Study Supports Total GFR Slope as a Surrogate Endpoint in Clinical Trials

Study findings presented at the European Renal Association 2023 congress in Milan, Italy, could have important implications for conducting clinical trials of medications to prevent progression of chronic kidney disease (CKD).

A meta-analysis of 66 randomized controlled clinical trials (RCTs) with a total of 186,312 participants demonstrated that the effect of treatment on glomerular filtration rate (GFR) over 3 years strongly predicted the clinical endpoint (kidney failure with replacement therapy, sustained GFR less than 15, and doubling of serum creatinine). Investigators concluded that their results support the use of total GFR slope as a primary endpoint for clinical trials of treatments to lower the risk for CKD progression. This could substantially reduce the size and duration of clinical trials.

Hiddo L. Heerspink, PhD, of the University Medical Center Groningen in Groningen, The Netherlands, and The George Institute of Global Health in Sydney, Australia, who presented the study findings, explained that the power of trials can be increased substantially by using GFR slope. He pointed out that recently completed RCTs such as DAPA-CKD and CREDENCE have included 4000 to 6000 patients. By using GFR slope as a surrogate endpoint, “we can decrease the sample size to about 1500 patients.”

He explained how total GFR slope would be of value in a hypothetical new RCT with large and small patient samples (1600 and 400 participants, respectively). For example, in a large trial, a mean difference in total GFR slope of 0.75 mL/min/1.73 m² per year at 3 years had a 100% probability of a 26% reduced risk for the clinical endpoint. In a small trial, that same treatment effect had a 97% probability of a 26% reduced risk. He and colleagues calculated that the minimum treatment effect on 3-year total GFR slope associated with a 97.5% probability of clinical benefit would be 0.44 and 0.79 mL/min/1.73 m² per year in a large and small trial, respectively.

The findings were consistent across subgroups by disease type and CKD severity.

Dr Heerspink concluded, “These data provide the necessary evidence to support use of total [GFR] slope over 3 years in randomized controlled trials evaluating therapies of CKD progression as a valid, fit-for-purpose, and robust surrogate endpoint that can be presented to regulatory agencies for approval for marketing authorization, to payors to support funding of these new therapies, and to health care professionals and patients to inform of their benefit of slowing CKD progression and preventing kidney failure.”

Dr Heerspink’s presentation coincided with publication of the study’s findings in Nature Medicine.

Disclosure: This research was supported by the National Kidney Foundation, AstraZeneca, Bayer, Boehringer Ingelheim, Cerium Pharma, Chinook, CSL Behring, Janssen, Novartis, NovoNordisk, ProKidney, and Travere. Please see the original reference for a full list of disclosures.

Reference

Heerspink HL, Inker L, Greene T, on behalf of the CKDepi-CT investigators. GFR slope as a surrogate endpoint for kidney failure in clinical trials: an updated meta-analysis. Presented at: ERA 2023 congress, June 15-18, Milan, Italy. Abstract 7046.

This article originally appeared on Renal and Urology News