Lesley A Inker1, Hiddo J Lambers Heerspink2, Hasi Mondal3, Christopher H Schmid4, Hocine Tighiouart3, Farzad Noubary3, Josef Coresh5, Tom Greene6, Andrew S Levey7. 1. Division of Nephrology, Tufts Medical Center, Boston, MA. Electronic address: linker@tuftsmedicalcenter.org. 2. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 3. The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center and Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA. 4. Department of Biostatistics, Brown University School of Public Health, Providence, RI. 5. Department of Epidemiology, Johns Hopkins, Baltimore, MD. 6. Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT. 7. Division of Nephrology, Tufts Medical Center, Boston, MA.
Abstract
BACKGROUND: There is increased interest in using alternative end points for trials of kidney disease progression. The currently established end points of end-stage renal disease and doubling of serum creatinine level, equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney disease (CKD), requiring large clinical trials with long follow-up. As part of a comprehensive evaluation of lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of intervention on the alternative and established end points in past trials. STUDY DESIGN: Diagnostic test study. SETTING & POPULATION: 9,488 participants from 37 randomized controlled trials of CKD progression across 5 intervention types. INDEX TEST: Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%, and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus nonconfirmed at the next visit. REFERENCE TEST: The historically established end point of time to composite of treated kidney failure (end-stage renal disease), untreated kidney failure (GFR<15mL/min/1.73m(2)), or doubling of serum creatinine level throughout study duration. RESULTS: Over a median of 3.62 years' follow-up, there were 3,070 established end points. Compared to the established end point, the number of alternative end points was greater for smaller versus larger declines in eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54) for 30% decline for the overall study duration, indicating consistency of treatment effects. LIMITATIONS: Limited variety of interventions tested and low statistical power for many CKD clinical trials. CONCLUSIONS: These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline.
BACKGROUND: There is increased interest in using alternative end points for trials of kidney disease progression. The currently established end points of end-stage renal disease and doubling of serum creatinine level, equivalent to a 57% decline in estimated glomerular filtration rate (eGFR), are late events in chronic kidney disease (CKD), requiring large clinical trials with long follow-up. As part of a comprehensive evaluation of lesser declines in eGFR as alternative end points, we describe the consistency of treatment effects of intervention on the alternative and established end points in past trials. STUDY DESIGN: Diagnostic test study. SETTING & POPULATION: 9,488 participants from 37 randomized controlled trials of CKD progression across 5 intervention types. INDEX TEST: Alternative end points including percentage change in eGFR from baseline (20%, 30%, 40%, and 57%) throughout study duration and to 12, 18, and 24 months. eGFR change confirmed versus nonconfirmed at the next visit. REFERENCE TEST: The historically established end point of time to composite of treated kidney failure (end-stage renal disease), untreated kidney failure (GFR<15mL/min/1.73m(2)), or doubling of serum creatinine level throughout study duration. RESULTS: Over a median of 3.62 years' follow-up, there were 3,070 established end points. Compared to the established end point, the number of alternative end points was greater for smaller versus larger declines in eGFR and longer versus shorter follow-up intervals. There was a general trend toward attenuation of the treatment effect with end points defined by a lesser eGFR decline, with greater attenuation with nonconfirmed end points, except for the low-protein-diet intervention, for which a stronger treatment effect was observed. The ratio (95% credible interval) of the HR for the alternative to established end point for the 5 intervention types ranged from 0.91 (0.64-1.43) to 1.12 (0.89-1.40) for 40% decline and from 0.88 (0.63-1.39) to 1.15 (0.88-1.54) for 30% decline for the overall study duration, indicating consistency of treatment effects. LIMITATIONS: Limited variety of interventions tested and low statistical power for many CKD clinical trials. CONCLUSIONS: These results provide some support for the use of lesser eGFR declines as a surrogate end point, with stronger support for the 40% than 30% decline.
Authors: Melanie P Chin; George L Bakris; Geoffrey A Block; Glenn M Chertow; Angie Goldsberry; Lesley A Inker; Hiddo J L Heerspink; Megan O'Grady; Pablo E Pergola; Christoph Wanner; David G Warnock; Colin J Meyer Journal: Am J Nephrol Date: 2018-01-18 Impact factor: 3.754
Authors: Lesley A Inker; Hiddo J L Heerspink; Hocine Tighiouart; Andrew S Levey; Josef Coresh; Ron T Gansevoort; Andrew L Simon; Jian Ying; Gerald J Beck; Christoph Wanner; Jürgen Floege; Philip Kam-Tao Li; Vlado Perkovic; Edward F Vonesh; Tom Greene Journal: J Am Soc Nephrol Date: 2019-07-10 Impact factor: 10.121
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: Meg J Jardine; Kenneth W Mahaffey; Bruce Neal; Rajiv Agarwal; George L Bakris; Barry M Brenner; Scott Bull; Christopher P Cannon; David M Charytan; Dick de Zeeuw; Robert Edwards; Tom Greene; Hiddo J L Heerspink; Adeera Levin; Carol Pollock; David C Wheeler; John Xie; Hong Zhang; Bernard Zinman; Mehul Desai; Vlado Perkovic Journal: Am J Nephrol Date: 2017-12-13 Impact factor: 3.754
Authors: Jan Skupien; James H Warram; Adam M Smiles; Robert C Stanton; Andrzej S Krolewski Journal: Diabetes Care Date: 2016-09-19 Impact factor: 19.112
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