Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation
Significance Statement Randomized controlled trials of CKD traditionally use clinical events that happen late in the course of CKD progression as study end points. Doing this requires large sample sizes and long follow-up periods that can make the studies very costly. The authors use statistical simulations to investigate circumstances in which using the change in GFR over time or GFR slope as a study end point reduces the required sample size or trial duration compared with clinical end points. They found that GFR slope performs better than clinical end points when patients’ initial GFRs are high and the treatment has no acute effect on GFR. The results along with other recent studies suggest GFR is a valid surrogate end point for CKD clinical trials that may allow for more efficient trials and help speed the development of new CKD therapies. Background Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. Methods We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up. Results In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients’ GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions. Conclusions Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.