Chronic renal allograft rejection and clinical trial design.

Both the choice of endpoints and the selection of patients will be critical study design features in randomized controlled trials needed to test the effectiveness of treatments for chronic renal allograft rejection. We examined the feasibility of carrying out clinical trials with different endpoints and patient inclusion criteria by analyzing data from a population of 627 cadaveric kidney transplant recipients who survived with a functioning allograft for at least six months. Among those who lost grafts to chronic rejection, decreases in renal function of 30% and 60% preceded graft loss by a median of only 1.1 and 0.7 years, respectively, suggesting that little would be gained in a clinical trial that used a predetermined reduction in renal function as a surrogate endpoint. Less clear is whether histologic changes could be used as a surrogate endpoint. At present, graft loss to chronic rejection and graft failure from any cause are the most reliable endpoints. Unfortunately, large numbers of patients are needed to demonstrate clinically relevant therapeutic effects on these endpoints. Limiting enrollment to patients who are at high risk for developing chronic rejection, by selecting patients who already have a decline in renal function, for example, may reduce the number of patients needed in a clinical trial. On the other hand, selecting patients with disease that is too advanced may diminish the effectiveness of therapy. In any case, it is impossible to accurately determine the number of patients needed for a definitive clinical trial without preliminary data demonstrating the expected magnitude of the treatment effect. Thus, well-designed pilot studies are needed to measure possible treatment effects before conducting large-scale clinical trials for chronic renal allograft rejection.