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http://hdl.handle.net/2445/176247
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DC Field | Value | Language |
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dc.contributor.author | Wlodek, E. | - |
dc.contributor.author | Kirkpatrick, R. B. | - |
dc.contributor.author | Andrews, Susan | - |
dc.contributor.author | Noble, R. | - |
dc.contributor.author | Schroyer, R. | - |
dc.contributor.author | Scott, J. | - |
dc.contributor.author | Watson, C. J. E. | - |
dc.contributor.author | Clatworthy, M. | - |
dc.contributor.author | Harrison, E. M. | - |
dc.contributor.author | Wigmore, S. J. | - |
dc.contributor.author | Stevenson, K. | - |
dc.contributor.author | Kingsmore, D. | - |
dc.contributor.author | Sheerin, N. S. | - |
dc.contributor.author | Bestard Matamoros, Oriol | - |
dc.contributor.author | Stirnadel-Farrant, H. A. | - |
dc.contributor.author | Abberley, L. | - |
dc.contributor.author | Busz, M. | - |
dc.contributor.author | Dewall, S. | - |
dc.contributor.author | Birchler, M. | - |
dc.contributor.author | Krull, D. | - |
dc.contributor.author | Thorneloe, K. S. | - |
dc.contributor.author | Weber, A. | - |
dc.contributor.author | Devey, L. | - |
dc.date.accessioned | 2021-04-16T10:40:45Z | - |
dc.date.available | 2021-04-16T10:40:45Z | - |
dc.date.issued | 2021-03-08 | - |
dc.identifier.uri | http://hdl.handle.net/2445/176247 | - |
dc.description.abstract | Introduction: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. Methods: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. Results: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. Conclusion: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. | - |
dc.format.extent | 23 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Public Library of Science (PLoS) | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0247972 | - |
dc.relation.ispartof | PLoS One, 2021, vol. 16, num. 3, p. e0247972 | - |
dc.relation.uri | https://doi.org/10.1371/journal.pone.0247972 | - |
dc.rights | cc by (c) Wlodek et al., 2021 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) | - |
dc.subject.classification | Trasplantament renal | - |
dc.subject.classification | Biòpsia | - |
dc.subject.classification | Diàlisi | - |
dc.subject.other | Kidney transplantation | - |
dc.subject.other | Biopsy | - |
dc.subject.other | Dialysis | - |
dc.title | A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2021-04-16T08:57:51Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 33684160 | - |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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journal.pone.0247972.pdf | 1.57 MB | Adobe PDF | View/Open |
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