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.

Metrics

  • 699
    Page views
  • 82
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Medicine
    2. Physics of Living Systems
    Dmitry Postnov et al.
    Research Article Updated

    Internephron interaction is fundamental for kidney function. Earlier studies have shown that nephrons signal to each other, synchronize over short distances, and potentially form large synchronized clusters. Such clusters would play an important role in renal autoregulation, but due to the technological limitations, their presence is yet to be confirmed. In the present study, we introduce an approach for high-resolution laser speckle imaging of renal blood flow and apply it to estimate the frequency and phase differences in rat kidney microcirculation under different conditions. The analysis unveiled the spatial and temporal evolution of synchronized blood flow clusters of various sizes, including the formation of large (>90 vessels) and long-lived clusters (>10 periods) locked at the frequency of the tubular glomerular feedback mechanism. Administration of vasoactive agents caused significant changes in the synchronization patterns and, thus, in nephrons’ co-operative dynamics. Specifically, infusion of vasoconstrictor angiotensin II promoted stronger synchronization, while acetylcholine caused complete desynchronization. The results confirm the presence of the local synchronization in the renal microcirculatory blood flow and that it changes depending on the condition of the vascular network and the blood pressure, which will have further implications for the role of such synchronization in pathologies development.

    1. Medicine
    2. Neuroscience
    Guido I Guberman et al.
    Research Article

    Background: The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships.

    Methods: Using cross-sectional data from 306 previously-concussed children aged 9-10 from the Adolescent Brain Cognitive Development Study, we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first representing microstructural complexity, the second representing axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 symptom measures.

    Results: Early multi-tract multi-symptom pairs explained the most covariance and represented broad symptom categories, such as a general problems pair, or a pair representing all cognitive symptoms, and implicated more distributed networks of white matter tracts. Further pairs represented more specific symptom combinations, such as a pair representing attention problems exclusively, and were associated with more localized white matter abnormalities. Symptom representation was not systematically related to tract representation across pairs. Sleep problems were implicated across most pairs, but were related to different connections across these pairs. Expression of multi-tract features was not driven by sociodemographic and injury-related variables, as well as by clinical subgroups defined by the presence of ADHD. Analyses performed on a replication dataset showed consistent results.

    Conclusions: Using a double-multivariate approach, we identified clinically-informative, cross-demographic multi-tract multi-symptom relationships. These results suggest that rather than clear one-to-one symptom-connectivity disturbances, concussions may be characterized by subtypes of symptom/connectivity relationships. The symptom/connectivity relationships identified in multi-tract multi-symptom pairs were not apparent in single-tract/single-symptom analyses. Future studies aiming to better understand connectivity/symptom relationships should take into account multi-tract multi-symptom heterogeneity.

    Funding: financial support for this work from a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (GIG), an Ontario Graduate Scholarship (SS), a Restracomp Research Fellowship provided by the Hospital for Sick Children (SS), an Institutional Research Chair in Neuroinformatics (MD), as well as a Natural Sciences and Engineering Research Council CREATE grant (MD).