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Proposal 1758

Title of the Proposed Research

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of Chronic Kidney Disease

Lead Researcher

Lesley A. Inker, MD

Affiliation

Tufts Medical Center/Tufts Medical School

Funding Source

Funding provided by the National Kidney Foundation

Potential Conflicts of Interest

Summary for all Researchers and Statistician

Lesley A Inker reports funding to Tufts Medical Center for research and contracts with the National Institutes of Health, National Kidney Foundation, Pharmalink (Largo, FL), Gilead Sciences (Foster City, CA), Otsuka (Tokyo, Japan), and has a provisional patent (L.A.I., J.C., and A.S.L.) filed August 15, 2014 entitled “Precise estimation of glomerular filtration rate from multiple biomarkers” (no. PCT/US2015/044567). The technology is not licensed in whole or in part to any company. Tufts Medical Center, John Hopkins University, and Metabolon, Inc. (Durham, NC), have a collaboration agreement to develop a product to estimate GFR from a panel of markers.Andrew S. Levey reports funding to Tufts Medical Center for research and contracts with the National Institutes of Health, National Kidney Foundation, Amgen, Pharmalink AB, Gilead Sciences, and has a provisional patent [Coresh, Inker and Levey] filed 8/15/2014 –“Precise estimation of glomerular filtration rate from multiple biomarkers” PCT/US2015/044567. The technology is not licensed in whole or in part to any company. 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. –“Precise estimation of glomerular filtration rate from multiple biomarkers” PCT/US2015/044567. The technology is not licensed in whole or in part to any company. 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. Hiddo L. Heerspink has consultancy agreements through his university with the following companies: Abbvie, Astra Zeneca, Boehringer Ingelheim, Fresenius, Janssen, and Merck. All honoraria are paid to his university.Hiddo L. Heerspink has consultancy agreements through his university with the following companies: Abbvie, Astra Zeneca, Boehringer Ingelheim, Fresenius, Janssen, and Merck. All honoraria are paid to his university.Edward F. Vonesh serves a consultant for ProMetic, a biopharmaceutical corporation with expertise in bioseparation technology for the development of best in class plasma-derived therapeutics. ProMetic is also active in developing its own novel small molecule therapeutics products. It is headquartered in Laval, Canada. As a consulting biostatistician, he has and continues to be involved in the protocol development (study design, sample size determination, statistical analysis plan, etc.) of a propose clinical trial to evaluate the safety and tolerability of a pharmaceutical agent in subjects with Chronic Kidney Disease (CKD) associated with type 2 diabetes mellitus. Josef Coresh reports funding to Johns Hopkins University for research and contracts with the National Institutes of Health, National Kidney Foundation, and has a provisional patent [Coresh, Inker and Levey] filed 8/15/2014 –“Precise estimation of glomerular filtration rate from multiple biomarkers” PCT/US2015/044567. The technology is not licensed in whole or in part to any company. 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. Tom H. Greene serves or has served as a consultant for Jansen (on the steering committee), Nephrogenix, Durect, and AtraZeneca. He has received grant support from Keryx.

Data Sharing Agreement Date

31 May 2017

Lay Summary

Chronic kidney disease (CKD) is a significant global public health problem, but the progression of CKD is often slow and there are few specific symptoms until the stage of kidney failure has been reached. As such, the major challenge in identifying new treatments for CKD are the expense and complexity of trials given the need for long duration of these trials to collect sufficient kidney failure outcomes.

Glomerular Filtration Rate (GFR), the rate at which the kidneys filter the blood to remove excess waste and fluid, is considered the best measure of kidney function. We previously showed strong relationships between change in estimated GFR (eGFR) and kidney failure and mortality in observational studies, and based on analyses from past clinical trials and simulations proposed that a 30 or 40% decline in eGFR would be an acceptable alternative endpoint in clinical trials in some circumstances. Application of this endpoint is limited at higher baseline GFR. As such, these alternative endpoints are less applicable in drug development for drugs targeted at earlier stages of kidney disease. Strategies to overcome these limitations include assessing changes in albuminuria (or proteinuria) as an earlier marker of kidney disease progression, alternative approaches to assessing GFR decline, and combinations of both strategies.

Proteinuria or albuminuria (herein referred to as ACR) occurs earlier in the disease course than a change in GFR and ACR is one of the most powerful markers of CKD and its progression. However, use of change in ACR as surrogate is also limited, in particular because unlike GFR, an increase in ACR is not necessarily on the path to kidney failure, and its relationship is not as strongly related to kidney failure as change in GFR. Previous work has examined whether change in ACR can be used as a surrogate outcome and/or treatment target for clinical trials but definitive conclusions have not been reached and recent debate has highlighted the significant controversy.

A conference focused on furthering the available data and conversation related to changes in albuminuria and GFR in early stages of CKD is important, timely and likely to make progress. The discussions at this conference will be borne out of results from a secondary analysis of randomized controlled trials of interventions in CKD and other trials in which kidney outcomes were measured. The overall goal of the conference is a better understanding of change in ACR and GFR as early measures of kidney disease progression. Findings from this analysis will be communicated to the public via publication in peer-reviewed journals.

Study Data Provided

NOVARTIS-CCIB002I2301: A Prospective, Multinational, Multicenter Trial to Compare the Effects of Amlodipine/Benazepril to Benazepril and Hydrochlorothiazide Combined on the Reduction of Cardiovascular Morbidity and Mortality in Patients With High Risk Hypertension
NOVARTIS-CLCZ696B2314: A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to enalapril on morbidity and mortality in patients with chronic heart failure and reduced ejection fraction

Statistical Analysis Plan

Publication Citation

The publication citation will be added after the research is published.

Summary Results

Results summary or link will be posted when available.