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
Phase: PHASE3
Conditions: Focal Segmental Glomerulosclerosis
Sponsor: Travere Therapeutics, Inc.

Protocol 
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 Focal 
Segmental Glomerulosclerosis (FSGS) 
Date of Document: 31 January 2024 
NCT03493685 

 
 
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 FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) 
 
Investigational Medicinal Product: 
Sparsentan 
Product Code: 
RE-021 
Protocol Number: 
021FSGS16010 (DUPLEX) 
IND Number: 
115903 
EudraCT Number: 
2016-00514123 
Developmental Phase: 
Phase 3 
 
 
Protocol Version and Date: 
Amendment 9: 18 January 2024  
(Version history contained in Section 15.4) 
 
 
Sponsor: 
Travere Therapeutics, Inc. 
3611 Valley Centre Drive, Suite 300 
San Diego, CA 92130 
USA 
 
 
CONFIDENTIAL 
The information contained herein is the property of Travere Therapeutics, Inc. and may not be 
reproduced, published, or disclosed to others without written authorization of 
Travere Therapeutics, Inc. 
 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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INVESTIGATOR’S AGREEMENT 
 
 
This protocol was designed and will be conducted, recorded, and reported in accordance with the 
principles of Good Clinical Practice as stated in the International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use and any applicable 
national and regional laws. 
 
I have read and agree to abide by the requirements of this protocol. 
Investigator Signature: Date: 
 
 
Investigator Name (print or type): 
Address: 
 
 
 
 
Telephone: 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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STUDY CONTACT INFORMATION 
 
Medical Monitor  
(Travere Therapeutics, Inc.): 
 MD 
, Nephrology 
Travere Therapeutics, Inc. 
Tel: 
 
Medical Emergency Tel:  
 
+1-973-659-6677 or 
 
+1-570-819-8565 
email: 
or 
 
Duplexmedmon@travere.com 
Medical Monitor (IQVIA): 
 MD, PhD 
 Cardiovascular, Renal, and 
Metabolic IQVIA 
Email:  
Mobile: 
24-hour Medical Emergency (any time): 
 
US: +1-973-659-6677 (main);  
 
 
+1-512-652-0864 (back-up) 
Serious Adverse Event 
Reporting: 
Qinecsa Solutions 
Email: clinicalsafety.travere@qinecsa.com  
Fax:  
See Investigator Site File 
Product Handling/Complaints: Tel:  
+1-888-211-5014 
email: 
InvestigationalProductComplaints@travere.com 
 
