Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy

Abstract

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated 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 postmarketing confirmatory trial.

Keywords: Glomerulonephritis; IGA; IgA nephropathy; Kidney Failure, Chronic; clinical trials; creatinine; kidney; proteinuria; risk factors; surrogate endpoint.

Figure 1.

Trial-level assessment of the validity of proteinuria as a surrogate end point. Circles are the observed treatment effects on the clinical outcome (vertical axis) and change in urine protein (horizontal axis) for each study or study group. The sizes of the circles are the inverse to the SEM of the treatment effect on the clinical end point, which is related to the number of events of interest. Colors indicate intervention. Red, renin-angiotensin system blockade; yellow, fish oil; green, immunosuppression; purple, steroids. Treatment effects on the clinical outcome are expressed as hazard ratios. Treatment effect on urine protein was computed as change in log urine protein (follow-up−baseline) in the treatment versus control groups. The treatment effect estimate was exponentiated to obtain the geometric mean ratio of the change in urine protein for the treatment versus control arm. A number <1 indicates a larger reduction in proteinuria in the treatment than in the control group. The brown regression line is the regression line from the Bayesian analyses summarizing the prediction of the true treatment effects on the clinical outcome from the true treatment effects on change in urine protein. Gray lines indicate the confidence band around the regression line. Overall, the slope is 2.15 with a 95% Bayesian credible interval range from 0.10 to 4.32 with R² of 0.91, 95% Bayesian credible interval range from 0.47 to 1.0, indicating that for a given treatment effect on urine protein excretion, the treatment effect on the clinical outcome is expected to be double the treatment effect on urine protein excretion when the respective treatment effects are expressed on the log hazard ratio and log geometric mean scales. The Bayesian credible interval around the slope was wide but did not cross zero, suggesting that there is a significant positive relationship between treatment effects on urine protein and on the clinical end point. D(dose), Donadio (dose); D(plc), Donadio (placebo); HKVIN, Hong Kong Study Using Valsartan in IgA Nephropathy; MMF, mycophenolate mofetil. Reprinted from ref. 38, with pending permission.

Figure 2.

Trial-level assessment of the validity of proteinuria as a surrogate end point with the addition of the data from the STOP-IgAN and TESTING trials. (A) With the results of Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) and Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) added as two separate trials. (B) With the results of TESTING combined with those of other trials of corticosteroids. Circles are the observed treatment effects on the clinical outcome (vertical axis) and change in urine protein (horizontal axis) for each study or study group as for Figure 1. The sizes of the circles are the inverse to the SEM of the treatment effect on the clinical end point, which is related to the number of events of interest. Colors indicate intervention. Red, renin-angiotensin system blockade; yellow, fish oil; green, immunosuppression; dark blue, steroids; light blue, TESTING trial; orange, STOP-IgAN trial. D(dose), Donadio (dose); D(plc), Donadio (placebo); HKVIN, Hong Kong Study Using Valsartan in IgA Nephropathy (43); MMF, mycophenolate mofetil; STOP, STOP-IgAN trial (39); TESTING, TESTING trial (40).