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

eLife

William Hope¹  Damian Krysan²  Tran Quang Binh³  Le Quoc Hung³  Nguyen Thi Thuy Ngan⁴  David G Lalloo⁵  Nicholas J White⁶  Nguyen Thi Hoang Mai⁷  Phan Hai Trieu⁷  Nguyen Ngo Vi Vi⁷  Duong Van Anh⁷  Ninh Thi Thanh Van⁷  Nhat Thanh Hoang Le⁷  Nguyen Hoan Phu⁷  Ronald Geskus⁸  Jeremy N Day⁸  Evelyne Kestelyn⁸  Guy E Thwaites⁸  Nguyen Phu Huong Lan⁹  Luong Thi Hue Tai⁹  Nguyen Van Vinh Chau⁹  Nguyen Le Nhu Tung⁹  Justin Beardsley^1,10 

[1] Centre of Excellence in Infectious Disease Research, Institute of Translational Medicine, Liverpool University, Liverpool, United Kingdom;Department of Paediatrics and Microbiology/Immunology, Carver College of Medicine, University of Iowa, Iowa City, United States;Department of Tropical Medicine, Cho Ray Hospital, Ho Chi Minh City, Viet Nam;Department of Tropical Medicine, Cho Ray Hospital, Ho Chi Minh City, Viet Nam;Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam;Liverpool School of Tropical Medicine, Liverpool, United Kingdom;Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom;Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam;Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam;Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom;The Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam;The University of Sydney, Marie Bashir Institute, NSW, Camperdown, Australia;Westmead Institute for Medical Research, Westmead, Australia;

关键词: cryptococcus neoformans;    cryptococcus gattii;    HIV;    randomised controlled trial;    cryptococcal meningitis;    Viet Nam;    Other;   

DOI  :  10.7554/eLife.68929

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY