Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis (DUET)

November 30, 2023 updated by: Travere Therapeutics, Inc.

Efficacy and Safety of RE-021, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients With Focal Segmental Glomerulosclerosis (FSGS): a Randomized, Double-Blind, Active-Control, Dose-Escalation Study

This study will investigate whether RE-021 (Sparsentan), a selective dual-acting receptor antagonist with affinity for endothelin (A type) and angiotensin II receptors (Type 1), is safe and effective in treating patients with focal segmental glomerulosclerosis (FSGS).

Study Overview

Status

Active, not recruiting

Detailed Description

Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disorder which results in frank proteinuria and progression to end-stage kidney disease (ESKD) over 5-10 years. Proteinuria reduction is widely regarded to be beneficial, and is considered the primary goal of treatment in FSGS and slowing its progressive course (D'Agati, et. al, 2011). Patients are currently treated with steroids, calcineurin inhibitors, angiotensin receptor blockers (ARB) and angiotensin converting inhibitors (ACE) to lower proteinuria (Cameron, 2003). Despite these therapies, many patients have nephrotic range proteinuria and new therapeutic agents are needed (Kiffel, et. al, 2011). Endothelin receptor antagonists (ERA) have been shown to lower proteinuria in clinical trials of diabetic nephropathy (Kohan, et. al, 2011) (Mann, et. al 2010) and have been speculated to be effective in FSGS (Barton, 2010).

Study Type

Interventional

Enrollment (Actual)

109

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Prague, Czechia
        • General Teaching Hospital Prague
      • Bari, Italy, 70124
        • Azienda Ospedaliero Universitaria Policlinico di Bari
      • Firenze, Italy, 50134
        • Azienda Ospedaliero Universitaria Careggi
      • Pavia, Italy, 27100
        • IRCCS Istituti Clinici Maugeri
      • Rome, Italy, 00168
        • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
    • California
      • San Diego, California, United States, 92123
        • Balboa Nephrology Medical Group
      • Torrance, California, United States, 90502
        • Los Angeles Biomedical Research Institute
    • Colorado
      • Denver, Colorado, United States, 80230
        • Colorado Kidney Care
    • Florida
      • Miami, Florida, United States, 33136
        • University of Miami Miller School of Medicine
      • Miami, Florida, United States, 33155
        • Miami Children's Hospital
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa Children's Hospital
    • Massachusetts
      • Springfield, Massachusetts, United States, 01107
        • Renal and Transplant Associates of New England, PC
    • Minnesota
      • Minneapolis, Minnesota, United States, 55454
        • University of Minnesota
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • The Children's Mercy Hospital
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center
      • New York, New York, United States, 10029
        • Icahn School of Medicine at Mount Sinai
      • New York, New York, United States, 10016
        • NYU Langone Medical Center
      • Stony Brook, New York, United States, 11794-8111
        • SUNY Stony Brook Hospital
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • UNC Kidney Center, Pediatrics
      • Chapel Hill, North Carolina, United States, 27599
        • University North Carolina (UNC) Kidney Center
    • Ohio
      • Akron, Ohio, United States, 44302
        • Akron Nephrology Associates
      • Cleveland, Ohio, United States, 44195
        • The Cleveland Clinic Foundation
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Unversity of Oklahoma Health Sciences Center
    • Pennsylvania
      • Bethlehem, Pennsylvania, United States, 18017
        • Northeast Clinical Research Center
      • Philadelphia, Pennsylvania, United States, 19104
        • The Children's Hospital of Philadelphia
      • Philadelphia, Pennsylvania, United States, 19140
        • Temple University School of Medicine
      • Philadelphia, Pennsylvania, United States, 19140
        • University of Pennsylvania, Perelman School of Medicine
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University Medical Center
    • Texas
      • San Antonio, Texas, United States, 78215
        • Clinical Advancement Center
    • Utah
      • Saint George, Utah, United States, 84790
        • Southern Utah Kidney and Hypertension Center
    • Washington
      • Seattle, Washington, United States, 98195
        • University of Washington
      • Tacoma, Washington, United States, 98405
        • Catholic Health Initiatives Franciscan
    • Wisconsin
      • Marshfield, Wisconsin, United States, 54449
        • Marshfield Clinic Research Foundation

