Favipiravir, lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind, 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19

  1. David M Lowe
  2. Li-An K Brown
  3. Kashfia Chowdhury
  4. Stephanie Davey
  5. Philip Yee
  6. Felicia Ikeji
  7. Amalia Ndoutoumou
  8. Divya Shah
  9. Alexander Lennon
  10. Abhulya Rai
  11. Akosua A Agyeman
  12. Anna Checkley
  13. Nicola Longley
  14. Hakim-Moulay Dehbi
  15. Nick Freemantle
  16. Judith Breuer
  17. Joseph F Standing
  18. FLARE Investigators

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Abstract

Background

Early antiviral treatment is effective for COVID-19 but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on SARS-CoV-2 viral load trajectory when administered early.

Methods

We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2×2 factorial, double-blind trial of outpatients with early COVID-19 (within 7 days of symptom onset) at two sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1800mg twice daily on Day 1 followed by 400mg four times daily on Days 2-7) plus lopinavir-ritonavir (400mg/100mg twice daily on Day 1, followed by 200mg/50mg four times daily on Days 2-7); favipiravir plus lopinavir-ritonavir placebo; lopinavir-ritonavir plus favipiravir placebo; or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. ClinicalTrials·gov: NCT04499677 .

Findings

Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo and placebo-only arms, we recruited 61, 59, 60 and 60 participants and analysed 55, 56, 55 and 58 participants respectively who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had decreased by 0.57 log 10 (95% CI -1.21 to 0.07, p=0.08) and in the lopinavir-ritonavir+placebo arm by 0.18 log 10 (95% CI -0.82 to 0.46, p=0.58) more than in the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log 10 , 95% CI -0.32 to 1.50, p=0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% vs 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p=0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm.

Interpretation

At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations.

Funding

LifeArc, UK.

Article activity feed

  1. Rapid Reviews Infectious Diseases

    Bumi Herman

    Review of "Favipiravir,lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19"

    Reviewer: Bumi Herman (Chulalongkorn University College of Public Health Sciences) | 📒📒📒 ◻️◻️

  2. Rapid Reviews Infectious Diseases

    Bumi Herman

    Review of "Favipiravir,lopinavir-ritonavir or combination therapy (FLARE): a randomised, double blind 2x2 factorial placebo-controlled trial of early antiviral therapy in COVID-19"

    Reviewer: Bumi Herman (Chulalongkorn University College of Public Health Sciences) | 📒📒📒 ◻️◻️

  3. ScreenIT

    SciScore for 10.1101/2022.02.11.22270775: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The study was approved by the Wales Research Ethics Committee 3 (Ref: 20/WA/0210) and all participants provided written, informed consent.
    Consent: The study was approved by the Wales Research Ethics Committee 3 (Ref: 20/WA/0210) and all participants provided written, informed consent.
    Sex as a biological variableFemale participants of childbearing potential were required to provide a negative pregnancy test before commencement of trial medication and on Day 14, and to use highly effective contraceptive measures during the trial; male participants with a female partner of childbearing potential were also required to use highly effective contraception.
    RandomizationThe ITT population is composed of all randomised participants.
    BlindingTrial medication kits, prepared by RenaClinical Ltd, were coded to maintain double blinding (investigators and participants)
    Power AnalysisSimulations showed a total of 216 participants would provide 90% power with two-sided alpha of 2.5% to detect a 0.9 log10 decrease in viral load of each active treatment on its own compared to placebo.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Kits contained favipiravir or colour and size matched placebo 200 mg tablets supplied by Fujifilm Toyama Chemical Co., Ltd and lopinavir-ritonavir 200mg/50 mg tablets (AbbVie Ltd) or colour and size matched placebos (RenaClinical Ltd).
    AbbVie
    suggested: (AbbVie, RRID:SCR_010484)

    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:
    Our study has some limitations. The recruited cohort was relatively young and healthy with lower viral loads than many reported elsewhere in the literature. We were unable to perform viral culture or infectivity assays which may have provided useful additional information. For logistical reasons, we were unable to obtain samples for pharmacokinetics on every participant in the study. In conclusion, our results do not support routine usage or Phase 3 trials of favipiravir or lopinavir-ritonavir at the doses investigated. However, the results may indicate an effect of favipiravir when used for early treatment of COVID-19, especially in those with high baseline viral load, but further investigation is needed regarding dosing schedule or additive medication. Another relatively small study would be sufficient to establish this. We have conclusively demonstrated the ineffectiveness of lopinavir-ritonavir even in early disease and have identified a new drug interaction between favipiravir and lopinavir-ritonavir with the latter apparently lowering plasma levels of the former. These results have important implications for the global efforts against COVID-19.

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

    IdentifierStatusTitle
    NCT04499677CompletedFLARE: Favipiravir +/- Lopinavir: A RCT of Early Antivirals

    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.

    Results from scite Reference Check: We found no unreliable references.

    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.

  4. Version published to 10.1101/2022.02.11.22270775v1 on medRxiv