TY - JOUR
T1 - Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus
T2 - Results From the SONICS Phase 3 Study
AU - Pivonello, Rosario
AU - Elenkova, Atanaska
AU - Fleseriu, Maria
AU - Feelders, Richard A.
AU - Witek, Przemyslaw
AU - Greenman, Yona
AU - Geer, Eliza B.
AU - Perotti, Paola
AU - Saiegh, Leonard
AU - Cohen, Fredric
AU - Arnaldi, Giorgio
N1 - Publisher Copyright:
© Copyright © 2021 Pivonello, Elenkova, Fleseriu, Feelders, Witek, Greenman, Geer, Perotti, Saiegh, Cohen and Arnaldi.
PY - 2021/4/7
Y1 - 2021/4/7
N2 - 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.
AB - 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.
KW - Cushing’s disease
KW - Cushing’s syndrome
KW - diabetes mellitus
KW - hypercortisolism
KW - levoketoconazole
UR - http://www.scopus.com/inward/record.url?scp=85104618011&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104618011&partnerID=8YFLogxK
U2 - 10.3389/fendo.2021.595894
DO - 10.3389/fendo.2021.595894
M3 - Article
AN - SCOPUS:85104618011
SN - 1664-2392
VL - 12
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
M1 - 595894
ER -