Application of the iBox prognostication system as a surrogate endpoint in the TRANSFORM randomised controlled trial: proof-of-concept study

Abstract

Objectives: Development of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We applied a validated integrative risk-prognostication system integrative Box (iBox) as a surrogate endpoint to the TRANSFORM Study, a large randomised controlled trial, to project individual patient long-term kidney allograft survival from 1 year to 11 years after randomisation.

Design: Post-hoc analysis of a randomised open-label controlled trial.

Setting: Multicentre study including 186 centres in 42 countries worldwide.

Participants: 2037 de novo kidney transplant recipients.

Intervention: Participants were randomised (1:1) to receive everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) or mycophenolic acid with standard-exposure CNI (MPA+sCNI).

Primary outcome measure: The iBox scores were computed for each participant at 1 year after randomisation using functional, immunological and histological parameters. Individual long-term death-censored allograft survival over 4, 6 and 11 years after randomisation was projected with the iBox risk-prognostication system.

Results: Overall, 940 patients receiving EVR+rCNI and 932 receiving MPA+sCNI completed the 1-year visit. iBox scores generated at 1 year yielded graft survival prediction rates of 90.9% vs 92.1%, 87.9% vs 89.5%, and 80.0% vs 82.4% in the EVR+rCNI versus MPA+sCNI arms at 4, 6, and 11 years post-randomisation, respectively (all differences below the 10% non-inferiority margin defined by study protocol). Inclusion of immunological and histological Banff diagnoses parameters in iBox scores resulted in comparable and non-inferior predicted graft survival for both treatments.

Conclusions: This proof-of-concept study provides the first application of a validated prognostication system as a surrogate endpoint in the field of transplantation. The iBox system, by projecting kidney allograft survival up to 11 years post-randomisation, confirms the non-inferiority of EVR+rCNI versus MPA+sCNI regimen. Given the current process engaged for surrogate endpoints qualification, this study illustrates the potential to fast track development of pharmaceutical agents.

Trial registration number: TRANSFORM trial: NCT01950819.iBox prognostication system: NCT03474003.

Keywords: clinical trials; renal transplantation; statistics & research methods; transplant medicine.

Conflict of interest statement

Competing interests: JP, FO, CS, FC, HT, SC, MH, FV, TS, YW and CL comprised the scientific steering committee of TRANSFORM Study. FO has received speaker fees and travel support from Novartis. HT has received educational and travel grants from Novartis. PB is an employee of Novartis. AL holds shares in Cibiltech, a company that builds software.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Patient disposition. DSA, donor-specific antibodies; EVR, everolimus; iBox, integrative Box; MPA, mycophenolic acid; rCNI, reduced-exposure calcineurin inhibitor; sCNI, standard-exposure calcineurin inhibitor.

Figure 2

iBox#1 scores at 1 year after randomisation and projected allograft survival. (A) Mean iBox#1 scores in the EVR+rCNI and MPA+sCNI arms at 1 year. (B) Projected allograft survival in EVR+rCNI arm (blue line) and MPA+sCNI arm (red line). The black dotted line corresponds to the 10% inferiority margin. The duration of TRANSFORM is the time between randomisation and the endpoint of the TRANSFORM Study (1 year post-randomisation). The projected kidney allograft survival takes into account the event (death-censored graft loss) that occurred during the duration of TRANSFORM Study. EVR, everolimus, iBox, integrative Box; MPA, mycophenolic acid; rCNI, reduced-exposure calcineurin inhibitor; sCNI, standard-exposure calcineurin inhibitor.

Figure 3

iBox#2 scores at 1 year after randomisation and projected allograft survival. (A) Mean iBox#2 scores in the EVR+rCNI and MPA+sCNI arms at 1 year. (B) Projected allograft survival in EVR+rCNI arm (blue line) and MPA+sCNI arm (red line). The black dotted line corresponds to the 10% inferiority margin. The duration of TRANSFORM is the time between randomisation and the endpoint of the TRANSFORM Study (1 year post-randomisation). The projected kidney allograft survival takes into account the event (death-censored graft loss) that occurred during the duration of TRANSFORM Study. DSA, donor-specific antibodies; EVR, everolimus; iBox, integrative Box; MPA, mycophenolic acid; rCNI, reduced-exposure calcineurin inhibitor; sCNI, standard-exposure calcineurin inhibitor.

Figure 4

iBox#3 scores at 1 year after randomisation and projected allograft survival. (A) Mean iBox#3 scores in the EVR+rCNI and MPA+sCNI arms at 1 year. (B) Projected allograft survival in EVR+rCNI arm (blue line) and MPA+sCNI arm (red line). The black dotted line corresponds to the 10% inferiority margin. The duration of TRANSFORM is the time between randomisation and the endpoint of the TRANSFORM Study (1 year post-randomisation). The projected kidney allograft survival takes into account the event (death-censored graft loss) that occurred during the duration of TRANSFORM Study. DSA, donor-specific antibodies; EVR, everolimus, iBox, integrative Box; MPA, mycophenolic acid; rCNI, reduced-exposure calcineurin inhibitor; sCNI, standard-exposure calcineurin inhibitor.