Efficacy and Safety of Sparsentan Compared With Irbesartan in Patients With Primary Focal Segmental Glomerulosclerosis: Randomized, Controlled Trial Design (DUET).

Primary focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease. There are no US Food and Drug Administration-approved therapies for FSGS, and treatment often fails to reduce proteinuria. Endothelin is an important factor in the pathophysiology of podocyte disorders, including FSGS. Sparsentan is a first-in-class, orally active, dual-acting angiotensin receptor blocker (ARB) and highly selective endothelin Type A receptor antagonist. This study is designed to evaluate whether sparsentan lowers proteinuria compared with an ARB alone and has a favorable safety profile in patients with FSGS. DUET is a phase 2, randomized, active-control, dose-escalation study with an 8-week, fixed-dose, double-blind period followed by 136 weeks of open-label sparsentan treatment. Patients aged 8 to 75 years with primary FSGS will be randomized to treatment with sparsentan or irbesartan for 8 weeks. The primary efficacy objective is to test the hypothesis that sparsentan over the dose range (200 mg, 400 mg, or 800 mg daily) is superior to irbesartan (300 mg daily) in decreasing the urinary protein-to-creatinine ratio (UPC) from baseline to 8 weeks postrandomization. As secondary objectives, the trial will evaluate the proportion of patients who achieve prespecified targets of UPC reduction, changes in laboratory and quality-of-life indices, and detailed safety analysis. Analyses will be conducted at the end of the double-blind (week 8) and open-label (week 144) periods. This study will provide important evidence on whether dual ARB and endothelin blockade may be an effective therapeutic strategy for FSGS and may provide the rationale for next-phase trials.