{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:02:16Z","timestamp":1791820936142,"version":"4.3.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,1,8]],"date-time":"2023-01-08T00:00:00Z","timestamp":1673136000000},"content-version":"vor","delay-in-days":114,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T00:00:00Z","timestamp":1663286400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11\u03b2-hydroxylase inhibitor, for treating Cushing's disease (CD).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design\/methods<\/jats:title>\n                  <jats:p>A total of 137 adults with CD and mean 24-h urinary free cortisol (mUFC) &amp;gt; 1.5 \u00d7 upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received \u2265 72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from the core study baseline.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Median osilodrostat exposure from the core study baseline to study end was 130 weeks (range 1\u2013245) and median average dose was 7.4 mg\/day (range 0.8\u201346.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained \u2264 ULN. Of 106 patients, 86 (81%) patients who entered the extension had mUFC \u2264 ULN at week 72. Improvements in cardiovascular\/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15\/137 (10.9%) and 12\/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1530\/eje-22-0317","type":"journal-article","created":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T13:06:41Z","timestamp":1660828001000},"page":"531-541","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-7","source":"Crossref","is-referenced-by-count":69,"title":["Long-term outcomes of osilodrostat in Cushing's disease: LINC 3 study extension"],"prefix":"10.1093","volume":"187","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9284-6289","authenticated-orcid":false,"given":"Maria","family":"Fleseriu","sequence":"first","affiliation":[{"name":"Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health & Science University , Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Newell-Price","sequence":"additional","affiliation":[{"name":"Department of Oncology and Metabolism, The Medical School, University of Sheffield , Sheffield, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9632-1348","authenticated-orcid":false,"given":"Rosario","family":"Pivonello","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Universit\u00e0 Federico II di Napoli , Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Shimatsu","sequence":"additional","affiliation":[{"name":"Advanced Medical Care Center, Omi Medical Center , Kusatsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Scaroni","sequence":"additional","affiliation":[{"name":"Endocrinology Unit, Department of Medicine, University Hospital , Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6674-6441","authenticated-orcid":false,"given":"Zhanna","family":"Belaya","sequence":"additional","affiliation":[{"name":"Department of Neuroendocrinology and Bone Disease, Endocrinology Research Centre , Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Feelders","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Endocrine Section, Erasmus Medical Center , Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greisa","family":"Vila","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna , Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghislaine","family":"Houde","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, University of Sherbrooke , Sherbrooke, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama","family":"Walia","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER) , Chandigarh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Izquierdo","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Roughton","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG , Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto M","family":"Pedroncelli","sequence":"additional","affiliation":[{"name":"Recordati AG , Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beverly M K","family":"Biller","sequence":"additional","affiliation":[{"name":"Neuroendocrine and Pituitary Tumor Clinical Center, Massachusetts General Hospital , Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,16]]},"reference":[{"key":"2023010809172161600_bib1","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/S0140-6736(14)61375-1","article-title":"Cushing's syndrome","volume":"386","author":"Lacroix","year":"2015","journal-title":"Lancet"},{"key":"2023010809172161600_bib2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1530\/EJE-11-1095","article-title":"The burden of Cushing's disease: clinical and health-related quality of life aspects","volume":"167","author":"Feelders","year":"2012","journal-title":"European Journal of