Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
Rosario Pivonello, Атанаска Еленкова, Maria Fleseriu, Richard A. Feelders, Przemysław Witek, Yona Greenman, Eliza B. Geer, Paola Perotti, Leonard Saiegh, Fredric J. Cohen, Giorgio Arnaldi
Abstract
Background: Cushing's syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS. Methods: SONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases. Results: = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal. Conclusions: Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM. Clinical Trial Registration: (ClinicalTrials.gov), NCT01838551.