دورية أكاديمية
A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function
| العنوان: | A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function |
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| المؤلفون: | Wlodek, E., Kirkpatrick, R. B., Andrews, S., Noble, R., Schroyer, R., Scott, J., Watson, C. J. E., Clatworthy, M., Harrison, E. M., Wigmore, S. J., Stevenson, K., Kingsmore, D., Sheerin, N. S., Bestard, O., Stirnadel-Farrant, H. A., Abberley, L., Busz, M., DeWall, S., Birchler, M., Krull, D., Thorneloe, K. S., Weber, A., Devey, L. |
| بيانات النشر: | Public Library of Science PLOS ONE |
| سنة النشر: | 2021 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Research Article, Medicine and health sciences, Biology and life sciences, Research and analysis methods |
| الوصف: | Funder: GlaxoSmithKline; funder-id: http://dx.doi.org/10.13039/100004330Test ; 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf; text/xml; application/zip |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/318551Test |
| DOI: | 10.17863/CAM.65665 |
| الإتاحة: | https://doi.org/10.17863/CAM.65665Test https://www.repository.cam.ac.uk/handle/1810/318551Test |
| حقوق: | Attribution 4.0 International (CC BY 4.0) ; https://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.2F56BE0E |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.65665 |
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