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

NCT ID: NCT01613118

Last Updated: 2025-05-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 109 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-03-31
• Study Completion Date: 2024-03-25

Brief Summary

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).

Detailed Description

Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disorder which results in frank proteinuria and in some patients 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 angiotensin receptor blockers (ARB) and angiotensin converting inhibitors (ACEI) to lower proteinuria with steroids, calcineurin inhibitors, and other immunosuppressive agents reserved for patients with severe proteinuria and in particular with nephrotic syndrome. Despite these therapies, many patients have nephrotic range proteinuria and new therapeutic agents are needed. Endothelin receptor antagonists (ERA) have been shown to lower proteinuria in clinical trials of diabetic nephropathy and have been speculated to be effective in FSGS.

Conditions

Focal Segmental Glomerulosclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

RE-021 (Sparsentan) 200 mg - Double-Blind Period

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.

Group Type: EXPERIMENTAL

RE-021 (Sparsentan)

Intervention Type: DRUG

Oral, once-daily

RE-021 (Sparsentan) 400 mg - Double-Blind Period

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.

Group Type: EXPERIMENTAL

RE-021 (Sparsentan)

Intervention Type: DRUG

Oral, once-daily

RE-021 (Sparsentan) 800 mg - Double-Blind Period

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.

Group Type: EXPERIMENTAL

RE-021 (Sparsentan)

Intervention Type: DRUG

Oral, once-daily

Irbesartan 300 mg - Double-Blind Period

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.

Group Type: ACTIVE_COMPARATOR

Irbesartan

Intervention Type: DRUG

Oral, once-daily

RE-021 (Sparsentan) - Open-Label Extension Period

Includes all subjects who completed the Double-Blind period and enrolled in the Open-Label Extension period of the study.

All subjects who completed the Double-Blind period were evaluated for response and safety at the Week 8 visit to determine eligibility for continued treatment on their assigned doses in an Open-Label Extension period for up to 496 additional weeks. Subjects treated with irbesartan during the Double-Blind period were offered sparsentan treatment at the dose they would have received according to the Double-Blind dose cohort in which they were enrolled.

Group Type: EXPERIMENTAL

RE-021 (Sparsentan)

Intervention Type: DRUG

Oral, once-daily

Interventions

RE-021 (Sparsentan)

Oral, once-daily

Intervention Type: DRUG

Irbesartan

Oral, once-daily

Intervention Type: DRUG

Other Intervention Names

Sparsentan; Avapro

Eligibility Criteria

Inclusion Criteria

1. Biopsy-proven FSGS 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.

• Minimum Eligible Age: 8 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Travere Therapeutics, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Howard Trachtman, M.D.

Role: PRINCIPAL_INVESTIGATOR

NYU School of Medicine

Locations

Balboa Nephrology Medical Group

San Diego, California, United States

Los Angeles Biomedical Research Institute

Torrance, California, United States

Colorado Kidney Care

Denver, Colorado, United States

University of Miami Miller School of Medicine

Miami, Florida, United States

Miami Children's Hospital

Miami, Florida, United States

University of Iowa Children's Hospital

Iowa City, Iowa, United States

Renal and Transplant Associates of New England, PC

Springfield, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

The Children's Mercy Hospital

Kansas City, Missouri, United States

NYU Langone Medical Center

New York, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

SUNY Stony Brook Hospital

Stony Brook, New York, United States

UNC Kidney Center, Pediatrics

Chapel Hill, North Carolina, United States

University North Carolina (UNC) Kidney Center

Chapel Hill, North Carolina, United States

Akron Nephrology Associates

Akron, Ohio, United States

The Cleveland Clinic Foundation

Cleveland, Ohio, United States

Unversity of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Northeast Clinical Research Center

Bethlehem, Pennsylvania, United States

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Temple University School of Medicine

Philadelphia, Pennsylvania, United States

University of Pennsylvania, Perelman School of Medicine

Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Clinical Advancement Center

San Antonio, Texas, United States

Southern Utah Kidney and Hypertension Center

St. George, Utah, United States

University of Washington

Seattle, Washington, United States

Catholic Health Initiatives Franciscan

Tacoma, Washington, United States

Marshfield Clinic Research Foundation

Marshfield, Wisconsin, United States

General Teaching Hospital Prague

Prague, , Czechia

Azienda Ospedaliero Universitaria Policlinico di Bari

Bari, , Italy

Azienda Ospedaliero Universitaria Careggi

Florence, , Italy

IRCCS Istituti Clinici Maugeri

Pavia, , Italy

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Rome, , Italy

Countries

United States; Czechia; Italy

References

D'Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011 Dec 22;365(25):2398-411. doi: 10.1056/NEJMra1106556. No abstract available.

Reference Type: BACKGROUND

PMID: 22187987 (View on PubMed)

Campbell KN, Gesualdo L, Murphy E, Rheault MN, Srivastava T, Tesar V, Komers R, Trachtman H. Sparsentan for Focal Segmental Glomerulosclerosis in the DUET Open-Label Extension: Long-term Efficacy and Safety. Kidney Med. 2024 Apr 26;6(6):100833. doi: 10.1016/j.xkme.2024.100833. eCollection 2024 Jun.

Reference Type: RESULT

PMID: 38831932 (View on PubMed)

Trachtman H, Nelson P, Adler S, Campbell KN, Chaudhuri A, Derebail VK, Gambaro G, Gesualdo L, Gipson DS, Hogan J, Lieberman K, Marder B, Meyers KE, Mustafa E, Radhakrishnan J, Srivastava T, Stepanians M, Tesar V, Zhdanova O, Komers R; DUET Study Group. DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS. J Am Soc Nephrol. 2018 Nov;29(11):2745-2754. doi: 10.1681/ASN.2018010091.

Reference Type: RESULT

PMID: 30361325 (View on PubMed)

Liu ID, Willis NS, Craig JC, Hodson EM. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev. 2025 May 8;5(5):CD003594. doi: 10.1002/14651858.CD003594.pub7.

Reference Type: DERIVED

PMID: 40337980 (View on PubMed)

Omachi K, O'Carroll C, Miner JH. PPAR delta Agonism Ameliorates Renal Fibrosis in an Alport Syndrome Mouse Model. Kidney360. 2023 Mar 1;4(3):341-348. doi: 10.34067/KID.0006662022.

Reference Type: DERIVED

PMID: 36657027 (View on PubMed)

Hodson EM, Sinha A, Cooper TE. Interventions for focal segmental glomerulosclerosis in adults. Cochrane Database Syst Rev. 2022 Feb 28;2(2):CD003233. doi: 10.1002/14651858.CD003233.pub3.

Reference Type: DERIVED

PMID: 35224732 (View on PubMed)

Other Identifiers

RET-D-001

Identifier Type: -

Identifier Source: org_study_id

NCT01622738

Identifier Type: -

Identifier Source: nct_alias