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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2015 by Retrophin, Inc.
Sponsor:
Information provided by (Responsible Party):
Retrophin, Inc.
ClinicalTrials.gov Identifier:
NCT01613118
First received: June 4, 2012
Last updated: February 18, 2015
Last verified: February 2015
  Purpose

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).


Condition Intervention Phase
Focal Segmental Glomerulosclerosis
Drug: RE-021 (Sparsentan)
Drug: Irbesartan
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Retrophin, Inc.:

Primary Outcome Measures:
  • Evaluate change in urine protein/creatinine (Up/C). [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    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.


Other Outcome Measures:
  • Characterize serum PK of RE-021 (Sparsentan) over the range of doses administered to FSGS patients [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    Evaluate the exposure or dose versus response relationship of primary and secondary PD/Biomarker endpoints.


Estimated Enrollment: 100
Study Start Date: December 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 the RE-021 (Sparsentan) dose for the 8 week duration.

Drug: RE-021 (Sparsentan)
Oral, once-daily
Other Name: 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 the RE-021 (Sparsentan) dose for the 8 week duration.

Drug: RE-021 (Sparsentan)
Oral, once-daily
Other Name: 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.

Drug: RE-021 (Sparsentan)
Oral, once-daily
Other Name: 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.

Drug: Irbesartan
Oral, once-daily
Other Name: Avapro

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).

  Eligibility

Ages Eligible for Study:   8 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 and <140/90 in adults. Mean seated BP for children should be >90/60 and <95th percentile for age, gender, and height.
  5. Patients who are on immunosuppressive medications (except for Rituximab or cyclophosphamide) at the time of screening are eligible for the study. However, the doses of the medications must be stable for at least 1 month- prior to randomization and cannot be changed during the 8 Week treatment period. Patients on Rituximab or cyclophosphamide will be eligible provided they have not been taking these medications in the prior 3 months from screening.
  6. US Sites: Males or females 8 to 65 years of age able to provide written informed consent and/or assent at the time of consenting, with informed consent signed by patient or legal guardian.
  7. EU Sites: Males or females 18 to 65 years of age able to provide written informed consent at the time of consenting, 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.
  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. Subjects 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 the screening.
  6. Patients with clinically significant cardiac conduction defects, including second or third degree atrioventricular (AV) 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 (ALT) and/or aspartate aminotransferase (AST) >2 times the upper limit of normal (ULN) at Screening.
  8. Patients positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) positive.
  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. K+ >5.5.
  13. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥200 pg/mL (57.8 pmol/L) in adults.
  14. Adult Patients with body mass index (BMI) >40. Pediatrics 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 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. Female patients of child-bearing potential, defined as all women physiologically capable of becoming pregnant who are unwilling or unable to use two acceptable methods of contraception, with at least one being a barrier method, in order to avoid pregnancy for the entire study period and for 90 days post study participation. Female patients of child-bearing potential must have a negative serum pregnancy test.
  20. Male patient and female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control (one of which must be a barrier method) to avoid pregnancy for the entire study period and for 90 days post study participation.
  21. Patients who have participated in another investigational drug study within 28 days prior to signing the informed consent form, or who will participate in another drug study during the course of this study.
  22. Prior exposure to Sparsentan, dual acting receptor antagonist (DARA), or PS433540.
  23. Patients who are unable to comply with the study procedures and assessments, including the ability swallow the study drug or control capsules.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01613118

Contacts
Contact: Radko Komers, M.D. 1-617-500-7992 radko.komers@retrophin.com
Contact: Howard Trachtman, M.D. 646-501-2663 howard.trachtman@nyumc.org

  Show 27 Study Locations
Sponsors and Collaborators
Retrophin, Inc.
Investigators
Principal Investigator: Howard Trachtman, M.D. NYU School of Medicine
  More Information

No publications provided

Responsible Party: Retrophin, Inc.
ClinicalTrials.gov Identifier: NCT01613118     History of Changes
Other Study ID Numbers: RET-D-001
Study First Received: June 4, 2012
Last Updated: February 18, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Retrophin, Inc.:
Primary FSGS
Nephrotic syndrome
Steroid Resistant

Additional relevant MeSH terms:
Glomerulosclerosis, Focal Segmental
Glomerulonephritis
Kidney Diseases
Nephritis
Urologic Diseases
Irbesartan
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Antihypertensive Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on February 27, 2015