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

  • Pituitary. 2022 Dec;25(6):911-926. doi: 10.1007/s11102-022-01263-7.
Rosario Pivonello  #  1 ,  Sabina Zacharieva  #  2 ,  Atanaska Elenkova  2 ,  Miklós Tóth  3 ,  Ilan Shimon  4 ,  Antonio Stigliano  5 ,  Corin Badiu  6 ,  Thierry Brue  7 ,  Carmen Emanuela Georgescu  8  9 ,  Stylianos Tsagarakis  10 ,  Fredric Cohen  11 ,  Maria Fleseriu  12
Affiliations
  • 1. Università Federico II Di Napoli, Naples, Italy. [email protected].
  • 2. Medical University Sofia, Sofia, Bulgaria.
  • 3. Semmelweis University, Budapest, Hungary.
  • 4. Rabin Medical Center and Tel Aviv University, Tel Aviv, Israel.
  • 5. Sant'Andrea Hospital, University of Rome "Sapienza", Rome, Italy.
  • 6. National Institute of Endocrinology CI Parhon and "C. Davila" University of Medicine and Pharmacy, Bucharest, Romania.
  • 7. Aix-Marseille Université and Assistance Publique - Hôpitaux de Marseille, Hôpital de la Conception, Marseille, France.
  • 8. Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
  • 9. Endocrinology Clinical Unit, Cluj County Emergency Hospital, Cluj-Napoca, Romania.
  • 10. Evangelismos Hospital, Athens, Greece.
  • 11. Xeris Biopharma, Chicago, IL, USA.
  • 12. Oregon Health and Science University, Portland, OR, USA.
  • # Contributed equally.
PMID: 36085339 DOI: 10.1007/s11102-022-01263-7
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 During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P =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.
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