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years to 73 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

  1. Biopsy-proven primary FSGS (Primary FSGS confirmed by renal biopsy report) OR documentation of a genetic mutation in a podocyte protein associated with the disease.
  2. Urine protein/creatinine ratio (Up/C) at or above 1.0 g/g.
  3. Estimated glomerular filtration rate (eGFR) >30.
  4. Mean seated blood pressure (BP) >100/60 mmHg and <145/95 in patients >/= 18 years of age. Mean seated BP for patients <18 years of age should be >90/60 mmHg and <95th percentile for age, gender, and height.
  5. If a patient is taking immunosuppressive medications (except for Rituximab or cyclophosphamide), the dose and/or levels must be stable for 1 month prior to randomization and the Investigator should not have plans to alter the regimen during the first 8 weeks of treatment, except to stabilize levels. Patients on Rituximab or cyclophosphamide will be eligible provided they have not been taking these medications for 3 months prior to randomization.
  6. US Sites: Males or females 8 to 75 years of age willing and able to provide written informed consent and/or assent, with informed consent signed by patient or parent/legal guardian.
  7. EU Sites: Males or females 18 to 75 years of age willing and able to provide written informed consent, with informed consent, signed by patient or legal guardian.

Exclusion Criteria

  1. Patients with FSGS secondary to another condition.
  2. Patients with history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (HBA1c>8%), or non-fasting blood glucose >180 mg/dL at screening.
  3. Patients who have had any organ transplant.
  4. Patients with a requirement for any of the medications indicated on the list of Excluded Medications, with the exception of ACE and ARBs.
  5. Patients with a documented history of heart failure (NYHA Class II-IV), and / or previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites and peripheral edema. Patients with clinically significant cerebrovascular disease (transient ischemic attack or stroke) and/or coronary artery disease (hospitalization for myocardial infarction or unstable angina, new onset of angina with positive functional tests or coronary angiogram revealing stenosis, coronary revascularization procedure) within 6 months before screening.
  6. Patients with clinically significant cardiac conduction defects, including second or third degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation, atrial flutter, an accessory bypass tract, or any arrhythmia requiring medication.
  7. Patients with jaundice, hepatitis, or known hepatobiliary disease (includes asymptomatic cholelithiasis); alanine aminotransferase and/or aspartate aminotransferase >2 times the upper limit of normal at Screening.
  8. Patients positive for human immunodeficiency virus (HIV), and markers indicating acute (positivity of at least one of the following: Hepatitis B surface antigen [HBsAg], Hepatitis B "e" antigen [HBeAg], Hepatitis B virus [HBV] DNA in blood or liver, Immunoglobulin M Hepatitis B core antibody) or chronic (HBsAg and/or HBeAg and/or Hepatitis B virus [HBV] DNA positivity) HBV infection, or hepatitis C virus (HCV) infection (reactive anti-HCV antibody and/or HCV RNA). Testing at screening is only required for patients >/= 18 years of age.
  9. History of malignancy other than adequately treated basal cell or squamous cell skin cancer within the past 5 years.
  10. Patients with hemodynamically significant valvular disease.
  11. Hematocrit (HCT) <27 or hemoglobin (Hgb) <9.
  12. Potassium >5.5 mEq/L.
  13. Patients >18 years of age with Estimated Glomerular Filtration Rate (eGFR) ≥60 ml mL/min who have N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥200 pg/mL (57.8 pmol/L). For patients >18 years of age with eGFR <60 mL/min, the following parameters requiring echocardiography (ECHO) at screening should be used for exclusion:

