Overview

To evaluate the safety, efficacy and tolerability of sparsentan oral suspension and tablets, and assess changes in proteinuria after once-daily dosing over 108 weeks.

Eligibility

Inclusion Criteria for All Subjects (All Three Populations):

        A subject must meet all of the following criteria to be eligible for participation in this
        study:
          -  The subject or parent/legal guardian (as appropriate) is willing and able to provide
             signed informed consent/assent, and where required, the subject is willing to provide
             assent before any screening procedures per local requirements.
          -  The subject has an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at
             screening.
          -  The subject has a mean seated blood pressure between the 5th and 95th percentile for
             sex and height.
        Inclusion Criteria for Population 1:
          -  The subject is male or female ≥1 year at screening and <18 years of age at Day 1
             (Baseline).
          -  The subject has a UP/C ≥1.5 g/g (170 mg/mmol) at screening AND one of the following:
          -  Kidney biopsy-proven FSGS or MCD histological patterns and clinical presentation
             consistent with primary FSGS or MCD and qualifying proteinuria at screening despite
             history or ongoing treatment with corticosteroids and/or other immunosuppressive
             disease-modifying agents.
          -  Documentation of a genetic mutation in a podocyte protein associated with FSGS or MCD.
             Subjects with a documented podocytic mutation do not require kidney biopsy.
          -  Kidney biopsy-proven FSGS histological pattern with medical history and clinical
             presentation consistent with maladaptive cause of the lesion.
        Note: The kidney biopsy may have been performed at any time in the past but must include
        light microscopy and electron microscopy characteristics and/or immunofluorescence findings
        consistent with FSGS or MCD.
        Inclusion Criteria for Population 2:
          -  The subject is male or female ≥2 years at screening and <18 years of age at Day 1
             (Baseline).
          -  The subject has UP/C ≥0.6 g/g (68 mg/mmol) at screening AND one of the following
             diagnoses:
          -  Kidney biopsy-confirmed IgAN, IgAV, or AS
          -  Diagnosis of AS by genetic testing (pathogenic X-linked Collagen, Type IV, Alpha-5
             (COL4A5) mutation OR autosomal-recessive mutations in both alleles of Collagen, Type
             IV, Alpha-3 (COL4A3) and/or Collagen, Type IV, Alpha-4 (COL4A4) OR autosomal-dominant
             COL4A3 and/or COL4A4 and digenic mutations [ie, simultaneous mutations in 2 of the
             COL4A3, COL4A4, and COL4A5 genes])
        Inclusion Criteria for Population 3:
          -  The subject is male or female ≥8 years at screening and <18 years of age at Day 1
             (Baseline).
          -  The subject has UP/C ≥1.0 g/g (113 mg/mmol) at screening AND has kidney
             biopsy-confirmed IgAN
          -  Subject weighs ≥40 kg
          -  The subject has been on ACEI and/or ARB therapy for at least 12 weeks prior to
             screening
        Exclusion Criteria for All Subjects (All Three Populations):
        A subject who meets any of the following will be excluded from this study:
          -  The subject weighs <7.3 kg at screening.
          -  The subject has FSGS or MCD histological pattern secondary to viral infections, drug
             toxicities, or malignancies.
          -  The subject has immunoglobulin A (IgA) glomerular deposits not in the context of
             primary IgAN or IgAV (ie, secondary to another condition; eg, systemic lupus
             erythematosus and liver cirrhosis).
          -  The subject has had an acute onset or presentation of glomerular disease or a
             diagnostic biopsy or a relapse of glomerular disease requiring new or different class
             of immunosuppressive treatment (including, but not limited to, systemic
             corticosteroids, calcineurin inhibitors and mycophenolate mofetil, abatacept,
             cyclophosphamide, rituximab, ofatumumab, and ocrelizumab) within 6 months before
             screening.
          -  Subjects taking chronic immunosuppressive medications (including systemic steroids)
             not on a stable dose for ≥1 month before screening.
          -  The subject requires any of the prohibited concomitant medications as defined in the
             study protocol.
          -  The subject has undergone any organ transplantation, with the exception of corneal
             transplants.
          -  The subject has a documented history of congenital or acquired heart failure (modified
             Ross heart failure classification for children Class II to Class IV) and/or previous
             hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal
             nocturnal dyspnea, ascites, and/or peripheral edema.
          -  The subject has hemodynamically significant cardiac valvular disease.
          -  The subject has clinically significant congenital vascular disease.
          -  The subject has jaundice, hepatitis, or known hepatobiliary disease, or alanine
             aminotransferase and/or aspartate aminotransferase >2 times the upper limit of the
             normal range at screening.
          -  The subject has a history of malignancy within the past 2 years.
          -  The subject has a screening hematocrit <27% (0.27 L/L) or a hemoglobin value <9 g/dL
             (90 g/L).
          -  The subject has a screening potassium value >5.5 milliequivalent (mEq)/L (5.5 mmol/L).
          -  The subject has any abnormal clinical laboratory screening values that are considered
             by the Investigator to be clinically significant.
          -  The subject has a history of allergic response to any angiotensin II antagonist or
             endothelin receptor antagonist, including sparsentan, or has a hypersensitivity to any
             of the excipients in the study medication.
          -  The female subject is pregnant, plans to become pregnant during the course of the
             study, or is breastfeeding.
          -  Female subjects of childbearing potential, beginning at menarche, who do not agree to
             use 1 highly reliable (ie, can achieve a failure rate of <1% per year) method of
             contraception from 7 days before the first dose of the study medication until 28 days
             after the last dose of study medication. Examples of highly reliable contraception
             methods include stable oral, implanted, transdermal, or injected contraceptive
             hormones associated with the inhibition of ovulation or an intrauterine device. One
             additional barrier method must also be used during vaginal sexual activity, such as a
             diaphragm, diaphragm with spermicide (preferred), or male partner's use of male condom
             or male condom with spermicide (preferred), from Day 1/Randomization until 28 days
             after the last dose of study medication. Female subjects of childbearing potential are
             defined as those who are fertile after menarche, unless permanently sterile; permanent
             sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral
             oophorectomy. All female subjects of childbearing potential must have a negative serum
             pregnancy test result at screening (Visit 1) and a negative urine pregnancy test
             result, with positive results confirmed by serum, at every study visit from Day 1
             (Visit 3) and after.
        Note: Before menarche, pregnancy testing and contraceptive use are not required. However,
        subjects and their parents/legal guardians must be advised that, immediately upon menarche,
        subjects will be required to begin pregnancy testing and initiate contraceptive use. This
        requirement cannot be waived.
          -  The subject has participated in a study of another study medication within 28 days
             before screening or plans to participate in such a study during the course of this
             study.
          -  The subject has had prior exposure to sparsentan.
          -  The subject or parent/legal guardian (as appropriate), in the opinion of the
             Investigator, are unable to adhere to the requirements of the study including but not
             limited to, a history of noncompliance and/or any other reason that causes the
             Investigator to believe the subject would not be a good candidate for the study.
          -  For Population 3 - the subject is unable to swallow the study medication tablets
             whole.