Endocrinology"},{"key":"2023010809172161600_bib3","first-page":"611","article-title":"Complications of Cushing's syndrome: state of the art","volume":"4","author":"Pivonello","year":"2016","journal-title":"Lancet: Diabetes and Endocrinology"},{"key":"2023010809172161600_bib4","doi-asserted-by":"crossref","first-page":"101505","DOI":"10.1016\/j.beem.2021.101505","article-title":"Quality of life in Cushing's syndrome","volume":"35","author":"Bride","year":"2021","journal-title":"Best Practice and Research: Clinical Endocrinology and Metabolism"},{"key":"2023010809172161600_bib5","doi-asserted-by":"crossref","first-page":"R207","DOI":"10.1530\/EJE-20-1309","article-title":"MANAGEMENT OF ENDOCRINE DISEASE: Cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing's syndrome: a practical approach","volume":"184","author":"Varlamov","year":"2021","journal-title":"European Journal of Endocrinology"},{"key":"2023010809172161600_bib6","first-page":"847","article-title":"Consensus on diagnosis and management of Cushing's disease: a guideline update","volume":"9","author":"Fleseriu","year":"2021","journal-title":"Lancet: Diabetes and Endocrinology"},{"key":"2023010809172161600_bib7","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1111\/joim.12975","article-title":"Current management of Cushing's disease","volume":"286","author":"Tritos","year":"2019","journal-title":"Journal of Internal Medicine"},{"key":"2023010809172161600_bib8","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1210\/er.2013-1048","article-title":"The treatment of Cushing's disease","volume":"36","author":"Pivonello","year":"2015","journal-title":"Endocrine Reviews"},{"issue":"Supplement 1","key":"2023010809172161600_bib9","doi-asserted-by":"crossref","first-page":"A521","DOI":"10.1210\/jendso\/bvab048.1063","article-title":"Long-term control of urinary free cortisol with osilodrostat in patients with Cushing's disease: final results from the LINC 2 study","volume":"5","author":"Fleseriu","year":"2021","journal-title":"Journal of the Endocrine Society"},{"key":"2023010809172161600_bib10","first-page":"748","article-title":"Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase","volume":"8","author":"Pivonello","year":"2020","journal-title":"Lancet: Diabetes and Endocrinology"},{"key":"2023010809172161600_bib11","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1007\/s11102-015-0692-z","article-title":"Osilodrostat, a potent oral 11\u03b2-hydroxylase inhibitor: 22-week, prospective, phase II study in Cushing's disease","volume":"19","author":"Fleseriu","year":"2016","journal-title":"Pituitary"},{"key":"2023010809172161600_bib12","doi-asserted-by":"crossref","first-page":"e2882","DOI":"10.1210\/clinem\/dgac178","article-title":"Randomized trial of osilodrostat for the treatment of Cushing's disease","volume":"107","author":"Gadelha","year":"2022","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2023010809172161600_bib13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s40271-013-0012-5","article-title":"Psychometric evaluation of the Cushing's quality-of-life questionnaire","volume":"6","author":"Nelson","year":"2013","journal-title":"Patient"},{"key":"2023010809172161600_bib14","doi-asserted-by":"crossref","first-page":"3269","DOI":"10.1017\/S0033291715001270","article-title":"Minimal clinically important difference on the beck depression inventory-II according to the patient's perspective","volume":"45","author":"Button","year":"2015","journal-title":"Psychological Medicine"},{"key":"2023010809172161600_bib15","doi-asserted-by":"crossref","first-page":"S115","DOI":"10.1016\/j.eprac.2022.03.273","article-title":"Abstract #1183049: Hypertension (HTN) and diabetes (DM) improvement during osilodrostat therapy in patients with Cushing's disease (CD): analyses from the phase III LINC 3 study","volume":"28","author":"Pivonello","year":"2022","journal-title":"Endocrine Practice"},{"key":"2023010809172161600_bib16","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1530\/EJE-19-0695","article-title":"Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease","volume":"182","author":"Newell-Price","year":"2020","journal-title":"European Journal of Endocrinology"},{"key":"2023010809172161600_bib17","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s11102-013-0475-3","article-title":"Combination therapy for Cushing's disease: effectiveness of two schedules of treatment: should we start with cabergoline or ketoconazole?","volume":"17","author":"Barbot","year":"2014","journal-title":"Pituitary"},{"key":"2023010809172161600_bib18","article-title":"Effect of dosing and titration of osilodrostat on efficacy and safety in patients with Cushing's disease: results from two phase III trials (LINC 3 and LINC 4)","author":"Feelders","year":"2021","journal-title":"Poster Presented at the 