HRA Pharma Prepares Observational Post-Approval Study of Ketoconazole

After receiving the approval of ketoconazole for the treatment of Cushing’s syndrome patients in the European Union, HRA Pharma is setting up to conduct a post-approval observation study that will closely monitor patients receiving the therapy for any adverse events.

The study is part of the mandatory pharmacovigilance requirement set as a condition of marketing authorization by the European Commission, and aims to address some concerns regarding treatment toxicity.

Its protocol was described in the poster, “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,” presented at the 21^st European Congress of Endocrinology in Lyon, France.

Ketoconazole is a steroidogenesis inhibitor, i.e., it blocks the production of cortisol and reverses its excess in patients with Cushing’s syndrome. It was originally developed as an antifungal agent and has been used off-label as a treatment option for Cushing’s for a long time.

However, the treatment may cause complications,  including liver toxicity, adrenal gland issues, and heart problems.

In 2014, the European Commission granted HRA Pharma the market authorization for ketoconazole for the treatment of endogenous Cushing’s syndrome in patients over 12 years of age. This authorization, however, was given on the condition that the company monitor the safety concerns associated with ketoconazole use through non-interventional studies.

In keeping with the condition of the authorization, the company has planned an observational post-authorization safety study (PASS) to obtain real-world data on the long-term safety and efficacy of ketoconazole in Cushing’s syndrome. Here, they describe the protocol and study design of the non-interventional trial.

The study will include 200 patients age 12 and older with endogenous Cushing’s disease starting ketoconazole treatment in routine clinical practice and listed in The European Register on Cushing’s syndrome (ERCUSYN).

Twenty-three sites across nine ERCUSYN-participating countries — Italy, France, Portugal, Croatia, the Netherlands, the United Kingdom, Sweden, Germany, and Spain — will be involved in the study.

The European Society of Endocrinology is a collaborator in the study and the owner of ERCUSYN, and will be providing information on patients’ characteristics at the study start (baseline), their treatment history, and long-term clinical and biochemical outcome.

The primary objective of PASS is to assess the safety profile of ketoconazole by recording adverse events such as liver toxicity and heart issues. Liver enzymes will be monitored for signs of liver toxicity, and heart rhythm disorders will be assessed by an echocardiogram.

The overall effectiveness and safety of ketoconazole, in addition to its impact on patients’ quality of life, will serve as the secondary objective of the study.

Efficacy evaluation includes cortisol levels, changes in clinical weight, body mass index, and blood pressure, and occurrence and treatment of comorbidities associated with Cushing’s syndrome. Quality-of-life assessments will be done through CushingQoL and EuroQoL 5D patient-reported questionnaires.

More detailed information about PASS design and rationale can be found here.