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 end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope.

Study design: Individual patient-level meta-analysis.

Setting & study populations: Individual data of 1,037 patients from 12 randomized trials.

Selection criteria for studies: Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 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 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 slopes 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 end point for studies of chronic kidney disease progression in IgAN.

Keywords: GFR slope; Glomerular filtration rate (GFR); IgA nephropathy (IgAN); end-stage renal disease (ESRD); kidney disease progression; meta-analysis; proteinuria; regulatory approval; renal function; surrogate end point; treatment effect; trial design; urine protein.

Figure 1:. Treatment effect on change in urine protein at 6 months, on 3-year total GFR slope, and on chronic slope

Treatment effects on urine protein are expressed as geometric mean ratios and were estimated by performing analyses of covariance within each study. Treatment effects on slope are difference in glomerular filtration rate between treatment and control arm and are expressed as ml/min/1.73m²/year and were estimated using a shared parameter mixed effects model. The circles represent the estimated treatment effects and the horizontal line the 95% confidence intervals. UP, urine protein measured in gram/day.

Figure 2.. Trial level associations between treatment effects on change in urine protein and treatment effects on total GFR slope at 3 years and chronic slope, for urine protein at 6 months

Shown is the relationship between estimated treatment effects on the 3-year GFR slope on the vertical axis to estimated treatment effects on the change in urine protein on the horizontal axis. Treatment effects on GFR slope are expressed as mean difference in treatment and control and expressed in ml/min/1.73m²/year. Treatment effects on urine protein are expressed as geometric mean ratios. Each circle is a separate intervention with the size of the circle proportional to the number of events. The colors of the circles indicate intervention type. The black line is the line of regression through the studies. The dark blue lines represent the 95% confidence band and the light blue lines represent the 80% confidence band computed from the model. RASB, renin angiotensin system blockers; GMR, geometric mean ratio.

Figure 3.. Posterior predictive probabilities of true treatment effect on GFR Slope at 3 years and chronic slope given true treatment effect on change in urine protein

Panel A shows the posterior predictive probabilities for total GFR Slope at 3 years and panel B shows posterior predictive probabilities for the chronic slope; UP, urine protein; GMR, geometric mean ratio, RCT, randomized controlled trial, GFR, glomerular filtration rate.