{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T03:33:27Z","timestamp":1774668807040,"version":"3.50.1"},"reference-count":20,"publisher":"The Endocrine Society","issue":"7","license":[{"start":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T00:00:00Z","timestamp":1647993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,6,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11\u03b2hydroxylase inhibitor, compared with placebo in patients with Cushing disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion\u2005\u2265\u20051.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC\u2005\u2264\u2005ULN at week 12. The key secondary endpoint was the proportion achieving mUFC\u2005\u2264\u2005ULN at week 36 (after 24 weeks\u2019 open-label osilodrostat).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seventy-three patients (median age, 39 years [range, 19-67]; mean\/median mUFC, 3.1\u2005\u00d7\u2005ULN\/2.5\u2005\u00d7\u2005ULN) received randomized treatment with osilodrostat (n\u2005=\u200548) or placebo (n\u2005=\u200525). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC\u2005\u2264\u2005ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P\u2005&amp;lt;\u20050.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC\u2005\u2264\u2005ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgac178","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T13:28:47Z","timestamp":1648214927000},"page":"e2882-e2895","source":"Crossref","is-referenced-by-count":96,"title":["Randomized Trial of Osilodrostat for the Treatment of Cushing Disease"],"prefix":"10.1210","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9250-3558","authenticated-orcid":false,"given":"M\u00f4nica","family":"Gadelha","sequence":"first","affiliation":[{"name":"Neuroendocrinology Research Center, Endocrinology Section, Medical School and Hospital Universit\u00e1rio Clementino Fraga Filho, Universidade Federal do Rio de Janeiro , Rio de Janeiro , Brazil"}]},{"given":"Marie","family":"Bex","sequence":"additional","affiliation":[{"name":"University Hospitals Leuven , Leuven , Belgium"}]},{"given":"Richard A","family":"Feelders","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Endocrine Section, Erasmus Medical Center , Rotterdam CA , The Netherlands"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3865-0810","authenticated-orcid":false,"given":"Anthony P","family":"Heaney","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles , CA , USA"}]},{"given":"Richard J","family":"Auchus","sequence":"additional","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, Departments of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor , MI , USA"}]},{"given":"Aleksandra","family":"Gilis-Januszewska","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Jagiellonian University Medical College , Krak\u00f3w , Poland"}]},{"given":"Przemyslaw","family":"Witek","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Endocrinology and Diabetes, Medical University of Warsaw , Warsaw , Poland"}]},{"given":"Zhanna","family":"Belaya","sequence":"additional","affiliation":[{"name":"Department of Neuroendocrinology and Bone Disease, Endocrinology Research Centre , Moscow , Russia"}]},{"given":"Yerong","family":"Yu","sequence":"additional","affiliation":[{"name":"West China Hospital of Sichuan University , Chengdu , China"}]},{"given":"Zhihong","family":"Liao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Sun Yat-sen University , Guangzhou , China"}]},{"given":"Chih Hao Chen","family":"Ku","sequence":"additional","affiliation":[{"name":"Clinica Los Yoses , San Pedro , Costa Rica"}]},{"given":"Davide","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universit\u00e1rio de S\u00e3o Jo\u00e3o, Universidade do Porto , Porto , Portugal"}]},{"given":"Michael","family":"Roughton","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel , Switzerland"}]},{"given":"Judi","family":"Wojna","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hanover , NJ , USA"}]},{"given":"Alberto M","family":"Pedroncelli","sequence":"additional","affiliation":[{"name":"Recordati AG , Basel , Switzerland"}]},{"given":"Peter J","family":"Snyder","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA , USA"}]}],"member":"80","published-online":{"date-parts":[[2022,3,23]]},"reference":[{"issue":"9996","key":"2022061616042203800_CIT0001","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/S0140-6736(14)61375-1","article-title":"Cushing\u2019s 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