Executive Director
Transplant Therapeutics Consortium (TTC)
Critical Path Institute
External validation of the abbreviated iBOX at 6-, 12-, and 24-months post-kidney transplant as a secondary endpoint prognostic for death-censored graft survival
Amanda Klein1, Luke Kosinski1, Eric Frey1, Alexandre Loupy2, Mark Stegall3, Ilkka Helanterä4, William E Fitzsimmons1.
1Transplant Therapeutics Consortium (TTC), Critical Path Institute, Tucson, AZ, United States; 2Paris Translational Research Centre for Organ Transplantation, Université de Paris, INSERM, Paris, France; 3Department of Surgery, Mayo Clinic, Rochester, MN, United States; 4Department of Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland
On behalf of Transplant Therapeutics Consortium .
Introduction: The Transplant Therapeutics Consortium seeks to translate the iBOX from Loupy et al., 2019,1 into a novel one-year endpoint predictive of five-year death-censored graft survival after kidney transplantation for use in pivotal studies. The iBOX was originally derived using: eGFR, proteinuria, kidney allograft biopsy, and donor-specific antibody, all fixed at one-year post-transplant. A separate abbreviated version of the iBOX was developed for use without biopsy findings. For expanded application in exploratory drug therapeutic studies and pivotal studies of longer duration, external validation of the abbreviated iBOX was performed at 6 and 24 months post-transplant to quantify its discrimination and calibration as a predictor of five-year death-censored graft survival at these additional time points.
Methods: External validation of the abbreviated iBOX was performed using outcomes data previously collected at 6, 12, and 24 months post-transplant from the CNI and CNI-free population in two RCTs (BENEFIT2 and BENEFIT-EXT3). The discrimination ability of the abbreviated iBOX was assessed using Harrell's c-statistic.4 Calibration was assessed using Poisson regression.5
Results: All c-statistic values for the combined RCTs are 0.7 or greater, indicating good discriminatory ability (Table 1). In addition to c-statistics, calibration data showed no significant differences in observed versus predicted graft loss events, demonstrating that the abbreviated iBOX has good prediction accuracy, including CNI and CNI-free populations at 6, 12, and 24 months post-kidney transplant (Table 2).
Conclusion: The abbreviated IBOX measured at 6, 12, and 24 months post-transplant was validated as an endpoint predictive of five-year death-censored graft survival in two RCTs, consisting of CNI and CNI-free populations. The limited number of biopsies performed at 24 months precluded a similar analysis of the full iBOX. However, the addition of biopsy information should only improve the performance. Therefore, the full iBOX could also be used post-transplant at these additional time points. As developed, the iBOX score may serve as an important endpoint for demonstrating superiority of new immunosuppressive therapies at various time points post-transplant in phase 2/proof-of-concept and confirmatory phase 3 clinical trials submitted for regulatory approval.
References:
[1] 1. Loupy, A., Aubert, O., Orandi, B. J., Naesens, M., Bouatou, Y., Raynaud, M., Divard, G., Jackson, A. M., Viglietti, D., Giral, M., Kamar, N., Thaunat, O., Morelon, E., Delahousse, M., Kuypers, D., Hertig, A., Rondeau, E., Bailly, E., Eskandary, F., … Lefaucheur, C. (2019). Prediction system for risk of allograft loss in patients receiving kidney transplants: International derivation and validation study. BMJ, l4923. https://doi.org/10.1136/bmj.l4923
[2] 2. Vincenti, F., Larsen, C. P., Alberu, J., Bresnahan, B., Garcia, V. D., Kothari, J., Lang, P., Urrea, E. M., Massari, P., Mondragon-Ramirez, G., Reyes-Acevedo, R., Rice, K., Rostaing, L., Steinberg, S., Xing, J., Agarwal, M., Harler, M. B., & Charpentier, B. (2012). Three-Year Outcomes from BENEFIT, a Randomized, Active-Controlled, Parallel-Group Study in Adult Kidney Transplant Recipients: Three-Year Outcomes from BENEFIT. American Journal of Transplantation, 12(1), 210–217. https://doi.org/10.1111/j.1600-6143.2011.03785.x
[3] 3. Medina Pestana, J. O., Grinyo, J. M., Vanrenterghem, Y., Becker, T., Campistol, J. M., Florman, S., Garcia, V. D., Kamar, N., Lang, P., Manfro, R. C., Massari, P., Rial, M. D. C., Schnitzler, M. A., Vitko, S., Duan, T., Block, A., Harler, M. B., & Durrbach, A. (2012). Three-Year Outcomes From BENEFIT-EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys: Three-Year Outcomes From BENEFIT-EXT. American Journal of Transplantation, 12(3), 630–639. https://doi.org/10.1111/j.1600-6143.2011.03914.x
[4] 4. Harrell, F. E., Lee, K. L., & Mark, D. B. (1996). Multivariable Prognostic Models: Issues in Developing Models, Evaluating Assumptions and Adequacy, and Measuring and Reducing Errors. Statistics in Medicine, 15(4), 361–387. https://doi.org/10.1002/(SICI)1097-0258(19960229)15:4<361::AID-SIM168>3.0.CO;2-4
[5] 5. Crowson, C. S., Atkinson, E. J., & Therneau, T. M. (2016). Assessing calibration of prognostic risk scores. Statistical Methods in Medical Research, 25(4), 1692–1706. https://doi.org/10.1177/0962280213497434
Lectures by Amanda Klein
| When | Session | Talk Title | Room |
|---|---|---|---|
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Tue-02 11:00 - 12:30 |
Patient Perspectives | External validation of the abbreviated iBOX at 6-, 12-, and 24-months post-kidney transplant as a secondary endpoint prognostic for death-censored graft survival | Grand Georgian |