Using the International IgA Nephropathy Prediction Tool to Enrich Clinical Trial Cohorts

Clinical trials on IgA nephropathy (IgAN) have historically demonstrated a treatment effect on adverse outcomes, such as a 50% decline in the estimated glomerular filtration rate (eGFR) or kidney failure. Thus, trials required long follow-up, were expensive, with limited feasibility. This changed in 2016 when the Kidney Health Initiative analysis of 11 clinical trials demonstrated that a treatment effect on proteinuria over approximately 9 months was a reasonable surrogate for the effect on a hard kidney end point.¹ In 2021, it was demonstrated that proteinuria reduction is also a surrogate for the treatment effect on eGFR slope.² Regulatory agencies now accept clinical trial designs for drug approval in IgAN based on demonstrating a substantial and clinically relevant effect on proteinuria over 9 months with confirmatory data demonstrating an effect on eGFR slope over 2 years. This has dramatically improved the landscape of clinical trials and drug development for IgAN, including the development of novel supportive and disease-modifying therapies.Considerable challenges remain in designing trials for IgAN treatment. Owing to the rarity of the disease, large sample sizes require multiple international sites with long recruitment periods, which increases the cost and complexity. The International IgAN Prediction Tool comprises 2 models, with and without ethnicity as a predictor and is a validated method for predicting disease progression to hard kidney outcomes that can be used up to 2 years after biopsy in adults and children.3, 4, 5, 6 To improve study power and reduce sample size, the adult Prediction Tool could be used to enrich trials with patients at higher predicted risk who experience more rapid eGFR decline. However, it is first necessary to determine the exact risk threshold to use for this purpose, the rate of eGFR decline that will be expected as a result, and whether eGFR slope over 2 years could instead be ascertained over shorter time periods. Because the majority of trials on IgAN only recruit adults, new therapies have not been well studied in children. A framework for extrapolating trial results to pediatric populations has been adopted by regulatory agencies to support drug development in children; however, it requires demonstrating similarity in disease progression with adults.⁷ We have previously shown that children with IgAN exhibit a unique disease trajectory with increasing eGFR up to the ages of 12 to 18 years, after which eGFR declines linearly and at a faster rate in those with higher predicted risk from the Prediction Tool.^4,6 However, the exact threshold of risk that could be used to identify a subgroup of adolescents with similar disease trajectories as adults to support an extrapolation plan for drug approval is unknown.Therefore, we used international multiethnic Prediction Tool cohorts to explore the correlation between risk thresholds and eGFR slope, consistency of slope estimates over various durations of follow-up in adults, and similarity within risk-based subgroups between eGFR trajectories in children aged 12 to 18 years and eGFR slope in adults. This was done using the post-biopsy Prediction Tool at a landmark time one-year after biopsy because this is suited to assess risk at the time of trial enrolment. Further details are in the Supplementary Methods.