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This study (LOGICS) evaluated drug-specificity of cortisol normalization.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14\u201319\u00a0weeks) followed by double-blind, randomized-withdrawal (~\u20098\u00a0weeks), and restoration (~\u20098\u00a0weeks) phases.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~\u20094\u00a0weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n\u2009=\u200922) or placebo (n\u2009=\u200922). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC)\u2009&gt;\u20091.5\u2009\u00d7\u2009upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: \u2212\u00a054.5% (95% CI \u2212\u00a075.7, \u2212\u00a027.4; <jats:italic>P<\/jats:italic>\u2009=\u20090.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; <jats:italic>P<\/jats:italic>\u2009=\u20090.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing\u2019s syndrome. No new risks of levoketoconazole treatment were identified.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11102-022-01263-7","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T18:21:53Z","timestamp":1662747713000},"page":"911-926","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Levoketoconazole in the treatment of patients with endogenous Cushing\u2019s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)"],"prefix":"10.1007","volume":"25","author":[{"given":"Rosario","family":"Pivonello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Zacharieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atanaska","family":"Elenkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikl\u00f3s","family":"T\u00f3th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilan","family":"Shimon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Stigliano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corin","family":"Badiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"Brue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Emanuela","family":"Georgescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stylianos","family":"Tsagarakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredric","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Fleseriu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,9]]},"reference":[{"issue":"9996","key":"1263_CR1","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/S0140-6736(14)61375-1","volume":"386","author":"A Lacroix","year":"2015","unstructured":"Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015) Cushing\u2019s syndrome. 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Br J Pharmacol 153(3):439\u2013447","journal-title":"Br J Pharmacol"}],"container-title":["Pituitary"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-022-01263-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11102-022-01263-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11102-022-01263-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,19]],"date-time":"2022-11-19T21:37:32Z","timestamp":1668893852000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11102-022-01263-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,9]]},"references-count":37,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["1263"],"URL":"https:\/\/doi.org\/10.1007\/s11102-022-01263-7","relation":{},"ISSN":["1386-341X","1573-7403"],"issn-type":[{"value":"1386-341X","type":"print"},{"value":"1573-7403","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,9]]},"assertion":[{"value":"15 July 2022","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 September 2022","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"RP reports receiving research support to Federico II University of Naples as a principal investigator for clinical trials from Corcept Therapeutics, HRA Pharma, Novartis, Recordati, and Xeris Biopharma\/Strongbridge Biopharma; receiving different research support to Federico II University of Naples from Novartis and Xeris\/Strongbridge; and receiving occassional consulting honoraria from Corcept Therapeutics, HRA Pharma, Novartis, Recordati, and Xeris\/Strongbridge. SZ reports receiving consulting honoraria from Novartis. AE reports serving as the principal investigator\/sub-investigator of clinical trials for Corcept Therapeutics and Novartis; and receiving consulting honoraria from Novartis. MT reports serving as the principal investigator of clinical trials for Corcept Therapeutics, HRA Pharma, Novartis, and Xeris\/Strongbridge; serving as an occasional scientific consultant to HRA Pharma and Recordati; and receiving speaker\u2019s fees from Medis, Novartis, and Xeris\/Strongbridge. IS reports receiving research grants, consulting, and lectureship fees from Medison Pharma, Novartis International, and Pfizer.  AS reports receiving no grants or consulting honoraria from pharmaceutical companies. CB reports serving as the principal investigator of research grants from Novo Nordisk and Xeris\/Strongbridge; and receiving consulting honoraria from Ipsen. TB reports serving as a clinical trial investigator for Novartis and Xeris\/Strongbridge; receiving research grants from Ipsen and Pfizer; and serving as an advisory board member or receiving speaker\u2019s fees from Ipsen, Novartis, Pfizer, and Xeris\/Strongbridge. CEG reports serving as the principal investigator of clinical trials for HRA Pharma and Xeris\/Strongbridge. ST reports receiving research and travel grants and consulting honoraria from Novartis; and receiving consulting honoraria from Recordati. FC is a former employee of Strongbridge Biopharma\/Xeris Pharma and reports receiving consulting fees from Xeris. MF reports serving as an investigator with research grants to OHSU from Novartis, Recordati, and Xeris\/Strongbridge; serving as an occasional scientific consultant to HRA Pharma, Recordati, Sparrow, and Xeris\/Strongbridge; and is on the Editorial Board of Pituitary.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was approved by an institutional review board or independent ethics committee at each site and conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and the ethical principles of the Declaration of Helsinki.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Written informed consent was provided by each patient to participate in the study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}