title: Utility and validity of estimated GFR-based surrogate time-to-event end points in CKD: a simulation study.
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.
  
  
  METHODS
  Simulation study.
  
  
  METHODS
  Simulations evaluating 3,060 scenarios representative of 19 treatment comparisons in 13 chronic kidney disease clinical trials.
  
  
  METHODS
  Surrogate end points defined as composite end points based on ESRD and either 30% or 40% eGFR declines.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT. Electronic address: tom.greene@hsc.utah.edu.
authors.forename: Tom
authors.initials: T
authors.lastname: Greene
authors.affiliation: Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Teng
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Inker
authors.affiliation: Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Andrew
authors.initials: A
authors.lastname: Redd
authors.affiliation: Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Jian
authors.initials: J
authors.lastname: Ying
authors.affiliation: Department of Epidemiology, Johns Hopkins University, Baltimore, MD.
authors.forename: Mark
authors.initials: M
authors.lastname: Woodward
authors.affiliation: Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, MA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Levey
mesh_terms: D003198:Computer Simulation / Q000592:standards* / Q000706:statistics & numerical data; D023381:Endpoint Determination / Q000592:standards* / Q000706:statistics & numerical data; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis* / Q000503:physiopathology; D013997:Time Factors
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