Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)

Abstract

Purpose: The efficacy of levoketoconazole for endogenous Cushing's syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization.

Methods: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14-19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases.

Results: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%).

Conclusions: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing's syndrome. No new risks of levoketoconazole treatment were identified.

Keywords: Cushing’s disease; Cushing’s syndrome; Hypercortisolism; Levoketoconazole; Placebo; Steroidogenesis inhibitor.

Fig. 1

Study design. BID twice daily, mUFC mean urinary free cortisol

Fig. 2

Patient disposition. ^aSponsor decision to halt randomization; these patients were enrolled into the long-term open-label extension study (OPTICS). ^b5 patients who directly rolled over to LOGICS (levoketoconazole: n = 1; placebo: n = 4) from SONICS were on a stable therapeutic dose for 12 weeks prior to screening and did not require dose titration. RES restoration, RW randomized withdrawal

Fig. 3

Proportion of patients who met a the primary endpoint, loss of therapeutic response during the RW phase, or b the key secondary endpoint, mUFC normalization at the end of the RW phase (ITT population). Loss of therapeutic response defined as mUFC > 1.5 × ULN (or mUFC > 40% above baseline if RW baseline was > 1.0 × ULN), or other rescue criterion met. 2 patients from the group that entered RW from TM phase had mUFC above ULN at RW baseline (1 in each treatment group). 4 patients in the levoketoconazole group and 21 patients in the placebo group received early rescue therapy. ITT intent-to-treat, mUFC mean urinary free cortisol, RW randomized-withdrawal, TM titration-maintenance, ULN upper limit of normal

Fig. 4

Changes in individual mUFC concentrations from RW baseline through the end of the RW (ITT population). Plot displays individual patient mUFC from RW baseline to the end of the RW phase. Each needle begins at RW baseline value (last nonmissing result prior to the first dose of study drug administration during the RW phase) and ends at the last measurement of mUFC in the RW phase (before early rescue in cases where early rescue occurred). ITT intent to treat, mUFC mean urinary free cortisol, RW randomized withdrawal, ULN upper limit of normal