AUTHOR=Pivonello Rosario , Elenkova Atanaska , Fleseriu Maria , Feelders Richard A. , Witek Przemyslaw , Greenman Yona , Geer Eliza B. , Perotti Paola , Saiegh Leonard , Cohen Fredric , Arnaldi Giorgio 

TITLE=Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study

JOURNAL=Frontiers in Endocrinology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.595894

DOI=10.3389/fendo.2021.595894

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>Normalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; <italic>P</italic> = 0.0006 <italic>vs</italic> null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; <italic>P</italic> = 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.</p></sec><sec><title>Conclusions</title><p>Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM.</p></sec><sec><title>Clinical Trial Registration</title><p>(<ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link>), NCT01838551.</p></sec>