التفاصيل البيبلوغرافية
| العنوان: |
A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function. |
| 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. |
| المصدر: |
PLoS ONE; 3/8/2021, Vol. 16 Issue 3, p1-23, 23p |
| مصطلحات موضوعية: |
KIDNEY transplantation, INTERLEUKIN-18, ACUTE kidney failure, PILOT projects, PATIENTS' attitudes |
| مستخلص: |
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. Trial registration: NCT02723786. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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