Tom Greene1, Chia-Chen Teng2, Lesley A Inker3, Andrew Redd2, Jian Ying2, Mark Woodward4, Josef Coresh5, Andrew S Levey3. 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.
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.
Authors: Tom Greene; Jian Ying; Edward F Vonesh; Hocine Tighiouart; Andrew S Levey; Josef Coresh; Jennifer S Herrick; Enyu Imai; Tazeen H Jafar; Bart D Maes; Ronald D Perrone; Lucia Del Vecchio; Jack F M Wetzels; Hiddo J L Heerspink; Lesley A Inker Journal: J Am Soc Nephrol Date: 2019-07-10 Impact factor: 10.121
Authors: Morgan E Grams; Yingying Sang; Josef Coresh; Shoshana H Ballew; Kunihiro Matsushita; Andrew S Levey; Tom H Greene; Miklos Z Molnar; Zoltan Szabo; Kamyar Kalantar-Zadeh; Csaba P Kovesdy Journal: J Am Soc Nephrol Date: 2016-02-08 Impact factor: 10.121
Authors: Megumi Oshima; Bruce Neal; Tadashi Toyama; Toshiaki Ohkuma; Qiang Li; Dick de Zeeuw; Hiddo J L Heerspink; Kenneth W Mahaffey; Gregory Fulcher; William Canovatchel; David R Matthews; Vlado Perkovic Journal: J Am Soc Nephrol Date: 2020-07-21 Impact factor: 10.121