140 Assessment of timing of evaluation of proteinuria decline to inform clinical trial design in focal segmental glomerulosclerosis: results from the PARASOL consortium

Objectives/Goals: Given previously demonstrated relationships between decline in proteinuria to thresholds below 0.3-1.5 g/g and kidney failure, we sought to assess if this relationship was maintained when proteinuria change was measured on a continuous scale and to compare the difference in association between changes measured at 12- and 24-months post-index. Methods/Study Population: PARASOL is a consortium of academic scientists, patient advocacy organizations, and industry partners who came together to identify candidate surrogate endpoints for clinical trials in focal segmental glomerulosclerosis (FSGS). Data were harmonized among international cohorts and registries of adults and children with clinically adjudicated FSGS without other causes. Index was identified as the first observed urine protein-creatinine ratio (UPCR)≥1.5 g/g with associated eGFR≥30 ml/min/1.73m2. Change in UPCR from index to 12 and 24 months was evaluated using the difference in log(UPCR) from baseline and follow-up and transformed to percent change. Time-updated landmark Cox regression models were fitted, and the interaction between UPCR change and the 24-month timepoint indicator was assessed. Results/Anticipated Results: 1366 participants with at least 12 months of follow-up post-index and UPCR measurements 6-12 and/or 18-24 post-index were included. Mean age was 27 years (SD=21); 46% were pediatric at index. Median (IQR) eGFR and UPCR at index were 83 (57, 110) ml/min/1.73m2 and 3.7 (2.3, 7.0) g/g, respectively. A 50% decrease in UPCR from index was associated with a 28% and 32% reduction in the probability of kidney failure at 12 and 24 months, respectively, with no difference detected based on timing of UPCR (HR 95% CI = 0.72 0.65-0.80 at 12m, 0.68 0.63-0.74 at 24m, interaction p-value = 0.46). In subgroups based on age, UPCR, and eGFR at index, results were consistent (HR range 0.66-0.72 at 12m and 0.58-0.78 at 24m), with only the eGFR≥60 ml/min/a.73m2 subgroup showing patterns of larger effects at 24m (HR = 0.62 vs. 0.72, p=0.08). Discussion/Significance of Impact: Continuous measures of proteinuria demonstrated consistent associations with kidney failure at 12- and 24-months post-index and across patient subgroups. If validated, these relationships support potential variation in timing of endpoint evaluation in clinical trials where there is mechanistic justification for earlier assessment.