Alternative Endpoints and Analysis Techniques in Kidney Transplant Trials

Abstract

Clinical trials in kidney transplantation suffer from several major issues including: 1) Unfeasibility due to low short-term event rates of hard outcomes and 2) Reliance on a composite outcome that consists of unequal endpoints that may generate misleading results. This thesis attempts to explore and apply methods to solve these issues and ultimately, improve kidney transplantation trials.

We present a secondary analysis of the ACE trial in kidney transplant using composites with alternative graft function surrogate endpoints. Typically, kidney transplant trials—including the ACE trial— use a time-to-event composite of death, end-stage renal disease (ESRD), and doubling of serum creatinine. Instead of doubling of serum creatinine, we investigated the use of percentage declines of estimate glomerular filtration rate (eGFR) within a time-to-event composite of death and ESRD. Additionally, we present an application of an innovative analysis method, the win ratio approach, to the ACE trial as a way of lessening concerns associated with unequal composite endpoints.

Composites of death, ESRD, and either a 40%, 30% or 20% decline in eGFR did not alter original ACE trial results, interpretations, or conclusions. The win ratio approach, and the presentation of a win ratio, generated very comparable results to a standard time-to-event analysis while lessening the impact of unequal composite endpoints and making fewer statistical assumptions. This research provides a novel, trial-level application of alternative endpoints and analysis techniques within a kidney transplant trial setting.