ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 P1107 | DOI: 10.1530/endoabs.63.P1107

European observational study of ketoconazole for endogenous cushing's syndrome in collaboration with European registry on cushing's syndrome ERCUSYN: PASS ketoconazole study design and rationale

Martine Bostnavaron1, Pauline Marsault1, Maura Arosio2, Jérôme Bertherat3, Thierry Brue4, Olivier Chabre5, Philippe Chanson6, João Sequeira Duarte7, Carmen Fajardo8, Richard Feelders9, Felicia Alexandra Hanzu10, Darko Kastelan11, Romana Netea-Maier12, John Newell-Price13, Alberto Pereira14, Oskar Ragnarsson15, Martin Reincke16, Christian Strasburger17, Antoine Tabarin18, Philippe Touraine19, Peter Trainer20, Aparna Pal21, Kathrin Zopf22, Holger Franz23, Gunter Stalla24, Alicia Santos25, Elena Valassi25, Sandy Werner26 & Susan Webb25

1HRA-Pharma, Chatillon, France; 2University of Milan, Milan, Italy; 3Hôpital Cochin, Paris, France; 4Hôpital de la Conception, Marseille, France; 5Hôpital Albert MichallonHôpital Albert Michallon, Grenoble, France; 6Hôpital Bicêtre, Le Kremlin Bicêtre, France; 7Hospital Egas Moniz, Lisbon, Portugal; 8Hospital Universitario de La Ribera, Alzira, Spain; 9Erasmus University Medical Center, Rotterdam, Netherlands; 10Hospital Clinic Barcelona, Barcelona, Spain; 11University Hospital Zagreb, Zagreb, Croatia; 12Radboud University Nijmegen Medical Centr, Nijmegen, Netherlands; 13Sheffield Teaching Hospitals NHS, Sheffield, UK; 14Leiden University Medical Center, Leiden, Netherlands; 15Goteborg University, Göteborg, Sweden; 16Klinikum der Universität München, Munich, Germany; 17Charité Universitats medizin Berlin, Berlin, Germany; 18Centre Hospitalier Universitaire de Bordeaux, Pessac, France; 19Hôpital pitié-salpêtrière, Paris, France; 20Christie Hospital NHS Trust, Manchester, UK; 21Oxford Radcliffe Hospitals NHS Trust, Oxford, UK; 22Charité Universitatsmedizin Berlin, Berlin, Germany; 23Lohmann & Birkner Health Care, Berlin, Germany; 24Medicover Neuroendokrinologie, Munich, Germany; 25Institut de Recerca de la Santa Creu i Sant Pau, Barcelona, Spain; 26Praxis, Oldenburg, Germany.

Introduction and rationale: Cushing’s syndrome (CS) is a rare disease with hypercortisolism caused either by ACTH excess from a pituitary or non-pituitary tumor or by an ACTH-independent primary adrenal overproduction of cortisol. It is associated with significant comorbidities potentially lethal: hypertension, diabetes, coagulopathy, cardiovascular disease, infections, and osteoporotic fractures. It is usually managed by surgery and/or medical treatment with steroidogenesis inhibitors or pituitary targeted therapies. As a condition of marketing authorization granting by European Commission for the use of ketoconazole for the treatment of CS in adults and adolescents above 12 years, the company (HRA Pharma) has to perform a mandatory pharmacovigilance activity with respect to some safety concerns in the format of a non-interventional PASS (Post-Authorization Safety Study).

Objectives: The primary objective of this non-interventional study is to document liver (hepatotoxicity) and cardiac (QT prolongation) tolerability profile of ketoconazole. The secondary objectives are overall safety of ketoconazole, effectiveness evaluations, drug utilization patterns of ketoconazole and the impact of the treatment on quality of life (QoL).

Patients and Methods: Patients (>12 years of age) with endogenous CS starting treatment (prospective dataset) with HRA ketoconazole® in routine clinical practice and included in ERCUSYN (European Registry on C.S) may be enrolled in the study. Two hundred prospective patients are to be enrolled. Safety assessments include adverse events, hepatic enzymes and ECG. Effectiveness assessments include cortisol levels, number and type of comorbidities (hypertension, diabetes, dyslipidemia, osteoporosis, psychiatric disorders, cardiovascular diseases) and related treatments and clinical symptoms of CS (weight, Body Mass Index, waist, blood pressure) over time. QoL assessment includes self-reported questionnaires CushingQoL & EuroQoL 5D. The primary endpoint is the incidence of hepatotoxicity and QT prolongation, time to onset since ketoconazole initiation, and time to recovery. This study is performed in collaboration with ESE as the owner of the ERCUSYN database comprising three major sections (baseline characteristics, therapies of CS and long term biochemical and clinical outcome). Twenty three sites in 9 European countries (Croatia, France, Germany, Italy, Portugal, The Netherlands, UK, Spain and Sweden) involved in ERCUSYN will participate. After obtaining patient’s informed consent, and having completed the core ERCUSYN data entry, the investigator will enter data in additional HRA modules created specifically for this study to collect safety data. Data entered in ERCUSYN and in HRA modules will be analyzed. Interim analyses will be performed yearly.

Conclusion: PASS ketoconazole will provide European real-world data to confirm the long-term safety and effectiveness of ketoconazole used in the treatment of CS.

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