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Am J Kidney Dis. 2014 Dec;64(6):867-79. doi: 10.1053/j.ajkd.2014.08.019. Epub 2014 Oct 31.

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

Author information

1
Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT. Electronic address: tom.greene@hsc.utah.edu.
2
Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
3
Division of Nephrology, Tufts Medical Center, Boston, MA.
4
Department of Epidemiology, Johns Hopkins University, Baltimore, MD.
5
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Abstract

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.

KEYWORDS:

Clinical trials; chronic kidney disease (CKD); eGFR trajectory; end-stage renal disease (ESRD); estimated glomerular filtration rate (eGFR) decline; kidney disease outcome; kidney disease progression; kidney end point; renal end point; renal function; simulation; surrogate end point

PMID:
25441440
DOI:
10.1053/j.ajkd.2014.08.019
[Indexed for MEDLINE]

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