Introduction and rationale: Cushings 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 patients 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.
18 - 21 May 2019
European Society of Endocrinology