7th ENEA Virtual Workshop"},{"key":"2023010809172161600_bib19","doi-asserted-by":"crossref","DOI":"10.1111\/cen.14551","article-title":"Osilodrostat in Cushing's disease: the risk of delayed adrenal insufficiency should be carefully monitored","author":"Castinetti","year":"2021","journal-title":"Clinical Endocrinology"},{"key":"2023010809172161600_bib20","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s11102-020-01097-1","article-title":"Corticotroph tumor progression during long-term therapy with osilodrostat in a patient with persistent Cushing's disease","volume":"24","author":"Fontaine-Sylvestre","year":"2021","journal-title":"Pituitary"},{"key":"2023010809172161600_bib21","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1210\/jc.2013-3628","article-title":"Ketoconazole in Cushing's disease: is it worth a try?","volume":"99","author":"Castinetti","year":"2014","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2023010809172161600_bib22","first-page":"855","article-title":"Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing's syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial","volume":"7","author":"Fleseriu","year":"2019","journal-title":"Lancet: Diabetes and Endocrinology"},{"key":"2023010809172161600_bib23","doi-asserted-by":"crossref","first-page":"595894","DOI":"10.3389\/fendo.2021.595894","article-title":"Levoketoconazole in the treatment of patients with Cushing's syndrome and diabetes mellitus: results from the SONICS phase 3 study","volume":"12","author":"Pivonello","year":"2021","journal-title":"Frontiers in Endocrinology"},{"issue":"Supplement 1","key":"2023010809172161600_bib24","doi-asserted-by":"crossref","first-page":"A526","DOI":"10.1210\/jendso\/bvab048.1072","article-title":"Safety and efficacy of levoketoconazole in the treatment of endogenous Cushing's syndrome (LOGICS): results from a double-blind, placebo-controlled, randomized withdrawal study","volume":"5","author":"Zacharieva","year":"2021","journal-title":"Journal of the Endocrine Society"},{"issue":"Supplement 1","key":"2023010809172161600_bib25","doi-asserted-by":"crossref","first-page":"A515","DOI":"10.1210\/jendso\/bvab048.1053","article-title":"Metyrapone treatment in endogenous Cushing's syndrome: results at week 12 from PROMPT, a prospective international multicenter, open-label, phase III\/IV study","volume":"5","author":"Nieman","year":"2021","journal-title":"Journal of the Endocrine Society"},{"key":"2023010809172161600_bib26","doi-asserted-by":"crossref","first-page":"4146","DOI":"10.1210\/jc.2015-2616","article-title":"Effectiveness of metyrapone in treating Cushing's syndrome: a retrospective multicenter study in 195 patients","volume":"100","author":"Daniel","year":"2015","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2023010809172161600_bib27","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1007\/s12020-018-1675-4","article-title":"Metyrapone treatment in Cushing's syndrome: a real-life study","volume":"62","author":"Ceccato","year":"2018","journal-title":"Endocrine"},{"key":"2023010809172161600_bib28","doi-asserted-by":"crossref","first-page":"101490","DOI":"10.1016\/j.beem.2021.101490","article-title":"Updates in adrenal steroidogenesis inhibitors for Cushing's syndrome \u2013 a practical guide","volume":"35","author":"Varlamov","year":"2021","journal-title":"Best Practice and Research: Clinical Endocrinology and Metabolism"},{"key":"2023010809172161600_bib29","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1210\/clinem\/dgab122","article-title":"Approach to the patient treated with steroidogenesis inhibitors","volume":"106","author":"Castinetti","year":"2021","journal-title":"Journal of Clinical Endocrinology and Metabolism"}],"container-title":["European Journal of Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/eje.bioscientifica.com\/view\/journals\/eje\/187\/4\/EJE-22-0317.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/eje.bioscientifica.com\/downloadpdf\/journals\/eje\/187\/4\/EJE-22-0317.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ejendo\/article-pdf\/187\/4\/531\/48516037\/eje-22-0317.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ejendo\/article-pdf\/187\/4\/531\/48516037\/eje-22-0317.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T16:18:08Z","timestamp":1676391488000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ejendo\/article\/187\/4\/531\/6972108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,16]]},"references-count":29,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,10,1]]}},"URL":"https:\/\/doi.org\/10.1530\/eje-22-0317","relation":{},"ISSN":["0804-4643","1479-683X"],"issn-type":[{"value":"0804-4643","type":"print"},{"value":"1479-683X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,10]]},"published":{"date-parts":[[2022,9,16]]}}}