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

Journal article
Published on March 4, 2017

Topics: Nephrology FSGS Sparsentan Phase 2 DUET

Contributors:
Komers R, Gipson DS, Nelson P et al.
Name of Journal:
Kidney International Reports


View Publication
DOI:
10.1016/j.ekir.2017.02.019
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Home » Publications » DUET Trial: Study Design

Summary

The DUET trial was designed to compare the efficacy and safety of sparsentan versus irbesartan in focal segmental glomerulosclerosis (FSGS)1

Background

Primary focal segmental glomerulosclerosis (FSGS) is the leading glomerular disease that contributes to end-stage kidney disease (ESKD).2 Treatment for FSGS aims to reduce proteinuria, a predictor of kidney survival.3

First-line therapies include renin-angiotensin system inhibitors (RASi), such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), combined with steroids or, in second-line, calcineurin inhibitors (CNI).1,3 However, there are no established alternatives for FSGS resistant to CNI.1 These patients are at higher risk of progression to ESKD.4 Further treatment options are therefore being investigated.5

Preclinical mechanistic studies indicate that endothelin type A receptor (ETAR) blockade may specifically target the pathology of FSGS.6,7 Sparsentan is therefore of interest as a first-in-class, dual endothelin and angiotensin receptor antagonist for patients with FSGS.1


Aim

DUET was designed to evaluate sparsentan versus irbesartan in FSGS for lowering proteinuria and to determine the safety profile of sparsentan.1


Approach

Study overview and eligibility criteria

DUET was a Phase 2, randomized, double-blind, active-control, dose-escalation trial evaluating sparsentan versus irbesartan in FSGS.1 Key inclusion criteria included1:

  • Age 8-75 years (in the US) and 18-75 years (in Europe)
  • Biopsy-proven FSGS or a disease-causing FSGS-associated genetic mutation
  • Urine protein-creatinine ratio (UPCR) ≥1.0 g/g
  • Estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2

Study design

During the double-blind period, patients were assigned to one of four treatment arms for 8 weeks1:

  • Sparsentan 200 mg/day
  • Sparsentan 400 mg/day
  • Sparsentan 800 mg/day
  • Irbesartan 300 mg/day

After Week 8, patients were eligible to receive sparsentan as part of the 144-week open-label period.1

Endpoints

The primary endpoint measured change in UPCR from baseline to Week 8.1 The secondary endpoint was proportion of patients achieving UPCR ≤1.5 g/g and >40% UPCR reduction from baseline to Week 8.1

Tertiary endpoints included1:

  • Clinical and laboratory parameters i.e. 24-hour urinary protein excretion, serum albumin and creatinine concentration, eGFR, blood pressure, and lipid profile
  • Quality of life using the 36-Item Short Form Health Survey questionnaire or Pediatric Quality of Life Inventory

Efficacy endpoints at Week 144 included1:

  • Changes from Week 8 in UPCR, serum albumin and creatinine concentration, eGFR, blood pressure, and lipid profile
  • The proportion of patients achieving UPCR ≤1.5 g/g and >40% UPCR reduction

Safety and tolerability of sparsentan was assessed by double-blind monitoring of several safety endpoints including physical parameters, clinical laboratory tests, and adverse events (AE).1

Read more about the DUET efficacy and safety findings.

Read more about the DUET efficacy and safety findings from the post hoc analysis.

Additional assessments

DUET explored the pharmacokinetic (PK) profiles of sparsentan and irbesartan.1 The protocol allowed for collection of biomarker data to further the mechanistic understanding of FSGS.1


Key takeaway

The protocol for the Phase 2 DUET trial was designed to evaluate dose-dependent efficacy and safety of sparsentan over an 8-week double-blind period against irbesartan and until Week 144 in an open-label period.1 The primary and secondary endpoints assessed change in proteinuria and those who achieved proteinuria ≤1.5 g/g, respectively.1




Related Content

Publication FSGS

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS

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Publication FSGS

Sparsentan versus Irbesartan in Focal Segmental Glomerulosclerosis

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Footnotes

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

ACEi, angiotensin-converting enzyme inhibitor; AE, adverse event; ARB, angiotensin receptor blocker; CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ETAR, endothelin type A receptor; FSGS, focal segmental glomerulosclerosis; PK, pharmacokinetics; RASi, renin-angiotensin system inhibitor; UPCR, urine protein-creatinine ratio; US, United States.

  1. Komers R et al. Kidney Int Rep. 2017;2(4):654-664.
  2. Spino C et al. Front Pediatr. 2016;4:25.
  3. KDIGO Glomerulonephritis Work Group. Kidney Int. 2012;Suppl 2:135.
  4. Kitiyakara C et al. Am J Kid Dis. 2004;44(5):815-825.
  5. Pullen N and Fornoni A. Kidney Int. 2016;89:1211-1220.
  6. Buelli S et al. J Am Soc Nephrol. 2014;25:523-533.
  7. Daehn I et al. J Clin Invest. 2014;124:1608-1621.

MA-SP-24-0121 | October 2024