Cargando…
Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial
BACKGROUND: We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). METHODS: This trial included three sub-studies: ZEBRA 1—a randomised...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9158153/ https://www.ncbi.nlm.nih.gov/pubmed/35650639 http://dx.doi.org/10.1186/s13075-022-02818-6 |
_version_ | 1784718778275201024 |
---|---|
author | Stern, Edward P. Host, Lauren V. Wanjiku, Ivy Escott, K. Jane Gilmour, Peter S. Ochiel, Rachel Unwin, Robert Burns, Aine Ong, Voon H. Cadiou, Helen O’Keeffe, Aidan G. Denton, Christopher P. |
author_facet | Stern, Edward P. Host, Lauren V. Wanjiku, Ivy Escott, K. Jane Gilmour, Peter S. Ochiel, Rachel Unwin, Robert Burns, Aine Ong, Voon H. Cadiou, Helen O’Keeffe, Aidan G. Denton, Christopher P. |
author_sort | Stern, Edward P. |
collection | PubMed |
description | BACKGROUND: We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). METHODS: This trial included three sub-studies: ZEBRA 1—a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A—a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B—an open label pharmacokinetic study of zibotentan in patients on haemodialysis. RESULTS: Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. CONCLUSIONS: Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. TRIAL REGISTRATION: EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077 |
format | Online Article Text |
id | pubmed-9158153 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-91581532022-06-02 Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial Stern, Edward P. Host, Lauren V. Wanjiku, Ivy Escott, K. Jane Gilmour, Peter S. Ochiel, Rachel Unwin, Robert Burns, Aine Ong, Voon H. Cadiou, Helen O’Keeffe, Aidan G. Denton, Christopher P. Arthritis Res Ther Comment BACKGROUND: We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). METHODS: This trial included three sub-studies: ZEBRA 1—a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A—a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B—an open label pharmacokinetic study of zibotentan in patients on haemodialysis. RESULTS: Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. CONCLUSIONS: Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. TRIAL REGISTRATION: EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077 BioMed Central 2022-06-01 2022 /pmc/articles/PMC9158153/ /pubmed/35650639 http://dx.doi.org/10.1186/s13075-022-02818-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Comment Stern, Edward P. Host, Lauren V. Wanjiku, Ivy Escott, K. Jane Gilmour, Peter S. Ochiel, Rachel Unwin, Robert Burns, Aine Ong, Voon H. Cadiou, Helen O’Keeffe, Aidan G. Denton, Christopher P. Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial |
title | Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial |
title_full | Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial |
title_fullStr | Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial |
title_full_unstemmed | Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial |
title_short | Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial |
title_sort | zibotentan in systemic sclerosis-associated chronic kidney disease: a phase ii randomised placebo-controlled trial |
topic | Comment |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9158153/ https://www.ncbi.nlm.nih.gov/pubmed/35650639 http://dx.doi.org/10.1186/s13075-022-02818-6 |
work_keys_str_mv | AT sternedwardp zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT hostlaurenv zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT wanjikuivy zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT escottkjane zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT gilmourpeters zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT ochielrachel zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT unwinrobert zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT burnsaine zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT ongvoonh zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT cadiouhelen zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT okeeffeaidang zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial AT dentonchristopherp zibotentaninsystemicsclerosisassociatedchronickidneydiseaseaphaseiirandomisedplacebocontrolledtrial |