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

Rosario Pivonello, Sabina Zacharieva, Atanaska Elenkova, Miklós Tóth, Ilan Shimon, Antonio Stigliano, Corin Badiu, Thierry Brue, Carmen Emanuela Georgescu, Stylianos Tsagarakis, Fredric Cohen, Maria Fleseriu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: − 54.5% (95% CI − 75.7, − 27.4; P =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

Original languageEnglish (US)
Pages (from-to)911-926
Number of pages16
JournalPituitary
Volume25
Issue number6
DOIs
StatePublished - Dec 2022

Keywords

  • Cushing’s disease
  • Cushing’s syndrome
  • Hypercortisolism
  • Levoketoconazole
  • Placebo
  • Steroidogenesis inhibitor

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Fingerprint

Dive into the research topics of 'Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)'. Together they form a unique fingerprint.

Cite this