A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19

  1. Drifa Belhadi
  2. Nathan Peiffer-Smadja
  3. François-Xavier Lescure
  4. Yazdan Yazdanpanah
  5. France Mentré
  6. Cédric Laouénan

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Abstract

Background

Although a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials.

Methods

A review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7 th 2020. The search was conducted using the search terms “2019-nCoV”, “COVID-19”, “SARS-CoV-2”, “Hcov-19”, “new coronavirus”, “novel coronavirus”. We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents.

Findings

Out of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%).

Interpretation

Numerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking.

Funding

None

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  1. ScreenIT

    SciScore for 10.1101/2020.03.18.20038190: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: We added the WHO clinical trial registry (http://apps.who.int/trialsearch/) and the International Standard Randomised Controlled Trial Number (ISRCTN) Registry, recognized by the WHO and the International Committee of Medical Journal Editors (ICMJE).
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    We selected the following clinical trial registries: U.S. (https://clinicaltrials.gov/), Chinese (www.chictr.org.cn/), Korean (https://cris.nih.go.kr/cris/en/), Iranian (https://www.irct.ir/), Japanese (https://rctportal.niph.go.jp/en/), and European (https://www.clinicaltrialsregister.eu/).
    https://www.clinicaltrialsregister.eu/
    suggested: (EU Clinical Trials Register, RRID:SCR_005956)

    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:
    However, although the number of trials identified is high, there are a number of caveats. First, numerous treatments have been selected based on various levels of supporting preclinical data. Most of the agents evaluated in clinical trials have shown an in vitro antiviral activity, sometimes including coronaviruses. Lopinavir/ritonavir is tested in 15 clinical trials in this review. This combination has shown an in vitro activity against SARS-CoV in several studies15 and appears to have activity against MERS-CoV in animal studies16. The use of this agent for treatment of COVID-19 has been described in case reports17,18 and in a case series of patients infected with SARS-CoV-2 in Singapore.19 We found 18 clinical trials evaluating hydroxychloroquine or chloroquine, whose mechanism of action is similar.20 The in vitro antiviral activity of chloroquine has been known for a long time21 and was described on a number of viruses including SARS-CoV.22 However, chloroquine failed to demonstrate a benefit in the treatment of viral diseases such as influenza, dengue or chikungunya.23–25 Regarding COVID-19, a recent publication reported an activity of chloroquine on SARS-CoV-226 and another encouraged the use of chloroquine for patients with COVID-19 on the basis of unreported clinical results.27 Experts in China have suggested the use of chloroquine for patients infected with SARS-CoV-2 but no clinical data has been provided yet to support this announcement.28,29 Remdesivir is evaluated...

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

    IdentifierStatusTitle
    NCT04280705CompletedAdaptive COVID-19 Treatment Trial (ACTT)
    NCT04252274RecruitingEfficacy and Safety of Darunavir and Cobicistat for Treatmen…

    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 10.1101/2020.03.18.20038190 on medRxiv