The US92 study determined whether, in de novo renal transplant patients, concentration-controlled everolimus (EVR) with reduced dose tacrolimus (RTAC) is non-inferior to CellCept® (mycophenolate mofetil [MMF] with standard dose tacrolimus [STAC]) on measures of allograft function and safety. Regulatory agencies use composite endpoints(CE) to evaluate transplant drugs where equal weight isaccorded to each component of the CE regardless of clinical significance. Death and graft loss have equal weight as acute rejection. But these endpoints impact patients differently so we analyzed data based on impact of overall endpoint in kidney transplantation, similar to methods adopted in cardiac studies (Ann Thorac Surg. 2012 Dec; 94(6): 1908–1913).

In this 12-month non-inferiority study, safety and efficacy of concentration-controlled EVR (1.5mg/day) with RTAC was compared to MMF (2g/day) with STAC in 613 de novo renal transplant patients. Primary efficacy variable was composite efficacy failure rate (CEFR; treated biopsy-proven acute rejection [tBPAR, based on local biopsy reading], graft loss, death or loss to follow-up) at 12 months post-transplant. In an alternative approach to CEs currently utilized in transplantation trials, different weightings were applied to differentiate clinically important events of death (1), graft loss (0.5), loss to follow-up (0.5), and tBPAR (0.25). Patients with multiple events were assigned the event with the highest weight.

TheobservedCEFRwas24.6%forEVRand20.4%forMMF,aratioof1.206.The ratio using the weighted CEFR was 1.01 (table). An imbalance in 5 baseline risk factors potentially disadvantaged the EVR arm: HLAmismatches≥3, DRlocimismatches, diabetes, deceased donors and extendedcriteriadonors

The CEFR between the 2treatment groups were almost identical for the weighted approach; when the traditional CE was used, EVR had a higher failure rate than MMF. This is indicative of the clinical impact that weighted endpoints offer and is in accordance with other disciplines.

CITATION INFORMATION: Kaplan B, MaCague K, Patel D, Vincenti F. A Weighted Approach to Composite Efficacy Analysis in Kidney Transplantation. Am J Transplant. 2016;16 (suppl 3).

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