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A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease

BACKGROUND: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 ye...

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Autores principales: Mader, Gregory, Mladsi, Deirdre, Sanon, Myrlene, Purser, Molly, Barnett, Christine L., Oberdhan, Dorothee, Watnick, Terry, Seliger, Stephen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578187/
https://www.ncbi.nlm.nih.gov/pubmed/36258169
http://dx.doi.org/10.1186/s12882-022-02956-8
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author Mader, Gregory
Mladsi, Deirdre
Sanon, Myrlene
Purser, Molly
Barnett, Christine L.
Oberdhan, Dorothee
Watnick, Terry
Seliger, Stephen
author_facet Mader, Gregory
Mladsi, Deirdre
Sanon, Myrlene
Purser, Molly
Barnett, Christine L.
Oberdhan, Dorothee
Watnick, Terry
Seliger, Stephen
author_sort Mader, Gregory
collection PubMed
description BACKGROUND: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking. METHODS: A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death. RESULTS: When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively. CONCLUSIONS: The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12882-022-02956-8.
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spelling pubmed-95781872022-10-19 A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease Mader, Gregory Mladsi, Deirdre Sanon, Myrlene Purser, Molly Barnett, Christine L. Oberdhan, Dorothee Watnick, Terry Seliger, Stephen BMC Nephrol Research BACKGROUND: Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking. METHODS: A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death. RESULTS: When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively. CONCLUSIONS: The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12882-022-02956-8. BioMed Central 2022-10-18 /pmc/articles/PMC9578187/ /pubmed/36258169 http://dx.doi.org/10.1186/s12882-022-02956-8 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 Research
Mader, Gregory
Mladsi, Deirdre
Sanon, Myrlene
Purser, Molly
Barnett, Christine L.
Oberdhan, Dorothee
Watnick, Terry
Seliger, Stephen
A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
title A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
title_full A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
title_fullStr A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
title_full_unstemmed A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
title_short A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
title_sort disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578187/
https://www.ncbi.nlm.nih.gov/pubmed/36258169
http://dx.doi.org/10.1186/s12882-022-02956-8
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