TY - JOUR
T1 - GFR slope as a surrogate end point for kidney disease progression in clinical trials
T2 - A meta-analysis of treatment effects of randomized controlled trials
AU - Inker, Lesley A.
AU - Heerspink, Hiddo J.L.
AU - Tighiouart, Hocine
AU - Levey, Andrew S.
AU - Coresh, Josef
AU - Gansevoort, Ron T.
AU - Simon, Andrew L.
AU - Ying, Jian
AU - Beck, Gerald J.
AU - Wanner, Christoph
AU - Floege, Jürgen
AU - Li, Philip Kam Tao
AU - Perkovic, Vlado
AU - Vonesh, Edward F.
AU - Greene, Tom
N1 - Funding Information:
The study was funded by the National Kidney Foundation. A variety of sources have supported the randomized, controlled trials included in the Chronic Kidney Disease Epidemiology Collaboration. These funding sources include government agencies such as the National Institutes of Health and medical research councils as well as foundations and industry sponsors listed in Supplemental Appendix 2.
Funding Information:
Dr. Inker reports funding to Tufts Medical Center for research and contracts with the National Institutes of Health (NIH), National Kidney Foundation (NKF), Retrophin, Omeros, Reata Pharmaceuticals, and Dialysis Clinic, Inc. She has consulting agreements with Tricida Inc. and Omeros Corp. Tufts Medical Center, John Hopkins University and Metabolon Inc. have a collaboration agreement to develop a product to estimate GFR from a panel of markers. Dr. Levey reports grants from the NIH and the NKF during the conduct of the study, and funding from Siemens outside of the submitted work. Dr. Coresh has grants from the NIH and the NKF related and unrelated to this research. Dr. Inker, Dr. Levey, and Dr. Coresh have a patent Precise estimation of GFR from multiple biomarkers pending to Dr. Coresh, Dr. Inker, and Dr. Levey; and Tufts Medical Center, John Hopkins University, and Metabolon Inc. have a collaboration agreement to develop a product to estimate GFR from a panel of markers. Dr. Heerspink reports grants and other from Abbvie, other from Astellas, grants and other from AstraZeneca, grants and other from Boehringer Ingelheim, grants and other from Janssen, other from Fresenius, other from Gilead, and other from Merck, outside of the submitted work. Dr. Wanner reports personal fees from Boehringer Ingelheim during the conduct of the study, and personal fees from Lilly, personal fees from AstraZeneca, and personal fees from MSD outside of the submitted work. Dr. Floege has received consultancy honoraria and/or speaker fees from Alnylam, Amgen, Bayer, Calliditas, Chugai, Fresenius, Omeros Corp., and Vifor. Dr. Perkovic reports personal fees for Advisory Boards or Scientific Presentations from Retrophin, Janssen, Merck, and Servier. He has served on Steering Committees for trials funded by Abbvie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, and Pfizer; and participated in Scientific Presentations/Advisory boards with Abbvie, Astellas, Astra Zeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Dimetrix, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Sanofi, Tricida, and Vitae, with fees paid to his institution. Dr. Vonesh served as a paid biostatistics consultant for the NKF for the expressed purpose of developing statistical models for use in the estimation and comparison of GFR slopes as a surrogate end point in CKD randomized, controlled trials. He is also serving as a biostatistics consultant to Prometic and Tricida, Inc., in which some of the work entails consulting on the design and analysis of clinical trials in patients with CKD. Dr. Greene reports grants from the NKF during the conduct of the study, and personal fees from DURECT Corporation, Janssen Pharmaceuticals, and Pfizer Inc., outside of the submitted work. Dr. Beck, Dr. Gansevoort, Dr. Ying, Dr. Tighiouart, Dr. Li, and Dr. Simon have no conflicts to report.
Publisher Copyright:
© 2019 by the American Society of Nephrology.
PY - 2019/9
Y1 - 2019/9
N2 - Background Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. Methods To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment’s effect on the clinical end point. Results Across all studies, the treatment effect on 3-year total GFR slope (median R2 =0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2 /yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability. Conclusions With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.
AB - Background Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. Methods To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment’s effect on the clinical end point. Results Across all studies, the treatment effect on 3-year total GFR slope (median R2 =0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2 /yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability. Conclusions With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.
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U2 - 10.1681/ASN.2019010007
DO - 10.1681/ASN.2019010007
M3 - Article
C2 - 31292197
AN - SCOPUS:85071785993
SN - 1046-6673
VL - 30
SP - 1735
EP - 1745
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 9
ER -