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Abstract: FR-PO247

Are Treatment Effects on eGFR Decline Greater in Patients with Faster Underling Disease Progression? A Report from an NKF FDA Workshop

Session Information

Category: CKD (Non-Dialysis)

  • 1902 CKD (Non-Dialysis): Clinical, Outcomes, and Trials

Author

  • Greene, Tom, University of Utah, Salt Lake City, Utah, United States

Group or Team Name

  • CKD-Epidemiology Collaboration
Background

Analyses at the individual and trial level support the validity of eGFR slope as a surrogate endpoint in chronic kidney disease (CKD) RCTs. The gain in statistical power for eGFR slope vs. the clinical endpoint of doubling serum creatinine or kidney failure is limited if treatments reduce the rate of eGFR decline proportionally to the rate of CKD progression (attenuating slopes of fast more than slow progressors), rather than uniformly (attenuating slopes independent of progression rate) [Greene et al, this meeting]. By definition, proportional effects, but not uniform effects, attenuate the standard deviation (SD) as well as mean of eGFR slopes. We describe the effects of treatments on the slope SD in past RCTs to inform selection of endpoints in future RCTs.

Methods

We used mixed effects analyses to estimate treatment effects on the mean and SD of eGFR slopes after 3 months follow-up (chronic slopes) for 47 CKD RCTS (59074 patients), and used meta-regression to relate the ratio of the chronic slope SDs to the ratio of mean chronic slopes between treatment and control groups while accounting for random error in each RCT.

Results

The figure shows that treatments that reduce the mean chronic slope also often reduce the SD, indicating that effective treatments tend to slow progression more in faster than in slower progressors. The slope of the meta-regression line is 0.45 ± 0.13, about half way between 0 (corresponding to uniform effects) and 1 (corresponding to proportional effects), suggesting treatment effects are usually intermediate between uniform and proportional.

Conclusion

Effective treatments usually reduce CKD progression by effects that are intermediate between uniform and proportional. For intermediate effects, our simulation studies demonstrate that slope-based endpoints can substantially reduce required sample sizes and follow-up times when there is no acute effect and baseline eGFR is high [Greene et al, this session].

Funding

  • Private Foundation Support