摘要 : 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 ... 展开 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 During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: ??54.5% (95% CI ??75.7, ??27.4;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. 收起