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

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

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Autores principales: Ngan, Nguyen Thi Thuy, Thanh Hoang Le, Nhat, Vi Vi, Nguyen Ngo, Van, Ninh Thi Thanh, Mai, Nguyen Thi Hoang, Van Anh, Duong, Trieu, Phan Hai, Lan, Nguyen Phu Huong, Phu, Nguyen Hoan, Chau, Nguyen Van Vinh, Lalloo, David G, Hope, William, Beardsley, Justin, White, Nicholas J, Geskus, Ronald, Thwaites, Guy E, Krysan, Damian, Tai, Luong Thi Hue, Kestelyn, Evelyne, Binh, Tran Quang, Hung, Le Quoc, Tung, Nguyen Le Nhu, Day, Jeremy N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547950/
https://www.ncbi.nlm.nih.gov/pubmed/34581270
http://dx.doi.org/10.7554/eLife.68929
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author Ngan, Nguyen Thi Thuy
Thanh Hoang Le, Nhat
Vi Vi, Nguyen Ngo
Van, Ninh Thi Thanh
Mai, Nguyen Thi Hoang
Van Anh, Duong
Trieu, Phan Hai
Lan, Nguyen Phu Huong
Phu, Nguyen Hoan
Chau, Nguyen Van Vinh
Lalloo, David G
Hope, William
Beardsley, Justin
White, Nicholas J
Geskus, Ronald
Thwaites, Guy E
Krysan, Damian
Tai, Luong Thi Hue
Kestelyn, Evelyne
Binh, Tran Quang
Hung, Le Quoc
Tung, Nguyen Le Nhu
Day, Jeremy N
author_facet Ngan, Nguyen Thi Thuy
Thanh Hoang Le, Nhat
Vi Vi, Nguyen Ngo
Van, Ninh Thi Thanh
Mai, Nguyen Thi Hoang
Van Anh, Duong
Trieu, Phan Hai
Lan, Nguyen Phu Huong
Phu, Nguyen Hoan
Chau, Nguyen Van Vinh
Lalloo, David G
Hope, William
Beardsley, Justin
White, Nicholas J
Geskus, Ronald
Thwaites, Guy E
Krysan, Damian
Tai, Luong Thi Hue
Kestelyn, Evelyne
Binh, Tran Quang
Hung, Le Quoc
Tung, Nguyen Le Nhu
Day, Jeremy N
author_sort Ngan, Nguyen Thi Thuy
collection PubMed
description BACKGROUND: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer 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 2 weeks – or standard care plus tamoxifen 300 mg/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: Fifty 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. CONCLUSIONS: 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.
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spelling pubmed-85479502021-10-27 An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis Ngan, Nguyen Thi Thuy Thanh Hoang Le, Nhat Vi Vi, Nguyen Ngo Van, Ninh Thi Thanh Mai, Nguyen Thi Hoang Van Anh, Duong Trieu, Phan Hai Lan, Nguyen Phu Huong Phu, Nguyen Hoan Chau, Nguyen Van Vinh Lalloo, David G Hope, William Beardsley, Justin White, Nicholas J Geskus, Ronald Thwaites, Guy E Krysan, Damian Tai, Luong Thi Hue Kestelyn, Evelyne Binh, Tran Quang Hung, Le Quoc Tung, Nguyen Le Nhu Day, Jeremy N eLife Medicine BACKGROUND: Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer 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 2 weeks – or standard care plus tamoxifen 300 mg/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: Fifty 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. CONCLUSIONS: 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. eLife Sciences Publications, Ltd 2021-09-28 /pmc/articles/PMC8547950/ /pubmed/34581270 http://dx.doi.org/10.7554/eLife.68929 Text en © 2021, Ngan et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Ngan, Nguyen Thi Thuy
Thanh Hoang Le, Nhat
Vi Vi, Nguyen Ngo
Van, Ninh Thi Thanh
Mai, Nguyen Thi Hoang
Van Anh, Duong
Trieu, Phan Hai
Lan, Nguyen Phu Huong
Phu, Nguyen Hoan
Chau, Nguyen Van Vinh
Lalloo, David G
Hope, William
Beardsley, Justin
White, Nicholas J
Geskus, Ronald
Thwaites, Guy E
Krysan, Damian
Tai, Luong Thi Hue
Kestelyn, Evelyne
Binh, Tran Quang
Hung, Le Quoc
Tung, Nguyen Le Nhu
Day, Jeremy N
An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
title An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
title_full An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
title_fullStr An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
title_full_unstemmed An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
title_short An open label randomized controlled trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis
title_sort open label randomized controlled trial of tamoxifen combined with amphotericin b and fluconazole for cryptococcal meningitis
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547950/
https://www.ncbi.nlm.nih.gov/pubmed/34581270
http://dx.doi.org/10.7554/eLife.68929
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