An Open Label, Adaptive, Phase 1 Trial of High‐Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS‐CoV‐2

  1. Lauren E. Walker
  2. Richard FitzGerald
  3. Geoffrey Saunders
  4. Rebecca Lyon
  5. Michael Fisher
  6. Karen Martin
  7. Izabela Eberhart
  8. Christie Woods
  9. Sean Ewings
  10. Colin Hale
  11. Rajith K. R. Rajoli
  12. Laura Else
  13. Sujan Dilly‐Penchala
  14. Alieu Amara
  15. David G. Lalloo
  16. Michael Jacobs
  17. Henry Pertinez
  18. Parys Hatchard
  19. Robert Waugh
  20. Megan Lawrence
  21. Lucy Johnson
  22. Keira Fines
  23. Helen Reynolds
  24. Timothy Rowland
  25. Rebecca Crook
  26. Emmanuel Okenyi
  27. Kelly Byrne
  28. Pavel Mozgunov
  29. Thomas Jaki
  30. Saye Khoo
  31. Andrew Owen
  32. Gareth Griffiths
  33. Thomas E. Fletcher
  34. the AGILE platform

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Abstract

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID‐19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically‐based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high‐dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice‐daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (C min ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self‐limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median C min was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID‐19.

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  1. Version published to 10.1002/cpt.2463
  2. ScreenIT

    SciScore for 10.1101/2021.09.10.21263376: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The study protocol was reviewed and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and West Midlands Edgbaston Research Ethics Committee.
    Consent: All participants provided written informed consent before enrolment.
    Sex as a biological variableParticipants: Eligible participants included healthy adult males and non-pregnant and non-lactating females between 18 and 75 years of age.
    Randomizationnot detected.
    Blindingnot detected.
    Power AnalysisThe sample size was flexible, based on the need for the study to adapt to accruing safety data.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    In previously published work, a physiologically based pharmacokinetic (PBPK) model was validated for nitazoxanide using Simbiology (MATLAB
    MATLAB
    suggested: (MATLAB, RRID:SCR_001622)
    , STATA version 16 and R version 4.0.2.
    STATA
    suggested: (Stata, RRID:SCR_012763)

    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:
    This is a limitation of all first-in-human healthy volunteer studies, within which it is always difficult to generate pharmacodynamic data. The median age and lack of medical comorbidities in this healthy volunteer cohort also differs from the main target population for early use of antivirals, although their use in post-exposure prophylaxis and to reduce isolation requirements in low-risk groups is also being considered. There is an urgent unmet need for safe and effective antiviral therapeutics in early-stage mild/moderate COVID-19. These are aimed at preventing progression of disease to hospitalisation and death, and possibly also reducing viral transmission in community settings. Re-purposing and dose escalation of nitazoxanide for COVID-19 is supported by in-vitro data, PBPK modelling and now robust safety and pharmacokinetic data at the 1500mg BD dose. This dose will provide the maximum potential to demonstrate antiviral activity of nitazoxanide in subsequent trials to provide a definitive outcome on the utility of this drug in COVID-19. Study Highlights: What is the current knowledge on the topic?: Nitazoxanide is an anti-parasitic medication licensed by the FDA at standard dosing (500mg BD) with an established safety profile. Antiviral activity has been demonstrated for numerous viruses with in vitro data demonstrating activity against SARS-CoV-2. No steady-state pharmacokinetic data are available at higher doses or in COVID-19 but PBPK modelling has indicated a 1500m...

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

    IdentifierStatusTitle
    NCT04746183RecruitingAGILE (Early Phase Platform Trial for COVID-19)

    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.

    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.

  3. Version published to 10.1101/2021.09.10.21263376v1 on medRxiv