Prospective, multi-country, observational study of patients with endogenous Cushing

Susan Webb; Alicia Santos; Maso Anna Aulinas; Karin Zibar Tomsic; Claudia Amaral; Richard Feelders; Oskar Ragnarsson; Emanuele Ferrante; Filippo Ceccato; Olivier Chabre; Justine Cristante; Felicia Hanzu; Martin Reincke; Philippe Chanson; Antoine Tabarin; Duarte Joao Sequeira; Daniela Guelho; Carmen Fajardo; Martine Bostnavaron; Nader Myriam Bou; Jerome Bertherat; Thierry Brue

doi:10.1530/endoabs.99.P2

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Endocrine Abstracts (2023) 99 P2 | DOI: 10.1530/endoabs.99.P2

ECE2024 Poster Presentations Adrenal and Cardiovascular Endocrinology (95 abstracts)

Prospective, multi-country, observational study of patients with endogenous Cushing’s syndrome exposed to Ketoconazole (using the existing European Registry on Cushing’s Syndrome (ERCUSYN)), to assess drug use, safety and effectiveness

Susan Webb ¹ , Alicia Santos ¹ , Anna Aulinas Maso ¹ , Karin Zibar Tomsic ² , Claudia Amaral ³ , Richard Feelders ⁴ , Oskar Ragnarsson ⁵ , Emanuele Ferrante ⁶ , Filippo Ceccato ⁷ , Olivier Chabre ⁸ , Justine Cristante ⁸ , Felicia Hanzu ⁹ , Martin Reincke ¹⁰ , Philippe Chanson ¹¹ , Antoine Tabarin ¹² , João Sequeira Duarte ¹³ , Daniela Guelho ¹⁴ , Carmen Fajardo ¹⁵ , Martine Bostnavaron ¹⁶ , Myriam Bou Nader ¹⁶ , Jerôme Bertherat ¹⁷ & Thierry Brue ¹⁸

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¹Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Ciberer Unit 747, UAB, Department of Endocrinology, Barcelona, Spain; ²University Hospital, Zagreb, Department of Endocrinology, Zagreb, Croatia; ³Centro Hospitalar Universitário do Santo António, Department of Endocrinology, Porto, Portugal; ⁴Erasmus University Medical Center Rotterdam, Department of Endocrinology, Rotterdam, Netherlands; ⁵Sahlgrenska University Hospital, Department of Endocrinology, Göteborg, Sweden; ⁶Fondazione IRCC Ca’ Granda Ospedale Maggiore Policlinico, Department of endocrinology, Milan, Italy; ⁷University Hospital of Padova, Department of Endocrinology, Padova, Italy; ^>8Centre Hospitalier Universitaire Grenoble Alpes, Department of Endocrinology, Grenoble, France; ⁹Hospital Clinic Univesity Barcelona, Idibaps, Department of Endocrinology, Barcelona, Spain; ¹⁰University Hospital of Münich, Medical Department IV, Münich, Germany; ¹¹APHP-Université Paris Saclay, Hôpital Bicêtre, Department of Endocrinology, Le Kremlin Bicêtre, France; ¹²Centre Hospitalier Universitaire, Department of Endocrinology, Bordeaux, France; ¹³Egas Moniz Hospital, Centro Hospitalar de Lisboa Ocidental, Department of Endocrinology CLO, Lisboa, Portugal; ¹⁴CHUC-HUC, Serviço de Endocrinologia, Diabetes e Metabolismo, Coimbra, Portugal; ¹⁵Hospital Universitario de La Ribera, Department of Endocrinology, Alzira, Spain; ¹⁶HRA Pharma Rare Diseases, Rare Diseases, Châtillon, France; ¹⁷Hôpital Cochin, Department of Endocrinology, Paris, France; ¹⁸Hôpital de la conception, Department of Endocrinology, Marseille, France

Background: Ketoconazole is a steroidogenesis inhibitor approved in Europe for the treatment of endogenous Cushing’s syndrome (CS) based on retrospective studies published over 3 decades. We present interim data from the first prospective observational, multicenter, international study on ketoconazole, a non-interventional PASS (Post-Authorization Safety study) requested by EMA at the time of registration to confirm ketoconazole good tolerance and effectiveness. This study is performed in collaboration with ESE owner of ERCUSYN (European Registry on CS).

Methods: Main inclusion criteria are: Patients (>12 years of age) with endogenous CS starting treatment with HRA ketoconazole^® in routine clinical practice. The primary endpoint is to document liver (hepatotoxicity) and cardiac (QT prolongation, QTc >450 msec and/or QTc increase >60 msec tolerability profile of ketoconazole. The main secondary endpoints are overall safety of ketoconazole and effectiveness evaluations.

Results: Last interim results (August 2023) included 93 patients (73 Females, 20 Males) from 17 centers in 5 countries. At baseline, median age was 47 years (17–85), main etiology was pituitary-dependent CS and median final dose was 400 mg/day. Median treatment duration was 212 days (3 to 2160 days). No case of QTc prolongation was reported. Liver function tests (LFT) abnormalities were reported in 37.5% (33/88) patients, occurring up to 4 weeks after ketoconazole start. Only 10.2% (9/88) patients had AST ≥ 3 ULN (Upper Limit of Normal) without increase of Total Bilirubin (TB) >2×ULN. Among these patients, 7 had liver injury with ALT ≥5× ULN assessed as hepatocellular (4), cholestatic (2) and mixed injury (1), which resolved after ketoconazole discontinuation. In 5 patients concomitant medication was also suspected. For 5 patients, 9 study-drug related serious adverse events (SAEs) other than severe hepatotoxicity occurred (pneumonia, acute kidney injury (2), hypokalemia, acute adrenal insufficiency (2), hyperkalemia (2), angioedema). Among the 45/91 (49,4%) patients for whom urinary free cortisol (UFC) and/or serum cortisol data were available, 31/45 (47.2%) patients had normalized UFC levels and/or serum cortisol at the last visit. A treatment benefit was evaluated by the physician in 90/91 (98.9%) patients. At the last visit, twelve 12/91 (13.2%) patients had at least one less drug for comorbidities by drug class (antihypertensive, antidiabetics, anti-osteoporosis, lipid lowering, ischemic heart disease medications or other treatments for comorbidities).

Conclusions: This prospective observational study in patients with CS confirms that ketoconazole has a tolerability profile similar to the previously reported safety profile and effectively lowers cortisol levels.