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

Journal article
Published on January 8, 2020

Topics: Nephrology FSGS Sparsentan Phase 3 DUPLEX

Contributors:
Komers R, Diva U, Inrig JK et al.
Name of Journal:
Kidney International Reports


View Publication
DOI:
10.1016/j.ekir.2019.12.017
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Home » Publications » DUPLEX Study Design

Summary

The DUPLEX study evaluated estimated glomerular filtration rate (eGFR) and FSGS partial remission endpoint (FPRE) in sparsentan versus irbesartan in focal segmental glomerulosclerosis (FSGS)1

Background

Focal segmental glomerulosclerosis (FSGS) can be classified as a primary, genetic, or secondary disorder:

  • Primary FSGS: Has no identifiable cause but may be due to circulating permeability factors2
  • Genetic FSGS: May include mutations in genes encoding proteins required for normal podocyte structure and/or function2,3
  • Secondary FSGS: May be caused by loss of renal mass, metabolic dysfunction, pre-existing diseases, infections, or drugs2

At least 50% of US patients with primary FSGS and nephrotic range proteinuria are resistant to treatment and will require renal replacement therapy in 5 to 10 years after diagnosis.1,4

Although patients with responsive FSGS do have treatment options, the current treatment landscape is associated with serious side effects, highlighting the need for effective, safe, and well-tolerated treatments for FSGS.1,5

Sparsentan is a first-in-class dual endothelin-angiotensin receptor antagonist.6 When compared to irbesartan in the DUET study, sparsentan demonstrated a greater proteinuria reduction at 8 weeks and a similar safety profile.7


Aim

The DUPLEX study aimed to evaluate the long-term efficacy and safety of sparsentan versus irbesartan in FSGS.1 This manuscript aims to describe the study design of DUPLEX.1

Read more about the 2-year data from DUPLEX .


Approach

Study overview and eligibility criteria

DUPLEX was a Phase 3, multicenter, double-blind, randomized trial that assessed sparsentan versus irbesartan in FSGS without known secondary causes.1 Key inclusion criteria included1:

  • Patients aged 8 to 75 years in the US and patients aged 18 to 75 outside the US
  • Biopsy-confirmed FSGS or documentation of a genetic mutation in a podocyte protein associated with FSGS
  • Urine protein-creatinine ratio (UPCR) of ≥1.5 g/g
  • Estimated glomerular filtration rate (eGFR) ≥30 mL/min per 1.73 m2

Study design

After successful screening, patients underwent a 2-week washout period from renin-angiotensin system inhibitors (RASi).1 Patients were randomly assigned 1:1 to 800 mg of sparsentan or 300 mg of irbesartan.1 The double-blind treatment period consisted of 108 weeks after which there was a 4-week no medication period.1

Study visits occurred at Weeks 4, 6, 8, 12, and then every 12 weeks.1

Endpoints

The primary efficacy endpoint was the slope of eGFR measured from Week 6 to Week 108.1

The surrogate efficacy endpoint was the proportion of patients at Week 36 that achieved a UPCR ≤1.5 g/g and a >40% reduction from baseline.1 The proteinuric outcome for the DUPLEX study was FSGS partial remission endpoint (FPRE).8

Secondary efficacy endpoints were a percent change in eGFR from1:

  • Week 6 to Week 108
  • Baseline to 4 weeks post-cessation of randomized treatment at Week 112

Safety and tolerability of sparsentan was assessed by double-blind monitoring of several safety endpoints.1

Read more about the 2-year data from DUPLEX.


Key takeaway

DUPLEX was a Phase 3, multicenter, double-blind, randomized trial that assessed sparsentan versus irbesartan in FSGS.1 The primary and secondary endpoints evaluated eGFR at different intervals.1 FPRE was the chosen surrogate efficacy endpoint.1





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Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis

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Focal Segmental Glomerulosclerosis Patient Baseline Characteristics in the Sparsentan Phase 3 DUPLEX Study

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Footnotes

As of September 2024, sparsentan is not FDA-approved for the treatment of FSGS.

eGFR, estimated glomerular filtration rate; FPRE, FSGS partial remission endpoint; FSGS, focal segmental glomerulosclerosis; RASi, renin-angiotensin system inhibitor; UPCR, urine protein-creatinine ratio.

  1. Komers R et al. Kidney Int Rep. 2020;5(4):494-502.
  2. D’Agati VD et al. N Engl J Med. 2011;365:2398-2411.
  3. Sadowski CE et al. J Am Soc Nephrol. 2015;26:1279-1289.
  4. Korbet SM. J Am Soc Nephrol. 2012;23:1769-1776.
  5. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100:S1-S276.
  6. Komers R and Plotkin H. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877-884.
  7. Trachtman H et al. J Am Soc Nephrol. 2018;29(11):2745-2754.
  8. Troost JP et al. Clin J Am Soc Nephrol. 2018;13:414-421.

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