Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1783681253947473920 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8059833 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT pivonellorosario levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT elenkovaatanaska levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT fleseriumaria levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT feeldersricharda levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT witekprzemyslaw levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT greenmanyona levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT geerelizab levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT perottipaola levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT saieghleonard levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT cohenfredric levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study AT arnaldigiorgio levoketoconazoleinthetreatmentofpatientswithcushingssyndromeanddiabetesmellitusresultsfromthesonicsphase3study |