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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

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 (25th,75th 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