Study of Sparsentan Treatment in Pediatrics With Proteinuric Glomerular Diseases

Study Overview
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Brief Summary
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To evaluate the safety, efficacy and tolerability of sparsentan oral suspension and assess changes in proteinuria after once-daily dosing over the 108-week treatment period.

Detailed Description
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This is a multicenter, open-label, 112-week study of sparsentan in approximately 57 pediatric subjects aged ≥1 year to <18 years with selected proteinuric glomerular diseases, divided into 2 populations, defined as follows: Population 1: Subjects with selected proteinuric glomerular diseases associated with Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD) histological patterns Population 2: Subjects with kidney biopsy-confirmed immunoglobulin A nephropathy (IgAN), immunoglobulin A vasculitis (IgAV), or subjects with Alport syndrome (AS) The study will evaluate long-term safety, tolerability, and efficacy with pharmacokinetic evaluations at Day 1 (Baseline), Day 2 (Visit 4), and Week 12 (Visit 9). For each population, subjects will be enrolled in 3 cohorts based on age ranges. Study Enrollment: Population 1: FSGS and/or MCD (30 subjects total) Cohort 1 (6 subjects): ≥8 years to <18 years Cohort 2 (18 subjects): ≥3 years to <8 years Cohort 3 (6 subjects): ≥1 year to <3 years Population 2: IgAN, IgAV, or AS (27 subjects total) Cohort 1 (9 subjects): ≥8 years to <18 years Cohort 2 (12 subjects): ≥5 years to <8 years Cohort 3 (6 subjects): ≥2 years to <5 years

Official Title
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A Phase 2, Open-Label, Single-Arm, Cohort Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Sparsentan Treatment in Pediatric Subjects With Selected Proteinuric Glomerular Diseases

Conditions
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Focal Segmental Glomerulosclerosis, Minimal Change Disease, Immunoglobulin A Nephropathy, IgA Vasculitis, Alport Syndrome

Intervention / Treatment
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* Drug: Sparsentan
* Drug: Sparsentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for All Subjects (Both 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 to <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]) Exclusion Criteria for All Subjects (Both 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Population 1: FSGS and/or MCD<br>Subjects with selected proteinuric glomerular diseases associated with FSGS and MCD histological patterns | Drug: Sparsentan<br>* Population 1: 800 mg Sparsentan<br>* Other names: RE-021;|
| Experimental: Population 2: IgAN, IgAV, or AS<br>Subjects with biopsy-confirmed immunoglobulin A nephropathy (IgAN), immunoglobulin A vasculitis (IgAV), or subjects with Alport syndrome (AS) | Drug: Sparsentan<br>* Population 2: 400 mg Sparsentan<br>* Other names: RE-021;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs leading to treatment discontinuation, and adverse events of interest (AEOIs) | The incidence of TEAEs, SAEs, AEs leading to treatment discontinuation, and AEOIs | After the last patient has undergone the week 108 visit (Visit 15). | 
| Urine protein/creatinine ratio (UP/C) at week 108 | Change from baseline in UP/C over the 108-week treatment period | After the last patient has undergone the Week 108 visit (Visit 15) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed plasma Pharmacokinetic (PK) concentrations | Observed plasma PK concentrations at scheduled timepoints and visits | At scheduled Day 1, Day 2 and Week 12 visits | 
| Steady-state PK parameters area under the plasma concentration-time curve during a dosing interval ([AUCτ]) | Steady-state PK parameters [AUCτ] | Week 108 | 
| Steady-state PK parameters [Cmax_ss] | Maximum steady-state plasma drug concentration during a dosage interval [Cmax_ss] | Week 108 | 
| Steady-state PK parameters [Cmin_ss] | Minimum steady-state plasma drug concentration [Cmin_ss] derived from population PK analysis | Week 108 | 
| Urine albumin/creatinine ratio (UA/C) over the 112 weeks | Change from baseline in UA/C through the end of the study (i.e. at Week 112) | Week 112 | 
| Urine protein/creatinine ratio (UP/C) over the 112 weeks | Change from baseline in UP/C through the end of the study (i.e. at Week 112) | Week 112 | 
| Estimated glomerular filtration rate (eGFR) over the 112 weeks | Change from baseline in eGFR through the end of the study (i.e. at Week 112) | Week 112 | 
| Proportion of subjects with FSGS and/or MCD histological patterns achieving partial remission | The proportion of subjects with FSGS and/or MCD histological patterns achieving partial remission defined as UP/C ≤1.5 g/g and >40% reduction in UP/C over the 108-week treatment period | Week 108 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alport, AS, FSGS, IgAN, IgAV, MCD, pediatrics, peds