Presentation (CTI)

OBJECTIVES: IgA nephropathy (IgAN) is a rare renal condition associated with a high risk of kidney failure (KF). Assessing interventions for IgAN in phase 3 trials using KF as a primary endpoint is often impractical due to sample size and follow-up requirements, especially in rare conditions such as IgAN where progression to KF takes many years. Measurement of surrogate outcomes is therefore necessary when assessing new treatments in randomized controlled trials. The validity of early change in proteinuria as a surrogate endpoint has been assessed in previous meta-analyses, and this research updates the analysis with additional patient-level data (PLD).
METHODS: The methodology from two previously published PLD meta-analyses was repeated, with additional PLD from the PROTECT study. Early change in proteinuria was defined as change from baseline at 9 months, with the composite clinical endpoint defined as any of doubling of serum creatinine, KF or death. PLD were evaluated via Bayesian mixed-effect regression to relate treatment effects on the clinical outcome to treatment effects on proteinuria with study as the unit of analysis.
RESULTS: Including PLD from PROTECT (N=404) in the updated PLD meta-analysis resulted in an overall slope of 1.03 (95% Bayesian credible interval −0.40 to 2.34) with an R2 of 0.80 (95% credible interval 0.07 to 1.00). This supports the use of early proteinuria as a valid surrogate endpoint in studies of IgAN including the most recent nephroprotective strategies, such as dual endothelin angiotensin receptor antagonism.
CONCLUSIONS: Proteinuria has been accepted as a valid surrogate outcome for use in clinical trials of new interventions for the treatment of IgA nephropathy by both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This analysis provides further evidence that interventions that reduce early proteinuria are likely to reduce progression to KF over periods longer than the trial duration.