQ) and hydroxychloroquine (HCQ) for the treatment of COVID-19 and provide recommendations for future clinical trials for the COVID-19 pandemic.

Method

A rapid systematic review was conducted by searching the PubMed, Embase, and China National Knowledge Infrastructure databases on April 13, 2020. Three clinical trial registry platforms, including ClinicalTrials.gov , the EU Clinical Trials Register, and the Chinese Clinical Trial Register were also complementarily searched.

Results

A total of 10 clinical studies were identified, including 3 randomized controlled trials (RCTs), 1 comparative nonrandomized trial, 5 single-arm trials, and 1 interim analysis. The heterogeneity among studies of the baseline disease severity and reported endpoints made a pooled analysis impossible. CQ and HCQ (with or without azithromycin) showed significant therapeutic benefit in terms of virologic clearance rate, improvement in symptoms and imaging findings, time to clinical recovery, and length of hospital stay in 1 RCT, 4 single-arm trials, and the interim analysis, whereas no treatment benefit of CQ or HCQ was observed in the remaining 4 studies. Limitations of the included studies ranged from small sample size, to insufficient information concerning baseline patient characteristics, to potential for selection bias without detailing the rationale for exclusion, and presence of confounding factors.

Conclusion

Based on the studies evaluated, there still lacked solid evidence supporting the efficacy and safety of HCQ and CQ as a treatment for COVID-19 with or without azithromycin. This emphasized the importance of robust RCTs investing HCQ/CQ to address the evidence uncertainties.

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  1. ScreenIT

    SciScore for 10.1101/2020.06.01.20118901: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationClinical studies including randomized control trial (RCT), comparative non-randomized trial, single-arm trial, and interim analysis with published results in both English and Chinese were included in this study.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    A strategic search of 2 English language databases (Medline and Embase via the OVID interface), 1 Chinese language database (China National Knowledge Infrastructure [CNKI]), 3 clinical trial registry platforms (ClinicalTrials.gov, the EU Clinical Trials Register, and Chinese Clinical Trial Register) and Google Scholar for grey literature was performed using the keywords of “COVID-19, SARS-COV-2, new coronavirus, coronavirus disease 2019, chloroquine, and hydroxychloroquine” on April 13, 2020.
    Medline
    suggested: (MEDLINE, RRID:SCR_002185)
    Embase
    suggested: (EMBASE, RRID:SCR_001650)
    Google Scholar
    suggested: (Google Scholar, RRID:SCR_008878)

    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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.

  2. Version published to 10.1101/2020.06.01.20118901 on medRxiv