Randomized, Double-Blind, Safety and Efficacy Study of RE-021 (Sparsentan) in Focal Segmental Glomerulosclerosis
Condition: Focal Segmental Glomerulosclerosis
MeSH terms: Glomerulosclerosis, Focal Segmental
Intervention: RE-021 (Sparsentan); Irbesartan
Intervention description: Oral, once-daily; Oral, once-daily
Intervention MeSH terms: Irbesartan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 109.0
Sex: All
Minimum age: 8 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Primary FSGS; Nephrotic syndrome; Steroid Resistant

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).
    

Eligibility 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 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.