Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS)

Study Overview
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Brief Summary
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To determine the long-term nephroprotective potential of treatment with sparsentan as compared to an angiotensin receptor blocker in patients with primary and genetic focal segmental glomerulosclerosis (FSGS).

Detailed Description
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This is a randomized, multicenter, double-blind, parallel, active-control study. Approximately 300 patients aged 8 to 75 years (inclusive) will be enrolled in the study. The study will be conducted in approximately 300 study centers, globally. The investigational drug (sparsentan) is a dual-acting angiotensin receptor blocker and endothelin receptor antagonist. The active control is irbesartan. Patients who meet eligibility criteria will require washout from renin-angiotensin-aldosterone system (RAAS) blockers, if applicable prior to their first dose of study drug. Patients will be randomly assigned in a 1:1 ratio to receive either sparsentan or active control (irbesartan). After completing the double-blind portion of the study, patients may participate in the open-label extension for treatment with sparsentan if they meet eligibility criteria. Primary completion date represents the anticipated completion date of the double-blind portion of the study. Study completion date represents the anticipated completion date of the open-label extension portion of the study.

Official Title
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A Randomized, Multicenter, Double-blind, Parallel, Active-control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS

Conditions
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Focal Segmental Glomerulosclerosis

Intervention / Treatment
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* Drug: sparsentan
* Drug: Irbesartan


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria for the Double-blind Period: Sites within the US and UK: The patient is male or female aged 8 to 75 years, inclusive, weighing ≥20 kg at screening Sites outside the US and UK: The patient is male or female aged 18 to 75 years, inclusive, weighing ≥20 kg at screening Biopsy-proven focal segmental glomerulosclerosis (FSGS) lesion(s) or documentation of a genetic mutation in a podocyte protein associated with FSGS. Urine protein/creatinine (UP/C) ≥1.5 g/g (170 mg/mmol) at screening eGFR ≥30 mL/min/1.73 m2 at screening. Women of childbearing potential must agree to the use of one highly reliable method of contraception from 7 days prior to the first dose of study medication until 90 days after the last dose of study medication, plus one additional barrier method during sexual activity Key Exclusion Criteria for the Double-blind Period: FSGS secondary to another condition Positive serological tests of another primary or secondary glomerular disease not consistent with a diagnosis of primary or genetic FSGS History of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus, or nonfasting blood glucose >180 mg/dL (10.0 mmol/L) Treated with rituximab, cyclophosphamide, or abatacept within ≤3 months prior to screening; if taking other chronic immunosuppressive medications, the dosage must be stable prior to screening Documented history of heart failure, coronary artery disease, or cerebrovascular disease Significant liver disease Positive at screening for the human immunodeficiency virus or markers indicating acute or chronic hepatitis B virus infection or hepatitis C infection History of malignancy other than adequately treated basal cell or squamous cell skin cancer or cervical carcinoma within the past 2 years Screening hematocrit value <27% (0.27 L/L) or hemoglobin value <9 g/dL (90 g/L) Screening potassium value of >5.5 mEq/L (5.5 mmol/L) Extreme obesity (ie, ≥18 years of age with a body mass index (BMI) >40, or is <18 years of age with a BMI in the 99th percentile plus 5 units at screening, in whom there is a causal relationship between obesity and the development of FSGS History of alcohol or illicit drug use disorder History of serious side effect or allergic response to any angiotensin II antagonist or endothelin receptor antagonist Female patient is pregnant, plans to become pregnant during the course of the study, or is breastfeeding. Key Inclusion Criteria for the Open-label Extension Based on assessments at the Week 108 visit: Complete participation in the double-blind period, including the Week 112 visit. Patient received blinded study medication through the duration of the double-blind period (ie, did not permanently discontinue study medication) Key Exclusion Criteria for the Open-label Extension Based on Assessments at Week 108 and 112 visits: Progression to end-stage renal disease requiring replacement therapy The patient developed criteria for discontinuation between Week 108 and Week 112 The patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors between Week 108 and Week 112 eGFR ≤20 mL/min/1.73 m2 at Week 108

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 75 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sparsentan for double-blind and open-label extension<br>Sparsentan will be administered as a single oral morning dose; an initial dose of 400 mg daily titrating up to a target dose of 800 mg, daily | Drug: sparsentan<br>* Double-blind period: target dose of 800 mg daily; Open-label extension: target dose based on dosage from week 114 daily<br>* Other names: RE-021;|
| Active Comparator: Irbesartan<br>Irbesartan will be administered as a single oral morning dose; an initial dose of 150 mg daily titrating up to a target dose of 300 mg, daily | Drug: Irbesartan<br>* target dose of 300 mg daily<br>* Other names: Irbesartan Tablets USP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slope of estimated glomerular filtration rate (eGFR) | The slope of eGFR from Day 1 to Week 108. (Secondary outcome measure in non-US countries) | Week 108 | 
| Proportion of patients achieving a urine protein/creatinine (UP/C) ≤1.5 g/g and a >40% reduction | Proportion of patients achieving a UP/C ≤1.5 g/g and a >40% reduction from baseline in UP/C at Week 36 | Week 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slope of eGFR | The slope of eGFR from 6 weeks post randomization at Week 108. (Primary outcome in non-US countries) | Week 6 to Week 108 | 
| Change in eGFR from baseline | Change in eGFR from baseline to 4 weeks post-cessation of treatment at Week 112. (Percent change in eGFR in non-US countries) | Week 112 | 
| Non-US countries: Percent change in eGFR | Percent change from Week 6 in eGFR at Week 108 | Week 6 to Week 108 |