An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis

  1. Nguyen Thi Thuy Ngan
  2. Nhat Thanh Hoang Le
  3. Nguyen Ngo Vi Vi
  4. Ninh Thi Thanh Van
  5. Nguyen Thi Hoang Mai
  6. Duong Van Anh
  7. Phan Hai Trieu
  8. Nguyen Phu Huong Lan
  9. Nguyen Hoan Phu
  10. Nguyen VV Chau
  11. David G Lalloo
  12. William Hope
  13. Justin Beardsley
  14. Nicholas J White
  15. Ronald Geskus
  16. Guy E Thwaites
  17. Damian Krysan
  18. Luong Thi Hue Tai
  19. Evelyne Kestelyn
  20. Tran Quang Binh
  21. Le Quoc Hung
  22. Nguyen Le Nhu Tung
  23. Jeremy N Day  Is a corresponding author
  1. Cho Ray Hospital, Viet Nam
  2. Oxford University Clinical Research Unit
  3. Hospital for Tropical Diseases, Viet Nam
  4. Liverpool School of Tropical Medicine, United Kingdom
  5. Liverpool University, United Kingdom
  6. University of Sydney, Australia
  7. Mahidol Oxford Tropical Medicine Research Unit, Thailand
  8. University of Iowa, United States

Abstract

Background: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anti-cancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential.

Methods:Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first two weeks - or standard care plus tamoxifen 300mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031 .

Results: 50 patients were enrolled, (median age 34 years, 35 male). Tamoxifen had no effect on EFA (- 0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference - 0.005log10CFU/ml/day, 95%CI: -0.16, 0.15, P=0.95). Tamoxifen caused QTc prolongation.

Conclusion: High dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed.

Funding:The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.

Data availability

The clinical trial has been conducted in Vietnam under the Ministry of Health and local Ethical Committee approvals. Requests to share the clinical data underlying the trial have to be acknowledged by the local Ethical Committee (and therefore we cannot hand over the data repository or management to an external party). The original de-identified clinical data underlying the study are available by emailing the OUCRU Data Access Committee at DAC@oucru.org or ekestelyn@oucru.org (Head of the Clinical Trials Unit and Data Access Committee Chair). The review procedures (the data sharing policy and the data request form) are available on the OUCRU website at http://www.oucru.org/data-sharing/The code for the study analysis is freely available at https://doi.org/10.5287/bodleian:XmeOzdR8z

The following data sets were generated

Article and author information

Author details

  1. Nguyen Thi Thuy Ngan

    Department of Tropical Medicine, Cho Ray Hospital, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  2. Nhat Thanh Hoang Le

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  3. Nguyen Ngo Vi Vi

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  4. Ninh Thi Thanh Van

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  5. Nguyen Thi Hoang Mai

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  6. Duong Van Anh

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  7. Phan Hai Trieu

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  8. Nguyen Phu Huong Lan

    Department of Microbiology, Hospital for Tropical Diseases, Ho Chi Minh CIty, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  9. Nguyen Hoan Phu

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  10. Nguyen VV Chau

    Department of Microbiology, Hospital for Tropical Diseases, Ho Chi Minh CIty, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  11. David G Lalloo

    Director, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. William Hope

    Centre of Excellence in Infectious Disease Research, Liverpool University, Liverpool, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Justin Beardsley

    Marie Bashir Institute, University of Sydney, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  14. Nicholas J White

    Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1897-1978
  15. Ronald Geskus

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
  16. Guy E Thwaites

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2858-2087
  17. Damian Krysan

    University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Luong Thi Hue Tai

    Infectious Diseases, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  19. Evelyne Kestelyn

    Oxford University Clinical Research Unit
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5728-0918
  20. Tran Quang Binh

    Department of Tropical Medicine, Cho Ray Hospital, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  21. Le Quoc Hung

    Department of Tropical Medicine, Cho Ray Hospital, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  22. Nguyen Le Nhu Tung

    Infectious Diseases, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam
    Competing interests
    The authors declare that no competing interests exist.
  23. Jeremy N Day

    Oxford University Clinical Research Unit
    For correspondence
    jday@oucru.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7843-6280

Funding

Wellcome Trust (Wellcome Trust Asia Programme Vietnam Core Grant 106680)

  • Guy E Thwaites

Wellcome Trust (WT097147MA)

  • Jeremy N Day

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The study protocol was approved by the Ethical Review Committees of the Hospital for Tropical Diseases, Cho Ray Hospital, and the Vietnamese Ministry of Health, and by the Oxford University Tropical Research Ethics Committee. A trial steering committee with 2 independent members oversaw the running of the trial, and an independent data and safety monitoring committee oversaw trial safety. The first safety analysis was performed after the first 20 patients had reached the primary endpoint. The funding bodies and drug manufacturers played no role in the study design, implementation, analysis, or manuscript preparation. All the authors made the decision to submit the manuscript for publication and vouch for the accuracy and completeness of the data and analyses presented. The trial was registered at https://clinicaltrials.gov/ct2/show/NCT03112031.

Reviewing Editor

  1. Frank L van de Veerdonk, Radboudumc Center for Infectious Diseases, Netherlands

Publication history

  1. Received: March 30, 2021
  2. Accepted: September 21, 2021
  3. Accepted Manuscript published: September 28, 2021 (version 1)
  4. Version of Record published: October 26, 2021 (version 2)

Copyright

© 2021, Ngan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nguyen Thi Thuy Ngan
  2. Nhat Thanh Hoang Le
  3. Nguyen Ngo Vi Vi
  4. Ninh Thi Thanh Van
  5. Nguyen Thi Hoang Mai
  6. Duong Van Anh
  7. Phan Hai Trieu
  8. Nguyen Phu Huong Lan
  9. Nguyen Hoan Phu
  10. Nguyen VV Chau
  11. David G Lalloo
  12. William Hope
  13. Justin Beardsley
  14. Nicholas J White
  15. Ronald Geskus
  16. Guy E Thwaites
  17. Damian Krysan
  18. Luong Thi Hue Tai
  19. Evelyne Kestelyn
  20. Tran Quang Binh
  21. Le Quoc Hung
  22. Nguyen Le Nhu Tung
  23. Jeremy N Day
(2021)
An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
eLife 10:e68929.
https://doi.org/10.7554/eLife.68929

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    Funding:

    Supported by KL2 career development grant by Miami CTSI under NIH Award UL1TR002736, Stanley Glaser Foundation, American College of Surgeons Franklin Martin Career Development Award, and Association for Academic Surgery Joel J. Roslyn Faculty Award (to J. Datta); NIH R01 CA161976 (to N.B. Merchant); and NCI/NIH Award P30CA240139 (to J. Datta and N.B. Merchant).