Estimated GFR Surrogate End Points in CKD Trials

As part of an analysis done in conjunction with a workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration (FDA), Tom Greene, PhD, and colleagues released findings in the American Journal of Kidney Diseases [2014;64(60:867-879]. The workshop, GFR Decline as an Endpoint for Clinical Trials in CKD, was held in 2012.

An FDA accepted end point of clinical trials of progression of kidney disease is the composite of doubling of serum creatinine level or kidney failure. However, those are both late events in chronic kidney disease (CKD).

Using the 2009 CKD-EPI (CKD Epidemiology Collaboration) creatinine equation, a doubling of serum creatinine level corresponds approximately to a 57% decline in estimated glomerular filtration rate (eGFR). Using end points based on lesser declines in eGFR provide more events in a shorter time, reducing follow-up times and/or sample sizes needed in clinical trials.

The authors performed a simulation study to define the circumstances under which treatment effects on time-to-event end points based on lesser declines in eGFR reliably predict treatment effects on time to kidney failure (end-stage renal disease [ESRD], defined as kidney failure treated by maintenance dialysis or kidney transplantation). Input parameters for the simulations were selected to represent a wide spectrum of scenarios in prior randomized clinical trials about CKD.

The design included simulations to evaluate 3060 scenarios representative of 19 treatment comparisons in 13 CKD clinical trials. Index tests were surrogate end points defined as composite end points based on ESRD and either 30% or 40% eGFR declines. The reference test was clinical outcome (ESRD) for type 1 error. The established end point (composite of ESRD and 57% decline in eGFR) was required sample size.

There was consistent >20% reduction in sample size with use of the 40% versus 57% declining in eGFR end point, while maintaining risk for type 1 error <10% in the presence of a small acute effect (<1.25 mL/min/1.73m2) for 2-, 3-, or 5-year trials with a high mean baseline eGFR (67.5 mL/min/1.73 m2), and for 2-year trials for an intermediate mean baseline eGFR (42.5 mL/min/1.73m2).

In the absence of an acute event, use of the 30% versus 40% eGFR decline end point often led to moderately larger reductions in sample size. This association was not seen in the presence of acute events.

Hazard ratios (HRs) were stable across end points with different declines in eGFR when there was no acute effect and a uniform long-term effect. The proportional treatment effect, implying a larger effect on the slopes of faster progressors, strengthened the HRs for ESRD alone and for the end points based on the larger eGFR declines, where events are restricted to the faster progressors. However, HRs attenuated toward 1 for the lesser of eGFR declines. Attenuation of the HR with lesser eGFR declines was increased in the presence of a negative acute effect, reflecting a greater relative impact of an acute eGFR decline for end points based on larger eGFR declines.

Limitations cited by the authors included the complexity of eGFR trajectories, which prevented evaluation of all scenarios for clinical trials.

“In conclusion, for treatments with small or no acute effects, use of a 40% eGFR decline in some cases can substantially increase statistical power compared to the current 57% threshold while avoiding a prohibitive inflation of type 1 error relative to the clinical end point of ESRD, thereby allowing smaller sample sizes and/or reduced follow-up times. Use of a 30% eGFR decline can provide moderately increased savings in required sample size compared to a 40% decline in certain situations, but is problematic if a moderate or large acute effect is present. The decision to use these end points should be made after thorough evaluation of their expected performance under the conditions of specific clinical trials,” the authors said.

Takeaway Points

  1. An FDA accepted end point of clinical trials of progression of kidney disease is the composite of doubling of serum creatinine level or kidney failure. However, those are both late events in chronic kidney disease (CKD).
  2. The design of this analysis included simulations to evaluate 3060 scenarios representative of 19 treatment comparisons in 13 CKD clinical trials. Index tests were surrogate end points defined as composite end points based on ESRD and either 30% or 40% eGFR declines.

 

  1. Hazard ratios (HRs) were stable across end points with different declines in eGFR when there was no acute effect and a uniform long-term effect.