Kidney Week

Abstract: SA-OR38

Change in Albuminuria and GFR Slope as Joint Surrogate End Points for Kidney Failure: Implications for Phase 2 Trials

Session Information

• High-Impact CKD Potpourri: Something for Everyone
  November 05, 2022 | Location: W307, Orange County Convention Center‚ West Building
  Abstract Time: 05:33 PM - 05:42 PM

Category: CKD (Non-Dialysis)

• 2202 CKD (Non-Dialysis): Clinical‚ Outcomes‚ and Trials

Authors

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

Tom Greene, PhD

• Inker, Lesley Ann, Tufts Medical Center, Boston, Massachusetts, United States

Lesley Ann Inker,

• L Heerspink, Hiddo Jan, Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

Hiddo Jan L Heerspink,

• Tighiouart, Hocine, Tufts Clinical and Translational Science Institute, Boston, Massachusetts, United States

Hocine Tighiouart,

• Collier, Willem H., University of Utah Health, Salt Lake City, Utah, United States

Willem H. Collier,

• Haaland, Benjamin, University of Utah Health, Salt Lake City, Utah, United States

Benjamin Haaland,

Group or Team Name

• Chronic Kidney Disease-Epidemiology Collaboration

Background

Change in urinary albumin:creatinine ratio (UACR) and GFR slope are individually used as surrogate endpoints in clinical trials of CKD progression. We developed a strategy that combined both endpoints to improve prediction of drug effects on clinical outcomes.

Methods

We used data from 43 randomized controlled trials of CKD progression and fitted trial-level Bayesian meta-regression models to characterize the joint relationship between the treatment effects on the clinical endpoint (sustained doubling of serum creatinine, GFR < 15 ml/min per 1.73m², or end-stage kidney disease) and those on UACR change and chronic GFR slope. We applied the results of the meta-regression to the design of a phase 2 trial to assess design implications (sample size, follow-up time) for using UACR change and GFR slope individually or in combination. For each design we calculated the positive predicted value (PPV) for inferring clinical benefit based on observed treatment effects on UACR and GFR slope.

Results

The median R² of the model was 0.926. The PPV of both surrogates on the clinical endpoint was almost exclusively determined by estimated treatment effects on UACR when the sample size was small (~60 patients per arm) and follow-up short (~1 year; fig1A), with the importance of GFR slope increasing when the sample size and follow-up increased (fig1B/C). At large sample sizes (>600 per group) or long follow-up (≥ 2 year), clinical benefit was solely determined by GFR slope (fig1D).

Conclusion

In phase 2 clinical trials with sample sizes of 100 to 200 patients per arm or follow-up times ranging between 1 and 2 years combining the information from treatment effects on UACR change and GFR slope improved prediction of treatment effects on clinical endpoints.

Funding

• Private Foundation Support