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The current study explored improvements in clinical signs and additional specific\u00a0manifestations of hypercortisolism during osilodrostat (potent oral 11\u03b2-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2\u00a0mg bid; maximum: 30\u00a0mg bid) that enrolled 137 adults with Cushing\u2019s disease and mUFC\u2009&gt;\u20091.5 times the upper limit of normal (ULN). mUFC (normal range 11\u2012138\u00a0nmol\/24\u00a0h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if\u2009\u2264\u2009ULN, partially controlled if\u2009&gt;\u2009ULN but\u2009\u2265\u200950% reduction from baseline, and uncontrolled if\u2009&gt;\u2009ULN and\u2009&lt;\u200950% reduction from baseline. Concomitant medications were permitted throughout\u00a0the study.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Improvements in clinical signs and additional specific\u00a0manifestations of hypercortisolism associated with Cushing\u2019s disease occurred alongside decreases in mUFC.<\/jats:p>\n                <jats:p><jats:italic>Trial registration<\/jats:italic> NCT02180217 (first posted July 2014).<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s40618-024-02359-6","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T10:01:45Z","timestamp":1714644105000},"page":"2437-2448","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial in\u00a0Cushing's disease"],"prefix":"10.1007","volume":"47","clinical-trial-number":[{"clinical-trial-number":"nct02180217","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9632-1348","authenticated-orcid":false,"given":"R.","family":"Pivonello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9284-6289","authenticated-orcid":false,"given":"M.","family":"Fleseriu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-5493","authenticated-orcid":false,"given":"J.","family":"Newell-Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9688-006X","authenticated-orcid":false,"given":"A.","family":"Shimatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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Eur J Endocrinol 182(2):207\u2013217","journal-title":"Eur J Endocrinol"}],"container-title":["Journal of Endocrinological Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40618-024-02359-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40618-024-02359-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40618-024-02359-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T10:18:17Z","timestamp":1726136297000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40618-024-02359-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,2]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["2359"],"URL":"https:\/\/doi.org\/10.1007\/s40618-024-02359-6","relation":{},"ISSN":["1720-8386"],"issn-type":[{"value":"1720-8386","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,2]]},"assertion":[{"value":"8 June 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"RP has received research funding from Recordati AG, Corcept Therapeutics, Strongbridge Biopharma, and Neurocrine Biosciences and served as a consultant for Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, and H Lundbeck A\/S. MF reports grants to her university and occasional scientific consulting fees from Recordati Rare Diseases, Sparrow, and Xeris (Strongbridge); she served as a member of the LINC 3 steering committee. JNP reports research grants and consultancy payments to his university from Crinetics, Diurnal, HRA Pharma, and Recordati Rare Diseases. AS reports serving as a speaker and consultant for Recordati; he also served as a member of the LINC 3 steering committee. RAF reports research grants from Strongbridge and Corcept Therapeutics and consultancy fees from Recordati Rare Diseases and Corcept Therapeutics. PK has no conflicts of interest to disclose. AT reports research contracts and consulting and conference fees from HRA Pharma, Ipsen-Biotech, Novartis, and Recordati Rare Diseases. TCB reports institutional research support from Sandoz and Pfizer and consultancy and lectureship fees from Novartis, Ipsen, Strongbridge, Pfizer, and Recordati Rare Diseases. EBG reports research grants to her hospital from Xeris (Strongbridge), Recordati Rare Diseases, Sparrow, and Corcept Therapeutics and personal consulting fees from Xeris (Strongbridge). AP is an employee of Recordati. AMP was an employee of Recordati when the analyses were conducted. BMKB reports research grants to her institution from Novartis, Strongbridge, and Millendo and occasional consulting honoraria from HRA Pharma, Novartis, Recordati Rare Diseases, Sparrow, and Xeris (Strongbridge); she served on the LINC 3 steering committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}},{"value":"The study was conducted in accordance with the Declaration of Helsinki, with an independent ethics committee\/institutional review board at each site approving the study protocol.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Patients provided written informed consent to participate.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}