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Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study

BACKGROUND: Cushing’s syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS. METHODS: SONICS, a prospective, open-label, phase 3 study in adults with...

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Autores principales: Pivonello, Rosario, Elenkova, Atanaska, Fleseriu, Maria, Feelders, Richard A., Witek, Przemyslaw, Greenman, Yona, Geer, Eliza B., Perotti, Paola, Saiegh, Leonard, Cohen, Fredric, Arnaldi, Giorgio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059833/
https://www.ncbi.nlm.nih.gov/pubmed/33897615
http://dx.doi.org/10.3389/fendo.2021.595894
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author Pivonello, Rosario
Elenkova, Atanaska
Fleseriu, Maria
Feelders, Richard A.
Witek, Przemyslaw
Greenman, Yona
Geer, Eliza B.
Perotti, Paola
Saiegh, Leonard
Cohen, Fredric
Arnaldi, Giorgio
author_facet Pivonello, Rosario
Elenkova, Atanaska
Fleseriu, Maria
Feelders, Richard A.
Witek, Przemyslaw
Greenman, Yona
Geer, Eliza B.
Perotti, Paola
Saiegh, Leonard
Cohen, Fredric
Arnaldi, Giorgio
author_sort Pivonello, Rosario
collection PubMed
description BACKGROUND: Cushing’s syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS. METHODS: SONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases. RESULTS: Normalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal. CONCLUSIONS: Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM. CLINICAL TRIAL REGISTRATION: (ClinicalTrials.gov), NCT01838551.
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spelling pubmed-80598332021-04-22 Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study Pivonello, Rosario Elenkova, Atanaska Fleseriu, Maria Feelders, Richard A. Witek, Przemyslaw Greenman, Yona Geer, Eliza B. Perotti, Paola Saiegh, Leonard Cohen, Fredric Arnaldi, Giorgio Front Endocrinol (Lausanne) Endocrinology BACKGROUND: Cushing’s syndrome (CS) is associated with numerous comorbidities, including diabetes mellitus (DM). Levoketoconazole, an orally administered ketoconazole stereoisomer, is in clinical trials for the treatment of CS. METHODS: SONICS, a prospective, open-label, phase 3 study in adults with confirmed CS and mean 24-h urinary free cortisol (mUFC) ≥1.5× ULN, included dose-titration, 6-month maintenance, and 6-month extension phases. This subanalysis evaluated the efficacy of levoketoconazole in patients with DM (n = 28) or without DM (n = 49) who entered the maintenance phase. Safety was evaluated in the overall population (N = 94) during the dose-titration and maintenance phases. RESULTS: Normalization of mUFC at the end of maintenance phase (EoM), without a dose increase during maintenance (SONICS primary endpoint) was observed in 46% of patients with DM (95% CI, 28 to 66%; P = 0.0006 vs null hypothesis of ≤20%) and 33% of patients without DM (95% CI, 20 to 48%; P = 0.0209). At EoM, mean HbA1c decreased from 6.9% at baseline to 6.2% in patients with DM and from 5.5 to 5.3% in patients without DM. Mean fasting blood glucose decreased from 6.85 mmol/L (123.4 mg/dl) to 5.82 mmol/L (104.9 mg/dl) and from 5.11 mmol/L (92.1 mg/dl) to 4.66 mmol/L (84.0 mg/dl) in patients with and without DM, respectively. Adverse events that were more common in patients with DM included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal. CONCLUSIONS: Treatment with levoketoconazole led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with DM. CLINICAL TRIAL REGISTRATION: (ClinicalTrials.gov), NCT01838551. Frontiers Media S.A. 2021-04-07 /pmc/articles/PMC8059833/ /pubmed/33897615 http://dx.doi.org/10.3389/fendo.2021.595894 Text en Copyright © 2021 Pivonello, Elenkova, Fleseriu, Feelders, Witek, Greenman, Geer, Perotti, Saiegh, Cohen and Arnaldi https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Pivonello, Rosario
Elenkova, Atanaska
Fleseriu, Maria
Feelders, Richard A.
Witek, Przemyslaw
Greenman, Yona
Geer, Eliza B.
Perotti, Paola
Saiegh, Leonard
Cohen, Fredric
Arnaldi, Giorgio
Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
title Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
title_full Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
title_fullStr Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
title_full_unstemmed Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
title_short Levoketoconazole in the Treatment of Patients With Cushing’s Syndrome and Diabetes Mellitus: Results From the SONICS Phase 3 Study
title_sort levoketoconazole in the treatment of patients with cushing’s syndrome and diabetes mellitus: results from the sonics phase 3 study
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059833/
https://www.ncbi.nlm.nih.gov/pubmed/33897615
http://dx.doi.org/10.3389/fendo.2021.595894
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