{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:04:48Z","timestamp":1790157888085,"version":"4.1.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute for Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS086312"],"award-info":[{"award-number":["R01NS086312"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute for Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS110519"],"award-info":[{"award-number":["R01NS110519"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute for Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K23NS137968"],"award-info":[{"award-number":["K23NS137968"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute for Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K23NS122601"],"award-info":[{"award-number":["K23NS122601"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K24AI184270"],"award-info":[{"award-number":["K24AI184270"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["D43TW009345"],"award-info":[{"award-number":["D43TW009345"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["KL2TR002492"],"award-info":[{"award-number":["KL2TR002492"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1TR002494"],"award-info":[{"award-number":["UL1TR002494"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Traditional antifungal trials have relied on all-cause mortality as the primary endpoint, which may overlook important treatment-related outcomes such as adverse events or tolerability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the use of hierarchical composite endpoints to capture clinically meaningful treatment differences in cryptococcal meningitis trials. A Delphi survey determined priorities in constructing the composite endpoint. We analyzed three randomized clinical trials on cryptococcal meningitis with win ratio and the Desirability of Outcome Ranking (DOOR). We estimated the Better DOOR Probability (BDP), which is the probability that a participant assigned to the study treatment would have a more desirable outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The Delphi survey received 34 respondents and most of them prioritized mortality and serious adverse events. In the AMBITION-cm trial, single-dose liposomal amphotericin B yielded a BDP of 55% (95% CI, 51%\u201359%) and win ratio of 1.23 (95% CI, 1.03\u20131.46), indicating superiority over standard-of-care therapy. In ENACT phase II trial, oral amphotericin B was associated with BDP of 52% (95% CI, 42%\u201363%) and win ratio of 1.14 (95% CI, .68\u20131.91), showing no statistically significant difference. The ASTRO-CM trial testing adjunctive sertraline showed no overall benefit with sertraline using either BDP (46%; 95% CI, 41%\u201352%) or win ratio 0.87 (95% CI, .70\u20131.08).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Hierarchical composite endpoints were feasible to implement in cryptococcal meningitis clinical trials and can enhance clinical relevance, especially in noninferiority designs where safety and tolerability matter. The two statistical approaches provided complementary perspectives\u2014DOOR offering absolute ranks and win ratio providing a more interpretable relative treatment effect estimate.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cid\/ciaf719","type":"journal-article","created":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T12:23:24Z","timestamp":1767443004000},"page":"112-119","source":"Crossref","is-referenced-by-count":2,"title":["Evaluating Desirability of Outcome Ranking (DOOR) and Win Ratio for Hierarchical Composite Endpoints in Cryptococcal Meningitis Trials"],"prefix":"10.1093","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4747-3687","authenticated-orcid":false,"given":"Biyue","family":"Dai","sequence":"first","affiliation":[{"name":"Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota , Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1118-4194","authenticated-orcid":false,"given":"Nicole","family":"Engen","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota , Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0000-8876","authenticated-orcid":false,"given":"Caleb P","family":"Skipper","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota Medical School , Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9601-3006","authenticated-orcid":false,"given":"Mahsa","family":"Abassi","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota Medical School , Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Nsangi","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, College of Health Sciences, Makerere University , Kampala ,","place":["Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C","family":"McHale","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota Medical School , Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8854-0321","authenticated-orcid":false,"given":"David B","family":"Meya","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota Medical School , Minneapolis, Minnesota ,","place":["USA"]},{"name":"Infectious Diseases Institute, College of Health Sciences, Makerere University , Kampala ,","place":["Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4715-0060","authenticated-orcid":false,"given":"David R","family":"Boulware","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota Medical School , Minneapolis, Minnesota ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"2026072309023254400_ciaf719-B1","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1093\/cid\/ciad440","article-title":"Oral lipid nanocrystal amphotericin B for cryptococcal meningitis: a randomized clinical 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