Inside the DUPLEX Trial: FSGS Design, Endpoints, and Exclusions

This episode, "Inside the DUPLEX Trial: FSGS Design, Endpoints, and Exclusions," features the panel examining how DUPLEX was built, and who it did and didn't include.

Dr. Campbell introduces the Phase 3 DUPLEX trial, the pivotal, multicenter, international, double-blind study that compared sparsentan to irbesartan one-to-one. Enrollment required biopsy or genetic confirmation of FSGS, proteinuria above 1.5 grams, and a GFR of at least 30 mL/min, while patients with FSGS traceable to another disease or drug, or those recently treated with rituximab or cyclophosphamide, were excluded. Baseline characteristics were well balanced, with median UPCR near 3.0 to 3.1 grams in both arms. The originally designed primary endpoint was eGFR slope at week 108, alongside a pre-specified interim surrogate at week 36 built around FSGS partial remission, and a secondary endpoint measuring GFR change through week 112.

Dr. Trachtman explains why secondary FSGS was excluded: when the trial was designed around 2018, the field viewed secondary FSGS as less threatening and more manageable by treating its underlying cause. He notes nephrologists are now rethinking that assumption, since secondary FSGS often proves less responsive to treating the underlying disorder than once assumed. Dr. Campbell adds that the partial remission threshold, a 40% proteinuria reduction to below 1.5 grams, drew on pooled data from FSGS trials and the NEPTUNE cohort, and that 42% of sparsentan patients hit that mark at week 36 versus 26% on irbesartan. Dr. Trachtman also flags a design weakness visible in retrospect: eGFR slope varies far more in glomerular disease than in diabetic nephropathy, making it a shakier primary outcome than trial designers realized at the time it was chosen. Asked whether he would use sparsentan in patients with less than 1.5 grams of proteinuria, Dr. Trachtman says yes, citing a reassuring safety profile across nearly 1,000 patients followed for three to five years between the IgA nephropathy program and the earlier DUET Phase 2 study he helped conduct.

In "DUPLEX Efficacy Results: Proteinuria Remission Beyond the Primary Endpoint," the panel will unpack what the trial's efficacy data actually showed, including a primary endpoint that missed its mark.