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Biopsy-proven acute rejection (BPAR) occurs in approximately 10% of kidney transplant recipients in the first year, making superiority trials unfeasible. iBOX, a quantitative composite of estimated glomerular filtration rate, proteinuria, antihuman leukocyte antigen donor-specific antibody, and + full/- abbreviated kidney histopathology, is a new proposed surrogate endpoint. BPAR's prognostic ability was compared with iBOX in a pooled cohort of 1534 kidney transplant recipients from 4 data sets, including 2 prospective randomized controlled trials. Discrimination analyses showed mean c-statistic differences between both iBOX compared with BPAR of 0.25 (95% confidence interval: 0.17-0.32) for full iBOX and 0.24 (95% confidence interval: 0.16-0.32) for abbreviated iBOX, indicating statistically significantly higher c-statistic values for the iBOX prognosis of death-censored graft survival. Mean (± standard error) c-statistics were 0.81 ± 0.03 for full iBOX, 0.80 ± 0.03 for abbreviated iBOX, and 0.57 ± 0.03 for BPAR. In calibration analyses, predicted graft loss events from both iBOX models were not significantly different from those observed. However, for BPAR, the predicted events were significantly (P < .01) different (observed: 64; predicted: 70; full iBOX: 76; abbreviated iBOX: 173 BPAR). IBOX at 1-year posttransplant is superior to BPAR in the first year posttransplant in graft loss prognostic performance, providing valuable additional information and facilitating the demonstration of superiority of novel immunosuppressive regimens., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Competing Interests: M.J.E. is employed by Takeda Pharmaceuticals and serves in a consultant/advisory board role for Hansa BioPharma, Veloxis Pharmaceuticals, and BioMatrix Specialty Pharmacy. In the last 24 months, M.J.E. has received grant funding for research from Bristol-Myers Squibb, Veloxis Pharmaceuticals, Octapharma, and CSL Behring. M.J.E. is also the inventor of Wellavive. R.RA. serves as a consultant for MedPace and Sanofi Genzyme. R.R.A. serves as a speaker for Veloxis Pharmaceuticals and Sanofi Genzyme. In the last 24 months, R.R.A. has received grant funding for research funding from Bristol-Meyers Squibb, Veloxis Pharmaceuticals, Hookipa, and Novartis. T.v.G. has received lecture fees and study grants from Chiesi and Astellas and consulting fees from Roche Diagnostics, Vitaeris, Astellas, Aurinia Pharma, and Novartis. The other authors declare no conflicts of interest.

New immunosuppressive therapies that improve long-term graft survival are needed in kidney transplant. Critical Path Institute's Transplant Therapeutics Consortium received a qualification opinion for the iBOX Scoring System as a novel secondary efficacy endpoint for kidney transplant clinical trials through European Medicines Agency's qualification of novel methodologies for drug development. This is the first qualified endpoint for any transplant indication and is now available for use in kidney transplant clinical trials. Although the current efficacy failure endpoint has typically shown the noninferiority of therapeutic regimens, the iBOX Scoring System can be used to demonstrate the superiority of a new immunosuppressive therapy compared to the standard of care from 6 months to 24 months posttransplant in pivotal or exploratory drug therapeutic studies. [ABSTRACT FROM AUTHOR]