Association of Treatment Effects on Early Change in Urine Protein and Treatment Effects on GFR Slope in IgA Nephropathy: An Individual Participant Meta-analysis.

Abstract Rationale & Objective An early change in proteinuria is considered a reasonably likely surrogate endpoint in IgA nephropathy (IgAN), and can be used as basis for accelerated approval of therapies with verification in a post-marketing confirmatory trial. GFR slope is a recently validated surrogate endpoint for CKD progression and may be considered as the endpoint used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria to change in eGFR slope. Study design Individual patient-level meta-analysis. Setting and Study Populations: Individual data of 1037 patients from 12 randomized trials. Selection Criteria for Studies Randomized trials of IgAN with proteinuria measurements at baseline and 6-months (range 2.5-14) and at least one further year of follow-up for the clinical outcome. Analytical Approach For each trial we estimated the treatment effects on proteinuria and on the eGFR slope, computed as either the total slope starting at baseline or the chronic slope starting 3-months after randomization. We used a Bayesian mixed effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria. Results Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R2=0.88 [95% Bayesian credible Interval (BCI) 0.06-1) and on the chronic slope (R2 0.98 [95% BCI 0.29-1]). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slope of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years. Limitations Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions. Conclusions These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate endpoint for studies of CKD progression in IgAN.