    1. NT-proBNP ≥300 pg/mL in patients >18 years of age with eGFR 45 59.9 mL/min
    2. NT-proBNP = 200-299 pg/mL in patients >18 years of age with eGFR 45 59.9 mL/min, and abnormal ejection fraction (EF <55) and/or diastolic dysfunction on ECHO
    3. NT-proBNP ≥400 pg/mL in patients >18 years of age with eGFR 30.0 44.9 mL/min
    4. NT-proBNP = 200-399 pg/mL in patients >18 years of age with eGFR 30.0 44.9 mL/min, and abnormal ejection fraction (EF <55) and/or diastolic dysfunction on ECHO.
  14. Patients >/= 18 years of age with body mass index (BMI) >40. Patients <18 years of age with a BMI in the 99% percentile plus 5 units.
  15. Patients who have abnormal clinical laboratory values at Screening, which are designated by the Principal Investigator as clinically significant.
  16. Patients with a history of drug or alcohol abuse within the past two years.
  17. Patients with a history of an allergic response to any angiotensin II antagonist or endothelin receptor antagonist.
  18. Women who are pregnant or breastfeeding.
  19. Women of child-bearing potential (WOCBP) who are unwilling or unable to use two reliable methods of contraception, with at least one being highly reliable (e.g. oral, implanted or injected contraceptive hormones or an intrauterine device) and one being a barrier method, in order to avoid pregnancy for the entire study period and for 90 days post study participation. WOCBP, defined as all women physiologically capable of becoming pregnant, includes any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral ovariectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months and for women on hormone replacement therapy, only with documented plasma follicle stimulating hormone level greater than 35 mIU/mL). Women using oral, implanted or injected contraceptive hormones, an intrauterine device, barrier methods (diaphragm, condoms, spermicidal) to prevent pregnancy, practicing abstinence or where the partner is sterile (e.g. vasectomy) As well as postmenopausal women who have fertilized eggs implanted are also considered WOCBP.
  20. Patients who have participated in another investigational drug study within 28 days prior to screening, or who will participate in another drug study during the course of this study.
  21. Prior exposure to Sparsentan, dual acting receptor antagonist (DARA), or PS433540.
  22. Patients who are unable to comply with the study procedures and assessments, including the ability swallow the study drug or control capsules.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: RE-021 (Sparsentan) 200 mg

RE-021 (Sparsentan) will be administered as a single oral morning dose. In this ARM the RE-021 (Sparsentan) dose will be 200mg.

Patients at </= 50kg will receive half of the RE-021 (Sparsentan) dose for the 8 week duration.

Oral, once-daily
Other Names:
  • Sparsentan
Experimental: RE-021 (Sparsentan) 400 mg

RE-021 (Sparsentan) will be administered as a single oral morning dose. In this ARM the RE-021 (Sparsentan) dose will be 400mg.

Patients at </= 50kg will receive half of the RE-021 (Sparsentan) dose for the 8 week duration.

Oral, once-daily
Other Names:
  • Sparsentan
Experimental: RE-021 (Sparsentan) 800 mg

RE-021 (Sparsentan) will be administered as a single oral morning dose. In this ARM the RE-021 (Sparsentan) dose will be 800mg.

Patients at </= 50kg will receive half of the RE-021 (Sparsentan) dose for the 8 week duration.

Oral, once-daily
Other Names:
  • Sparsentan
Active Comparator: Irbesartan 300 mg

The control will be administered irbesartan as a single oral dose of 150mg for the first week before escalating to 300mg for the remaining 7 weeks.

Patients at </= 50kg will receive 150mg irbesartan for the 8 week duration.

Oral, once-daily
Other Names:
  • Avapro

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Change in Urine Protein/Creatinine (Up/C)
Time Frame: 8 weeks
Primary efficacy objective is to determine the change in Up/C in FSGS patients receiving RE-021 (Sparsentan) over a range of dose levels compared to treatment with irbesartan as active control.
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Howard Trachtman, M.D., NYU School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2014

Primary Completion (Actual)

June 1, 2016

Study Completion (Estimated)

February 1, 2026

Study Registration Dates

First Submitted

June 4, 2012

First Submitted That Met QC Criteria

June 5, 2012

First Posted (Estimated)

June 6, 2012

Study Record Updates

Last Update Posted (Actual)

December 4, 2023

Last Update Submitted That Met QC Criteria

November 30, 2023

Last Verified

November 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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