Background: Cushings syndrome (CS) has numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole is a ketoconazole stereoisomer in clinical trials for treatment of CS.
Methods: SONICS is a prospective, open-label, phase 3 maintenance-of-benefit study in adults with confirmed CS and mean urinary free cortisol (mUFC) of ≥1.5x upper limit of normal (ULN). Repeated hospitalization due to hyperglycemia or any complication related to DM during the previous 12 months were exclusion criteria. There were 3 study phases: dose-titration (DT; to normalize mUFC; 221 weeks), maintenance (M; 6 months), and extension (6 months). The study met the primary end point of mUFC normalization at the end of M (EoM) without a preceding dose increase during M as recently described (Fleseriu M, et al. ICE 2018). Secondary end points included measures of glycemic control: fasting blood glucose (FBG) and hemoglobin A1c (HbA1c). This analysis compares patients with DM to overall study population.
Results: Intention-to-treat (ITT) population comprised 94 patients; 77 completed DT, 61 completed M. At baseline, overall median (range) age was 44 (1875) years; 82% were female; 85% had Cushings disease (CD); and 38% had DM at screening. In 36 patients with DM: median (range) age was 48 (2275) years; 92% were female; 81% had CD. Median (range) baseline mUFC was similar for the DM subset (2.6x [1.2x30x] ULN) and ITT population (3.0x [1.2x30x] ULN). At EoM, 30% (95% CI, 21%40%) of ITT population achieved the primary end point; DM was not a significant factor in the mUFC normalization model (odds ratio 1.25; P=0.6058). In the DM subset, 34% had mUFC normalization (95% CI, 19%53%). Patients with versus without DM had mean baseline FBG of 123 mg/dL versus 92 mg/dL, and HbA1c of 6.9% versus 5.5%; at EoM, mean FBG was 105 mg/dL versus 84 mg/dL, and mean HbA1c was 6.2% versus 5.3%. Adverse events (AEs) were reported for 97% of DM and 98% of ITT patients; 11% with DM and 13% of ITT discontinued due to AEs. The most common AEs in DM patients were nausea (58%), vomiting (19%), and urinary tract infection (17%); and in ITT population were nausea (32%), headache (28%), and peripheral edema (19%).
Conclusions: In this prospective trial, levoketoconazole at a stable therapeutic dose maintained mUFC normalization for 6 months in 34% of patients with DM versus 30% in the ITT population. Improvements in HbA1c were more notable among patients with DM.
18 - 21 May 2019
European Society of Endocrinology