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Open Access 09-09-2022 | Cushing's Syndrome

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

Authors: 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

Published in: Pituitary | Issue 6/2022

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 During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: − 54.5% (95% CI − 75.7, − 27.4; P =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

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As per protocol, patients who completed SONICS (through 12 months of maintenance treatment) within 6 months of LOGICS screening visit and demonstrated maintenance of clinical benefit on a stable therapeutic dose of levoketoconazole for at least 12 weeks immediately prior to screening were eligible to enter LOGICS. SONICS completers who did not fulfill these requirements were potentially eligible if they met the inclusion criteria; however, the criteria pertaining to elevated mUFC and LNSC (or abnormal dexamethasone suppression test) did not apply for patients currently using levoketoconazole.

Hy’s Law components: (1) higher incidence of ≥ threefold elevations above the ULN of ALT or AST for study drug versus placebo, (2) ≥ 1 patient with aminotransferase elevation(s) also shows elevation of serum total bilirubin to > 2 × ULN, and (3) no other reason can be found for the combination of increased aminotransferase(s) and total bilirubin (e.g., viral hepatitis, preexisting or acute liver disease) [32].

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Title: Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)
Authors: 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
Publication date: 09-09-2022
Publisher: Springer US
Keywords: Cushing's Syndrome
Endogenous Cushing's Syndrome
Published in: Pituitary / Issue 6/2022
Print ISSN: 1386-341X
Electronic ISSN: 1573-7403
DOI: https://doi.org/10.1007/s11102-022-01263-7

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