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

Andrew S. Levey, Ron T. Gansevoort, Josef Coresh, Lesley A. Inker, Hiddo L. Heerspink, Morgan E. Grams, Tom Greene, Hocine Tighiouart, Kunihiro Matsushita, Shoshana H. Ballew, Yingying Sang, Edward Vonesh, Jian Ying, Tom Manley, Dick de Zeeuw, Kai Uwe Eckardt, Adeera Levin, Vlado Perkovic, Luxia Zhang, Kerry Willis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)84-104
Number of pages21
JournalAmerican Journal of Kidney Diseases
Volume75
Issue number1
DOIs
StatePublished - Jan 2020

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Albuminuria
United States Food and Drug Administration
Glomerular Filtration Rate
Clinical Trials
Kidney
Education
Albumins
Creatinine
Kidney Diseases
Disease Progression
Meta-Analysis
Biomarkers
Chronic Renal Insufficiency
Sample Size
Observational Studies
Renal Insufficiency
Cohort Studies

Keywords

  • 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
  • Surrogate endpoints
  • trial design

ASJC Scopus subject areas

  • Nephrology

Cite this

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. / Levey, Andrew S.; Gansevoort, Ron T.; Coresh, Josef; Inker, Lesley A.; Heerspink, Hiddo L.; Grams, Morgan E.; Greene, Tom; Tighiouart, Hocine; Matsushita, Kunihiro; Ballew, Shoshana H.; Sang, Yingying; Vonesh, Edward; Ying, Jian; Manley, Tom; de Zeeuw, Dick; Eckardt, Kai Uwe; Levin, Adeera; Perkovic, Vlado; Zhang, Luxia; Willis, Kerry.

In: American Journal of Kidney Diseases, Vol. 75, No. 1, 01.2020, p. 84-104.

Research output: Contribution to journalArticle

Levey, Andrew S. ; Gansevoort, Ron T. ; Coresh, Josef ; Inker, Lesley A. ; Heerspink, Hiddo L. ; Grams, Morgan E. ; Greene, Tom ; Tighiouart, Hocine ; Matsushita, Kunihiro ; Ballew, Shoshana H. ; Sang, Yingying ; Vonesh, Edward ; Ying, Jian ; Manley, Tom ; de Zeeuw, Dick ; Eckardt, Kai Uwe ; Levin, Adeera ; Perkovic, Vlado ; Zhang, Luxia ; Willis, Kerry. / 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. In: American Journal of Kidney Diseases. 2020 ; Vol. 75, No. 1. pp. 84-104.
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T2 - A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency

AU - Levey, Andrew S.

AU - Gansevoort, Ron T.

AU - Coresh, Josef

AU - Inker, Lesley A.

AU - Heerspink, Hiddo L.

AU - Grams, Morgan E.

AU - Greene, Tom

AU - Tighiouart, Hocine

AU - Matsushita, Kunihiro

AU - Ballew, Shoshana H.

AU - Sang, Yingying

AU - Vonesh, Edward

AU - Ying, Jian

AU - Manley, Tom

AU - de Zeeuw, Dick

AU - Eckardt, Kai Uwe

AU - Levin, Adeera

AU - Perkovic, Vlado

AU - Zhang, Luxia

AU - Willis, Kerry

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N2 - 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.

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KW - albuminuria change

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KW - clinical trials

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KW - eGFR slope

KW - eGFR trajectory

KW - estimated GFR (eGFR)

KW - evidence synthesis

KW - glomerular filtration rate (GFR)

KW - kidney disease progression

KW - renal outcome

KW - Surrogate endpoints

KW - trial design

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