@article{42561d1d43c04a3bbe4f1bbe6800c086,
title = "Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency",
abstract = "The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR > 30 mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0 mL/min/1.73 m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.",
keywords = "Surrogate endpoints, albuminuria, albuminuria change, biomarker, chronic kidney disease (CKD), clinical trials, drug approval, eGFR slope, eGFR trajectory, estimated GFR (eGFR), evidence synthesis, glomerular filtration rate (GFR), kidney disease progression, renal outcome, trial design",
author = "Levey, {Andrew S.} and Gansevoort, {Ron T.} and Josef Coresh and Inker, {Lesley A.} and Heerspink, {Hiddo L.} and Grams, {Morgan E.} and Tom Greene and Hocine Tighiouart and Kunihiro Matsushita and Ballew, {Shoshana H.} and Yingying Sang and Edward Vonesh and Jian Ying and Tom Manley and {de Zeeuw}, Dick and Eckardt, {Kai Uwe} and Adeera Levin and Vlado Perkovic and Luxia Zhang and Kerry Willis",
note = "Funding Information: Andrew S. Levey, MD*, Ron T. Gansevoort, MD, PhD*, Josef Coresh, MD, PhD, Lesley A. Inker, MD, MS, Hiddo L. Heerspink, PharmD, PhD, Morgan E. Grams, MD, MHS, PhD, Tom Greene, PhD, Hocine Tighiouart, MS, Kunihiro Matsushita, MD, PhD, Shoshana H. Ballew, PhD, Yingying Sang, MS, Edward Vonesh, PhD, Jian Ying, PhD, Tom Manley, RN, Dick de Zeeuw, MD, PhD, Kai-Uwe Eckardt, MD, Adeera Levin, MD, Vlado Perkovic, MBBS, PhD, Luxia Zhang, MD, PhD, and Kerry Willis, PhD. *Conference Co-Chairs. The following companies provided a grant to the NKF to support the data analysis and workshop: Alexion, Astellas, AstraZeneca, Aurinia, Bayer, Boehringer-Ingelheim, Calliditas, Gilead, Ironwood, Janssen, Kyowa Hakko Kirin, Merck, Novartis, Novo-Nordisk, Reata, Retrophin, Tricida, and Vifor Fresenius Medical Care. The workshop sponsors had no role in the development of the workshop agenda or objectives. The sponsors were restricted from viewing any part of the workshop report manuscript until it was accepted for publication and therefore had no role in the content developed for this report. Dr Levey reports grants from the National Institutes of Health (NIH) and the NKF during the conduct of the study, and funding from Siemens outside the submitted work. Dr Coresh has grants from the NIH and the NKF related and unrelated to this research. Dr Inker reports funding to Tufts Medical Center for research and contracts with the NIH, NKF, Retrophin, Omeros, and Reata Pharmaceuticals and consulting agreements with Tricida Inc. and Omeros Corp. Drs Inker, Levey, and Coresh have a patent ?Precise estimation of glomerular filtration rate from multiple biomarkers? pending to Coresh, Inker, and Levey; 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 payments from Abbvie, AstraZeneca, Boehringer Ingelheim, and Janssen; and other payments from Astellas, Fresenius, Gilead, and Merck (all outside the submitted work). Dr Greene reports grants from the NKF during the conduct of the study; and personal fees from DURECT Corp, Janssen Pharmaceuticals, and Pfizer Inc outside the submitted work. Dr Matsushita reports research funding and personal fee outside of the work from Kyowa Hakko Kirin and personal fee outside of the work from Akebia. Dr Vonesh is currently under contract as a consultant to Prometic, and Tricida Inc (related to current article) and Epividian Inc (unrelated to current article) and reports prior funding from the NKF for related work. Dr Perkovic reports receiving personal fees for Advisory Boards or Scientific Presentations from Retrophin, Janssen, Merck, and Servier; was a member of the SONAR Steering Committee; has served on Steering Committees for trials funded by Abbvie, Boehringer Ingelheim, GSK, Janssen, Novo Nordisk, Retrophin, and Tricida; and participated in Scientific Presentations/Advisory boards with Abbvie, Astellas, Astra Zeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Vifor, and Tricida. Dr Gansevoort received grant support and consultancy fees from Abbvie, Bayer, Ipsen, Sanofi-Genzyme, and Otsuka; all money was paid to the employing institution. Dr de Zeeuw was on the advisory boards and/or speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi-Tanabe; Steering Committees and/or speaker for AbbVie and Janssen; and Data Safety and Monitoring Committees for Bayer. Mr Manley and Dr Willis are employed by NKF. All other authors declare that they have no relevant financial interests. The authors are grateful to Juhi Chaudhari, MPH, for assistance with manuscript preparation. Received April 1, 2019, in response to an invitation from the journal. Evaluated by 3 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form June 13, 2019. Funding Information: Dr Levey reports grants from the National Institutes of Health (NIH) and the NKF during the conduct of the study, and funding from Siemens outside the submitted work. Dr Coresh has grants from the NIH and the NKF related and unrelated to this research. Dr Inker reports funding to Tufts Medical Center for research and contracts with the NIH, NKF, Retrophin, Omeros, and Reata Pharmaceuticals and consulting agreements with Tricida Inc. and Omeros Corp. Drs Inker, Levey, and Coresh have a patent “Precise estimation of glomerular filtration rate from multiple biomarkers” pending to Coresh, Inker, and Levey; 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 payments from Abbvie , AstraZeneca , Boehringer Ingelheim , and Janssen; and other payments from Astellas, Fresenius, Gilead , and Merck (all outside the submitted work). Dr Greene reports grants from the NKF during the conduct of the study; and personal fees from DURECT Corp, Janssen Pharmaceuticals, and Pfizer Inc outside the submitted work. Dr Matsushita reports research funding and personal fee outside of the work from Kyowa Hakko Kirin and personal fee outside of the work from Akebia. Dr Vonesh is currently under contract as a consultant to Prometic, and Tricida Inc (related to current article) and Epividian Inc (unrelated to current article) and reports prior funding from the NKF for related work. Dr Perkovic reports receiving personal fees for Advisory Boards or Scientific Presentations from Retrophin, Janssen, Merck, and Servier; was a member of the SONAR Steering Committee; has served on Steering Committees for trials funded by Abbvie , Boehringer Ingelheim , GSK , Janssen, Novo Nordisk , Retrophin, and Tricida; and participated in Scientific Presentations/Advisory boards with Abbvie, Astellas, Astra Zeneca, Bayer, Baxter, BMS, Boehringer Ingelheim, Dimerix, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck, Mitsubishi Tanabe, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Sanofi, Servier, Vifor, and Tricida. Dr Gansevoort received grant support and consultancy fees from Abbvie , Bayer , Ipsen , Sanofi-Genzyme , and Otsuka; all money was paid to the employing institution. Dr de Zeeuw was on the advisory boards and/or speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi-Tanabe; Steering Committees and/or speaker for AbbVie and Janssen; and Data Safety and Monitoring Committees for Bayer. Mr Manley and Dr Willis are employed by NKF. All other authors declare that they have no relevant financial interests. Publisher Copyright: {\textcopyright} 2019 National Kidney Foundation, Inc.",
year = "2020",
month = jan,
doi = "10.1053/j.ajkd.2019.06.009",
language = "English (US)",
volume = "75",
pages = "84--104",
journal = "American Journal of Kidney Diseases",
issn = "0272-6386",
publisher = "W.B. Saunders Ltd",
number = "1",
}