Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis

Abstract

Introduction: Focal segmental glomerulosclerosis (FSGS), a histologic lesion in the kidney caused by varied pathophysiological processes, leads to end-stage kidney disease in a large proportion of patients. Sparsentan is a first-in-class orally active compound combining endothelin type A (ET_A) receptor blockade with angiotensin II type 1 (AT₁) receptor antagonism in a single molecule. A Randomized, Multicenter, Double-Blind, Parallel, Active-Control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS (DUPLEX) study evaluates the long-term antiproteinuric efficacy, nephroprotective potential, and safety profile of sparsentan compared with an AT₁ receptor blocker alone in patients with FSGS.

Methods: DUPLEX is a multicenter, international, phase 3, randomized, double-blind, active-controlled study of sparsentan in patients with FSGS. Approximately 300 patients aged 8 to 75 years, inclusive (United States), and 18 to 75 years, inclusive (outside United States) will be randomized 1:1 to daily treatment with sparsentan or irbesartan. After renin-angiotensin-aldosterone system inhibitor washout, treatment will be administered for 108 weeks, with the final assessment at week 112, four weeks after withdrawal of study drug.

Results: The primary endpoint will be the slope of estimated glomerular filtration rate from week 6 to week 108. A novel surrogate efficacy endpoint, the proportion of patients achieving urinary protein-to-creatinine (UP/C) ratio of ≤1.5 g/g and >40% reduction from baseline in UP/C (FSGS partial remission endpoint: FPRE), will be evaluated at a planned interim analysis at week 36. Safety and tolerability of sparsentan will also be assessed.

Conclusion: The phase 3 DUPLEX study will characterize the long-term antiproteinuric efficacy and nephroprotective potential of dual ET_A and AT₁ receptor blockade with sparsentan in patients with FSGS.

Keywords: angiotensin II type 1 receptor blockade; endothelin type A receptor blockade; focal segmental glomerulosclerosis; irbesartan; proteinuria; sparsentan.

Figure 1

A Randomized, Multicenter, Double-Blind, Parallel, Active-Control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS study design. ^aFor patients who are undergoing washout from renin-angiotensin-aldosterone system inhibitor (RAASI). ^bPatients whose body weight is ≤50 kg at screening will receive half the otherwise specified doses of sparsentan or irbesartan (active control). Weight will be measured at each visit and the dose increased at the investigator’s discretion if the patient’s weight reaches >50 kg. ^cDay 1 events shown will occur in the order in which they are listed. ^dRandomization will be stratified by estimated glomerular filtration rate (eGFR) value (≥30 to <60 ml/min per 1.73 m² and ≥60 ml/min per 1.73 m² for all patients) and urinary protein-to-creatinine ratio (UP/C) (≤3.5 g/g and >3.5 g/g [patients ≥18 yr of age] or ≤2 g/g and >2 g/g [patients <18 yr of age]) at screening. ^eFollowing the 108-week blinded treatment period, treatment with study medication will be discontinued. At this time, the investigator should resume standard-of-care treatment, including treatment with RAASI (with the exception of irbesartan) provided there are no contraindications for their use. The investigator may make additional adjustments in antihypertensive medications as clinically indicated to adequately control the patient’s blood pressure. AEs, adverse events; ECG, electrocardiogram; PRO, patient-reported outcome; QOL, quality of life.