TY - JOUR
T1 - Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome
T2 - a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)
AU - Pivonello, Rosario
AU - Zacharieva, Sabina
AU - Elenkova, Atanaska
AU - Tóth, Miklós
AU - Shimon, Ilan
AU - Stigliano, Antonio
AU - Badiu, Corin
AU - Brue, Thierry
AU - Georgescu, Carmen Emanuela
AU - Tsagarakis, Stylianos
AU - Cohen, Fredric
AU - Fleseriu, Maria
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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 During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: − 54.5% (95% CI − 75.7, − 27.4; P =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.
AB - 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.
KW - Cushing’s disease
KW - Cushing’s syndrome
KW - Hypercortisolism
KW - Levoketoconazole
KW - Placebo
KW - Steroidogenesis inhibitor
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U2 - 10.1007/s11102-022-01263-7
DO - 10.1007/s11102-022-01263-7
M3 - Article
C2 - 36085339
AN - SCOPUS:85136871434
SN - 1386-341X
VL - 25
SP - 911
EP - 926
JO - Pituitary
JF - Pituitary
IS - 6
ER -