GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials

Abstract

BackgroundSurrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits.MethodsTo assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment’s effect on the clinical end point.ResultsAcross all studies, the treatment effect on 3-year total GFR slope (median R2=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability.ConclusionsWith large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.

Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, preserves renal function irrespective of acute changes in the estimated glomerular filtration rate in Japanese patients with type 2 diabetes

“…More specifically, baseline eGFR in the present study was comparable with that reported in the CANVAS program, and eGFR was maintained during the long term [4]. Moreover, a recent study suggested that chronic changes in eGFR 3 months after initiating intervention might be a reliable surrogate marker of renal outcomes [18]. Thus, it might be expected that many of the patients would have had stable renal function after 52 weeks in the present study.…”

“…Since the chronic eGFR slope from 3 months after initiating intervention is considered to be a reliable surrogate marker of long-term renal outcomes such as end-stage kidney disease [18], we additionally examined the impact of acute decline in eGFR within 2 weeks on changes in eGFR from weeks 12 to 52. The tertile of acute changes in eGFR within 2 weeks was not associated with changes in eGFR from weeks 12 to 52 (Table 3).…”

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

“…27,28,45 For the albuminuria change analyses, 11 key inclusion criteria were biological plausibility of albuminuria change as a surrogate end point for the intervention, quantifiable measurements of albuminuria or proteinuria at BL and within 12 months of F/U, and information on ESKD incidence. For the GFR slope analyses, 13 key inclusion criteria were Scr measurements at BL and at F/U at 12 months or earlier, and at least 12 months' F/U after that second measurement. For both analyses, small studies (n < 100) were pooled if the disease and intervention were the same.…”

“…Detail for the data analyses is provided in separate publications. [10][11][12][13][14][15] Perspectives from the FDA, EMA, and patient representatives are provided in accompanying editorials. [16][17][18] Additional information about the workshop is included in Item S1.…”

Clinical Trial Data Sharing: The Time Is Now

“…This paper illustrates dramatically the value of data sharing. 4 In the early days of meta-analyses, studies mostly relied only on the published data. That is no longer the case.…”