Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784590480143548416 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8547950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ngannguyenthithuy anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT thanhhoanglenhat anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT vivinguyenngo anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT vanninhthithanh anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT mainguyenthihoang anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT vananhduong anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT trieuphanhai anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT lannguyenphuhuong anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT phunguyenhoan anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT chaunguyenvanvinh anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT lalloodavidg anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT hopewilliam anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT beardsleyjustin anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT whitenicholasj anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT geskusronald anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT thwaitesguye anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT krysandamian anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT tailuongthihue anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT kestelynevelyne anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT binhtranquang anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT hunglequoc anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT tungnguyenlenhu anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT dayjeremyn anopenlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT ngannguyenthithuy openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT thanhhoanglenhat openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT vivinguyenngo openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT vanninhthithanh openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT mainguyenthihoang openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT vananhduong openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT trieuphanhai openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT lannguyenphuhuong openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT phunguyenhoan openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT chaunguyenvanvinh openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT lalloodavidg openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT hopewilliam openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT beardsleyjustin openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT whitenicholasj openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT geskusronald openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT thwaitesguye openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT krysandamian openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT tailuongthihue openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT kestelynevelyne openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT binhtranquang openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT hunglequoc openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT tungnguyenlenhu openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis AT dayjeremyn openlabelrandomizedcontrolledtrialoftamoxifencombinedwithamphotericinbandfluconazoleforcryptococcalmeningitis |