Surrogate Endpoints

Surrogate Endpoints
Proteinuria has been established as a marker of kidney damage in experimental studies and clinicians consider an early reduction in albuminuria as indicative of a favorable response to treatment.

Overview

CKD is defined as GFR <60 ml/min per 1.73 m2 or a change in a marker of kidney damage, which most commonly is elevated urine albumin or protein, for 3 months or more, and is staged by level of GFR, urine albumin and cause. Thus, GFR and urine albuminuria are the most widely used biomarkers in CKD and have been extensively evaluated as candidate surrogate endpoints.

Criteria for validity of surrogate endpoints include 1) biological plausibility, 2) association with the clinical endpoint in epidemiologic studies, and 3) prediction of the clinical endpoint in clinical trials. Kidney failure is the generally accepted “hard” clinical endpoint for studies of kidney disease progression, and doubling of serum creatinine (equivalent to a 57% decline in eGFR) is accepted as a valid surrogate endpoint by the FDA and EMA and is usually included in a composite with kidney failure as the clinical endpoint in clinical trials. Both change in albuminuria and GFR decline have strong biological plausibility and are strongly associated with the clinical endpoint. Our studies have focused on evaluating the strength of evidence in meta-analysis of individual patient data from clinical trials for the prediction of the effect of an intervention on the clinical endpoint by the effect of the intervention on changes in albuminuria and GFR decline and have informed several key workshops in collaboration with the FDA and EMA.

For information on joining the CKD-EPI CT research group by sharing data or supporting the consortium, please contact Juhi.Chaudhari@tuftsmedicine.org or Anthony Gucciardo anthonyg@kidney.org

Our existing collaborators can access the confidential results here. 
 
Albuminuria and proteinuria

Proteinuria has been established as a marker of kidney damage in experimental studies, and clinicians consider an early reduction in albuminuria as indicative of a favorable response to treatment. Albuminuria is a sensitive marker of kidney disease progression in the early stages of CKD and appears to be a cause of CKD progression in some disease. Albuminuria would not be expected to be a valid surrogate endpoint across all CKD causes and thus unlike GFR, its use would require understanding that both the disease effect albuminuria and that the intervention is expected to impact its change. In a meta-analysis of 48 clinical trials of various interventions for various causes of kidney disease, we provide evidence that support change in albuminuria as a reasonably likely surrogate endpoint, particularly in patients with higher baseline albuminuria and where there are large treatment effects. In a meta-analysis of 13 clinical trials of various interventions for IgA nephropathy, we showed strong evidence in support of changes in albuminuria as a reasonably likely surrogate and has been accepted by the FDA and EMA for this purpose. Changes in albuminuria are now being used in phase 2 and dose-finding studies to demonstrate proof of concept in prevalent CKD, as a bridging biomarker to translate the obtained efficacy evidence of a therapy from one population to another and is currently under review as full approval endpoint in focal segmental glomerulosclerosis.
GFR decline

A decline in glomerular filtration rate (GFR) is on the path to the development of kidney failure and is highly predictive of the development of kidney failure and the clinical endpoint. Thus, GFR decline is an intermediate endpoint. We have investigated both time to thresholds of GFR decline of 30 and 40% as well as annualized continuous changes in GFR (i.e. GFR slope) and have also published simulation studies that inform us when GFR decline is most useful to replace the clinical endpoint. The strength of the trial-level associations for GFR slope and 40% decline in GFR indicates a uniquely strong surrogate endpoint and considerably stronger than for other surrogate endpoints used other fields such as oncology and cardiovascular disease. For GFR slope, we have also demonstrated that results are consistent across disease and by severity of CKD as defined by baseline level of GFR, albuminuria and rate of progression in the study’s control arm. The European Medicines Agency has accepted and published the Qualification Opinion for GFR slope as a Validated Surrogate Endpoint for RCTs in CKD. The USFDA is using change in GFR as a valid surrogate endpoint for studies in rare kidney disease.

A technical report on timing strategies for estimating the acute GFR effect is available for your reference:

Support for CKD-EPI CT was obtained from multi-sponsor funding to the National Kidney Foundation (NKF). The NKF received consortium support from the following companies:

CKD sponsors