Utility and validity of estimated GFR-based surrogate time-to-event end points in CKD: a simulation study.

BACKGROUND: There is interest in surrogate end points for clinical trials of chronic kidney disease progression because currently established end points-end-stage renal disease (ESRD) and doubling of serum creatinine level-are late events, requiring large clinical trials with long follow-up. Doubling of serum creatinine level is equivalent to a 57% decline in estimated glomerular filtration rate (eGFR). We evaluated type 1 error and required sample size for clinical trials using surrogate end points based on lesser eGFR declines.

STUDY DESIGN: Simulation study.

SETTING & PARTICIPANTS: Simulations evaluating 3,060 scenarios representative of 19 treatment comparisons in 13 chronic kidney disease clinical trials.

INDEX TESTS: Surrogate end points defined as composite end points based on ESRD and either 30% or 40% eGFR declines.

REFERENCE TEST: Clinical outcome (ESRD) for type 1 error. Established end point (composite of ESRD and 57% eGFR decline) for required sample size.

RESULTS: Use of the 40% versus 57% eGFR decline end point consistently led to a reduction in sample size > 20% while maintaining risk for type 1 error < 10% in the presence of a small acute effect (<1.25mL/min/1.73m(2)) for: (1) 2-, 3-, or 5-year trials with a high mean baseline eGFR (67.5mL/min/1.73m(2)), and (2) 2-year trials with an intermediate mean baseline eGFR (42.5mL/min/1.73m(2)). Use of the 30% versus the 40% eGFR decline end point often led to moderately larger reductions in sample size in the absence of an acute effect, but not in the presence of acute effects.

LIMITATIONS: The complexity of eGFR trajectories prevented evaluation of all scenarios for clinical trials.

CONCLUSIONS: Use of end points based on 30% or 40% eGFR declines is an appropriate strategy to reduce sample size in certain situations. However, risk for type 1 error is increased in the presence of acute effects, particularly for 30% eGFR declines. The decision to use these end points should be made after thorough evaluation of their expected performance under the conditions of specific clinical trials.