02673nas a2200217   4500000000100000008004100001100001800042700001300060700001400073700001300087700001400100700001200114700001200126700001200138245011000150250001500260300001100275490000700286520211100293020005102404       2014                            d1 aWoodward Mark1 aLevey A.1 aCoresh J.1 aInker L.1 aGreene T.1 aTeng C.1 aRedd A.1 aYing J.00aUtility and validity of estimated GFR-based surrogate time-to-event end points in CKD: a simulation study  a2014/12/03  a867-790 v643 a<p>
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 &amp; 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 &gt; 20% while maintaining risk for type 1 error &lt; 10% in the presence of a small acute effect (&lt;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.
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