{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T07:33:35Z","timestamp":1782804815136,"version":"3.54.5"},"reference-count":59,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2019,1,22]],"date-time":"2019-01-22T00:00:00Z","timestamp":1548115200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["106680"],"award-info":[{"award-number":["106680"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background<\/ns4:bold>\n                    : Cryptococcal meningitis is a leading cause of death in HIV-infected patients. International treatment guidelines recommend induction therapy with amphotericin B and flucytosine. This antifungal combination is most effective, but unfortunately flucytosine is expensive and unavailable where the burden of disease is greatest. Where unavailable, guidelines recommend treatment with amphotericin and fluconazole, but this is less effective, with mortality rates of 40-50%. Faster rates of clearance of yeast from cerebrospinal fluid (CSF) are associated with better outcomes - improving the potency of antifungal therapy is likely to be an effective strategy to improve survival. Tamoxifen, a selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing synergistic when combined\n                    <ns4:italic>in vitro<\/ns4:italic>\n                    with amphotericin, and fungicidal when combined with fluconazole. It is concentrated in the brain and macrophages, off-patent, cheap and widely available. We designed a randomized trial to deliver initial efficacy and safety data for tamoxifen combined with amphotericin and fluconazole.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Method<\/ns4:bold>\n                    : A phase II, open-label, randomized (1:1) controlled trial of tamoxifen (300mg\/day) combined with amphotericin (1mg\/kg\/day) and fluconazole (800mg\/day) for the first 2 weeks therapy for HIV infected or uninfected adults with cryptococcal meningitis. The study recruits at Cho Ray Hospital and the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. The primary end point is Early Fungicidal Activity (EFA-the rate of yeast clearance from CSF), over the first two weeks of treatment. 50 patients will be recruited providing \u224880% and 90% power to detect a difference in the EFA of -0.11 or -0.13 log10CFU\/ml\/day, respectively.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Discussion:<\/ns4:bold>\n                    The results of the study will inform the decision to proceed to a larger trial powered to mortality. The size of effect detectable has previously been associated with reduced mortality from this devastating disease. Particular side effects of interest include QT prolongation.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Trial registration<\/ns4:bold>\n                    : Clinicaltrials.gov\n                    <ns4:ext-link xmlns:ns3=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns3:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03112031\">NCT03112031<\/ns4:ext-link>\n                    (11\/04\/2017)\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.15010.1","type":"journal-article","created":{"date-parts":[[2019,1,22]],"date-time":"2019-01-22T10:38:08Z","timestamp":1548153488000},"page":"8","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["A randomized open label trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis."],"prefix":"10.12688","volume":"4","author":[{"given":"Nguyen Thi Thuy","family":"Ngan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Thi Hoang","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Le Nhu","family":"Tung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Phu Huong","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luong Thi Hue","family":"Tai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Hoan","family":"Phu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguyen Van Vinh","family":"Chau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Quang","family":"Binh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le Quoc","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1978-1559","authenticated-orcid":false,"given":"Justin","family":"Beardsley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7680-2200","authenticated-orcid":false,"given":"David","family":"Lalloo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damian","family":"Krysan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Hope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2740-3155","authenticated-orcid":false,"given":"Ronald","family":"Geskus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Wolbers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nhat","family":"Le Thanh Hoang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2858-2087","authenticated-orcid":false,"given":"Guy","family":"Thwaites","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5728-0918","authenticated-orcid":false,"given":"Evelyne","family":"Kestelyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-6280","authenticated-orcid":false,"given":"Jeremy","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2019,1,22]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"525-530","DOI":"10.1097\/QAD.0b013e328322ffac","article-title":"Estimation of the current global burden of cryptococcal meningitis among persons living with HIV\/AIDS.","volume":"23","author":"B Park","year":"2009","journal-title":"AIDS."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"e442","DOI":"10.1371\/journal.pmed.0030442","article-title":"Projections of global mortality and burden of disease from 2002 to 2030.","volume":"3","author":"C Mathers","year":"2006","journal-title":"PLoS Med."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"499-508","DOI":"10.1086\/313992","article-title":"Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. 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Appendices - A randomised controlled trial of tamoxifen for cryptococcal meningitis","author":"J Day","year":"2019"},{"key":"ref-59","article-title":"R: A Language and Environment for Statistical Computing (version 2.9.0)","year":"2015"}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,10]],"date-time":"2022-09-10T15:51:42Z","timestamp":1662825102000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,22]]},"references-count":59,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.15010.1","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.16375.r34633","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.16375.r34634","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.16375.r34634","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.16375.r34633","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.16375.r34627","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,22]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.16375.r34633, Joshua Rhein, Infectious Diseases Institute of Makerere University, Kampala, Uganda, 05 Feb 2019, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1#referee-response-34633","order":0,"name":"referee-response-34633","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Jeremy Day<\/b>; <i>Posted: 06 Feb 2019<\/i>; Many thanks for the thoughtful comments. Were agree, particularly within the light of the recently published ACTA trial, that it is possible that a drug may have mortality benefits that are not necessarily detectable through measurement of EFA. However, in general, increased rates of EFA are strongly associated at the population level with improvements in survival. Particularly, the combination of amphotericin with flucytosine, which appears synergistic <i>in vitro<\/i> for the majority (~80%) of clinical isolates (as we found for tamoxifen and amphotericin), delivers the steepest declines in CSF fungal load, so EFA seemed an appropriate endpoint for this combination at this juncture. &nbsp;This this will be the first use of tamoxifen within humans with cryptococcal disease - we felt it imperative to generate these efficacy and safety data prior to any trial powered to mortality. However, all patients will be followed until 10 weeks after randomisation, although we will lack power to demonstrate and effect with this sample size.Publication of the protocol after the commencement of study enrolment represents unfortunate inefficiency on the part of the PI. The protocol was or course peer reviewed prior to ethical submissions and funding.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1#referee-comment-3799","order":1,"name":"referee-comment-3799","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.16375.r34634, William G Powderly, Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA, 19 Feb 2019, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-8\/v1#referee-response-34634","order":2,"name":"referee-response-34634","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This study was supported by the Wellcome Trust [106680]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}