A Hierarchical Composite Endpoint for Chronic Kidney Disease Progression in Patients with Focal Segmental Glomerulosclerosis

BACKGROUND: We recently developed and validated a hierarchical composite endpoint (HCE) for chronic kidney disease (CKD) progression combining time-to-event kidney outcomes with the rate of estimated glomerular filtration rate (eGFR) decline (eGFR slope). The CKD progression HCE is an informative endpoint for clinical trials in rare kidney diseases, such as focal segmental glomerulosclerosis (FSGS), where event-driven trials are often infeasible.

METHODS: We applied a HCE for CKD progression to the subset of patients with FSGS from the DAPA-CKD trial, a randomized double-blind, placebo-controlled clinical trial, to assess the effects of the sodium glucose co-transporter 2 inhibitor dapagliflozin on CKD progression in 4304 participants. We compared treatment effects for the primary composite endpoint (sustained 50% eGFR decline, kidney failure, or death due to kidney or cardiovascular causes), eGFR slope, and CKD progression HCE. We also compared statistical power for these outcomes using a bootstrap sampling procedure to evaluate the impact on trial efficiency.

RESULTS: Overall, 115 participants were included (mean age, 54 years; 68% male; median urinary albumin-to-creatinine ratio, 1283 mg/g; mean eGFR, 42 mL/min/1.73m2). The effect of dapagliflozin on the primary composite endpoint (hazard ratio 0.45 [95% confidence interval [CI]: 0.13, 1.49]) and total eGFR slope (0.9 mL/min/1.73m2 (95%CI: -0.6, 2.3) were consistent with the overall trial results but the 95% CI crossed unity. The win-odds for the CKD progression HCE suggested benefits for dapagliflozin and the 95%CI did not cross unity (win-odds: 1.52 [95%CI: 1.01, 2.28]). Power calculations suggested that for a given sample size, statistical power was higher for the CKD progression HCE compared with the primary composite endpoint or eGFR slope.

CONCLUSION: Our findings suggest that a CKD progression HCE, which integrates established CKD endpoints and eGFR slope, provides a sensitive and efficient measure to assess treatment effects in patients with FSGS. Validation of the HCE in prospective clinical trials will support its implementation.