Kidney Week

Abstract: TH-OR109

Change in Proteinuria as a Surrogate End Point for GFR Slope: Individual Patient Meta-Analysis of 12 Randomized Clinical Trials in IgA Nephropathy

Session Information

• Mostly IgA Nephropathy
  November 07, 2019 | Location: Ballroom C, Walter E. Washington Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Glomerular Diseases

• 1203 Glomerular Diseases: Clinical, Outcomes, and Trials

Author

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

Lesley Inker, MD



Dr. Inker is an attending physician and the director of the Kidney and Blood Pressure Center in the William B. Schwartz, M.D. Division of Nephrology at Tufts Medical Center, and an associate professor at Tufts University School of Medicine. Dr. Inker’s extensive research has established her as an expert in the implementation of estimated glomerular filtration rate by clinical laboratories, as well as an expert in estimating and measuring kidney function — including in specific populations such as the elderly and HIV-positive people. Dr. Inker, a leader in clinical trials end points research, also served as co-chair of the trial level analytical team for the recent joint workshop with NKF, the U.S. Food and Drug Administration and European Medicines Agency on End Points for Clinical Trials in Early Chronic Kidney Disease. The workshop was undertaken to review the results of a major, multi-year meta-analysis examining the largest compilation of data ever collected on chronic kidney disease.

Group or Team Name

• Chronic Kidney Disease-Epidemiology (CKD-EPI) Collaboration

Background

A recent study demonstrated associations between treatment effects on urine protein (UP) and clinical endpoint (i.e. ESKD). Reasonably likely surrogate endpoints can be used as a basis for accelerated or conditional approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a post-marketing confirmatory trial. For patients with IgAN, endpoints to such confirmatory trials may be GFR slope given the low likelihood of sufficient clinical endpoints.

Methods

Using a pooled dataset of 990 participants from 12 studies, we computed change in UP from baseline to 6 months (25^th,75^th 5.9, 6.9 month), and the GFR slope from randomization to 1, 2, and 3 years (total slope[TS]) as well as after excluding the initial 3 months after randomization (chronic slope[CS]). We performed Bayesian mixed models to relate the treatment effects on change in UP to GFR slope and to those on the clinical endpoint (CE), defined as ESKD, eGFR<15 or doubling of creatinine.

Results

Figure shows associations of treatment effects on change in UP compared to that of TS at 3 years and CS. Slopes are significant and intercepts are nonsignificant, supporting strong trial level associations. For TS, associations are consistent at 2 years [R² 0.62 (0.01, 0.96)]. In sensitivity analyses, similar associations were noted for CS computed using truncated data with follow-up time of 18-24 months and when computing change in UP at 9 and 12 months. Associations between treatment effects on TS and CS to the clinical endpoint are very strong (e.g. TS 3 years R² 0.99 (95% CI 0.28, 1.00)).

Conclusion

Our results suggest that treatment effects on early changes in UP confirmed by treatment effects on GFR slope might be a useful strategy for evaluation of treatment benefit in IgA.

To convert to percentage UP reduction (1-GMR)*-100. Black line is meta-regression line and blue lines are 95% confidence intervals around the regression line.

Funding

• Commercial Support –