Common Adverse Events During Levoketoconazole Titration: An Integrated Analysis of Data from Two Prospective Cushing’s Syndrome (CS) Clinical Trials

Objective:
Illustrate common AEs reported during titration phases of the Phase 3 SONICS and LOGICS studies in adult patients with CS to inform the clinical use of levoketoconazole and enhance patient counseling.

Methods:
Treatment-emergent AE data with levoketoconazole were pooled from two prospective relatively similarly designed dose-titration phases from SONICS and LOGICS for integrated analysis. Titrations of up to 7 dose levels (from 150 mg BID to 600 mg BID) occurred no more frequently than once every 2 weeks as needed to normalize mean 24-hour urine free cortisol. AE preferred terms describing similar events were combined to form 24 mutually exclusive AE syndromic categories. Categories with a reported-patient frequency of ≥10% (n=14) were analyzed descriptively as to frequency, severity, action taken, times to onset and resolution, and recurrences during titration.

Results:
Patient frequency of common AEs ranged between 10% (myalgia) and 30% (nausea/vomiting), with no apparent dose relationship among 13 of 14 AE categories (exception of upper respiratory infection). Drug-exposure duration differed by dose. Investigator-assessed AE severity was most often Grade 1 (mild, median patient frequency for 14 categories combined: 69%, range 41% to 90%). Overall, Grade 3 (severe) events were reported for 25% of patients with liver abnormality/injury, 15% with hypertension, and less than 10% for all other categories. Levoketoconazole dose reductions or interruptions were used for management of AEs most often for arrhythmia (typically asymptomatic QT interval prolongation; in 37% of arrhythmia events) and nausea/vomiting (19%), whereas withdrawal of levoketoconazole was most often used for management of liver abnormality/injury (29%). Median time to first onset for common AEs combined was 49.5 d, with fatigue the earliest onset (median 27 d) and arrhythmia (median 77 d) the latest. Median time to event resolution was 17 d, with headache (median 3d) the quickest to resolve and hypokalemia (median 64 d) the slowest. Among patients with a common AE, recurrence averaged 18% of patients across categories: nausea/vomiting (36%) recurring most often and hypertension (3.7%) least often. Median time to first recurrence following initial event resolution for combined categories was 25 d. Mean number of recurrences/patient was highest for hypokalemia (1.8±0.5).

Discussion/Conclusion:
Detailed characterization of common AEs from an integrated dataset of 2 clinical studies populations during titration with levoketoconazole provides new knowledge relevant to levoketoconazole clinical use as chronic medical treatment in adult patients with CS.