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

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:

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%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 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.

• Authors: Rosario Pivonello, Atanaska Elenkova, Maria Fleseriu, Richard A Feelders, Przemyslaw Witek, Yona Greenman, Eliza B Geer, Paola Perotti, Leonard Saiegh, Fredric Cohen, Giorgio Arnaldi
• Journal: Frontiers in endocrinology (Front Endocrinol (Lausanne)) Vol. 12 Pg. 595894 ( 2021) ISSN: 1664-2392 [Print] Switzerland
• PMID: 33897615 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Pivonello, Elenkova, Fleseriu, Feelders, Witek, Greenman, Geer, Perotti, Saiegh, Cohen and Arnaldi.

Chemical References

• Blood Glucose
• Enzyme Inhibitors
• Ketoconazole

Topics

• Adult
• Aged
• Blood Glucose (metabolism)
• Cushing Syndrome (complications, drug therapy, metabolism)
• Diabetes Complications (drug therapy, metabolism)
• Enzyme Inhibitors (administration & dosage, adverse effects)
• Female
• Humans
• Ketoconazole (administration & dosage, adverse effects)
• Male
• Middle Aged
• Prospective Studies
• Treatment Outcome