Early Change in Proteinuria as a Surrogate Endpoint in Studies of IgA Nephropathy: An Updated Patient-Level Meta-analysis and Discussion of Appropriate Methodology.

INTRODUCTION

Immunoglobulin A (IgA) nephropathy is a rare renal condition associated with a high risk of kidney failure. However, conducting phase 3 clinical trials with kidney failure as a primary endpoint is generally not feasible because of sample size and protracted follow-up requirements. Hence, surrogate outcomes are necessary when assessing new treatments in randomized controlled trials. Previous meta-analyses have assessed the validity of early change in proteinuria as a surrogate endpoint, and the present research updates the analysis with additional patient-level data.

METHODS

The same methodology as two previously published individual patient-level meta-analyses was used, with additional data from the PROTECT study included. Early change in proteinuria was defined as change from baseline at 9 months, and the clinical endpoint was defined as the composite of doubling of serum creatinine level, kidney failure or death. The association of treatment effects was ascertained using individual patient data via a Bayesian mixed-effect regression model to relate treatment effects on the clinical outcome to treatment effects on proteinuria with study as the unit of analysis.

RESULTS

The updated individual patient-level meta-analysis including data from PROTECT resulted in an overall slope of 1.03 (95% Bayesian credible interval - 0.40 to 2.34) between treatment effects on early change in proteinuria versus longer-term treatment effects on the clinical outcome, with an R2 of 0.80 (95% Bayesian credible interval 0.07 to1.00). This corroborates the use of early proteinuria as a valid surrogate endpoint for a treatment's effect on progression to kidney failure in studies of IgA nephropathy.

CONCLUSIONS

The FDA and EMA have accepted proteinuria as a valid surrogate outcome for use in clinical trials of new interventions for the treatment of IgA nephropathy, and the present analysis provides further indications that interventions that reduce proteinuria in a short-term trial are likely to improve kidney outcomes over the long term.