 
 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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1. 
SYNOPSIS 
NAME OF COMPANY: 
Travere Therapeutics, Inc. 
3611 Valley Centre Drive, Suite 300 
San Diego, CA 92130 
USA 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
NAME OF ACTIVE INGREDIENT: 
sparsentan 
TITLE: 
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 Focal 
Segmental Glomerulosclerosis (FSGS) 
PROTOCOL NUMBER: 021FSGS16010 (DUPLEX) 
STUDY PHASE: Phase 3 
INVESTIGATOR STUDY SITES: 
Approximately 300 investigational study centers globally will participate in this study. 
OBJECTIVES: 
Efficacy: 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). 
Safety: To assess the safety and tolerability of sparsentan by double-blind monitoring of safety endpoints. 
Open-label: To assess the long-term efficacy, safety, and tolerability of open-label sparsentan in patients with 
FSGS. 
METHODOLOGY: 
This is a 112-week, randomized, multicenter, double-blind, parallel, active-control study (also referred to as 
DUPLEX) with an open-label extension of up to 156 weeks, for a total study duration of up to 268 weeks. 
Approximately 300 patients aged 8 to 75 years, inclusive (United States [US] and United Kingdom [UK]), and 18 
to 75 years, inclusive (countries other than the US and UK), weighing ≥20 kg, will be enrolled in the study. 
Double-blind Period 
Patients who meet inclusion criteria during screening who are taking inhibitors of the 
renin-angiotensin-aldosterone system (RAAS) will undergo a 2-week washout period from these agents prior to 
Day 1/Randomization. 
Following screening (and the washout period for patients taking RAAS inhibitors), all patients will undergo 
comprehensive baseline evaluations and clinical laboratory tests and will be randomly assigned in a 1:1 ratio to 
receive either sparsentan or active control (irbesartan) (see Dose/Route/Regimen). Randomization will include 
stratification by screening estimated glomerular filtration rate (eGFR) and urine protein/creatinine ratio (UP/C) 
values. The strata will be as follow: 
• 
eGFR strata: 
o 
≥30 to <60 mL/min/1.73 m2 (all patients) 
o 
≥60 mL/min/1.73 m2 (all patients) 
• 
UP/C strata: 
o 
≤3.5 g/g (396 mg/mmol; patients ≥18 years of age) or ≤2 g/g (226 mg/mmol; patients <18 years of age) 
o 
>3.5 g/g (396 mg/mmol; patients ≥18 years of age) or >2 g/g (226 mg/mmol; patients <18 years of age)  
 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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NAME OF COMPANY: 
Travere Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
Sparsentan and irbesartan concentrations in plasma will be evaluated. At applicable visits, 1 trough sample will be 
obtained pre-dose in the clinic. 
Unless otherwise specified, endpoints will use pretreatment values obtained prior to randomization as baseline. 
The follow-up visits to obtain measurements will be conducted at 3-month intervals unless otherwise specified. 
Additional antihypertensive agents are allowed during the study to maintain blood pressure ≤130/80 mmHg 
(patients ≥18 years of age) or ≤ the 75th percentile (patients <18 years of age; Banker 2016), with the exception of 
those that inhibit the RAAS and endothelin systems (see Section 15.2.1 for concomitant medication 
considerations). 
An unblinded analysis will be performed after 36 weeks following randomization of at least 190 patients 
(approximately 95 per treatment group) to evaluate the surrogate efficacy endpoint (ie, the proportion of patients 
achieving a UP/C ≤1.5 g/g [170 mg/mmol] and a >40% reduction in UP/C at Week 36). 
Following the 108-week blinded treatment period, treatment with study medication will be discontinued, and 
patients may be evaluated for eligibility in the open-label extension using values from the Week 108 visit as 
screening assessments. At this time, the Investigator should resume standard-of-care treatment, including 
treatment with RAAS inhibitors provided there are no contraindications for their use. If the patient was treated 
with irbesartan at study entry, an alternative ARB at an equivalent dose is required from Week 108 to Week 112. 
The Investigator may make additional adjustments in antihypertensive medications as necessary to adequately 
control the patient’s blood pressure. 
Patients will return to the site for the final visit of the double-blind period 4 weeks after study medication has 
been discontinued. 
Open-label Extension 
Patients may be evaluated for eligibility in the open-label extension using values from the Week 108 visit as 
screening assessments. Patients with an eGFR <30 (but >20) mL/min/1.73 m2 will be eligible for participation in 
the open-label extension at the discretion of the Investigator, but will require close monitoring of eGFR and 
serum potassium (see Exclusion Criteria for the Open-label Extension). 
For patients who agree to participate in the open-label extension and meet eligibility criteria, the Week 112 visit 
will also serve as the baseline visit for the open-label extension. Standard-of-care treatment (ACEI and/or ARB 
therapy) will be discontinued before the Week 112 visit. The final dose of an ACEI and/or ARB should be taken 
on the day before the Week 112 visit. At this visit, patients will sign a new informed consent (if not already 
completed previously) for the open-label extension and begin taking open-label sparsentan. All Week 112 
evaluations must be completed prior to the first dose of open-label sparsentan. Patients taking 2 or 4 capsules of 
study medication at the end of the double-blind period will initiate treatment in the open-label extension at one-
half the corresponding dose of open-label sparsentan for the first 2 weeks, then titrate to the target dose after 
confirmation of tolerability at Week 114. Patients taking 1 capsule of study medication at the end of the double-
blind period will initiate treatment in the open-label extension at 200 mg open-label sparsentan and continue on 
that dose throughout the open-label extension. Detailed information on the dosing regimen for the open-label 
extension period is included in the Dose/Route/Regimen section. 
Patients will participate in the open-label extension for up to 156 weeks, for a total of 268 weeks in the study 
(ie, double-blind and open-label). If the product becomes commercially available during the open-label extension 
period, eligible patients may transition out of the study and onto commercial product before the end of the 
open-label extension period. After the patient completes the study (Week 268), if sparsentan is not commercially 
available, patients may potentially receive sparsentan via alternative means depending upon regulations and 
commercial status in each country. 
Supportive Measures for Coronavirus Disease 2019/Unexpected Circumstances 
If an on-site visit by the patient is not feasible due to the challenges related to the coronavirus disease 2019 
(COVID-19) pandemic or other unexpected circumstances, contingency measures will be implemented to ensure 
patient safety while participating in the study. These safety measures will continue to be implemented in any 
situation that interrupts on-site safety oversight and includes visits at home by a trained medical professional 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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NAME OF COMPANY: 
Travere Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
(eg, licensed nurse), shipping study medication directly to the patient and using courier services for first morning 
void samples and local laboratories. Details are included in the protocol. 
NUMBER OF PATIENTS: 
Approximately 300 patients aged 8 to 75 years, inclusive (US and UK) and 18 to 75 years, inclusive (countries 
other than the US and UK) will be enrolled in the study. 
INCLUSION/EXCLUSION CRITERIA: 
Eligibility must be confirmed, and signed/dated informed consent obtained, prior to any study-related procedure. 
When applicable, this includes the patients beginning the 2-week washout from RAAS inhibitors. 
For patients who require RAAS inhibitor washout, certain evaluations at Visit 3 (randomization) may no longer 
fall within the limits set by the inclusion/exclusion criteria. These patients will remain eligible for the study based 
on their screening results, unless at Visit 3 they have a positive pregnancy test (positive urine pregnancy tests will 
be confirmed by a serum test) or have experienced the occurrence of any medical condition or circumstance that, 
in the opinion of the Investigator, exposes them to substantial risk and/or does not allow them to adhere to the 
requirements of the protocol. 
If in the Investigator’s opinion, a laboratory value at screening is deemed unlikely to be representative of the 
patient’s true status, the Investigator may repeat the measurement on that variable through the central laboratory 
to assess patient eligibility. The Investigator is required to consult with the Medical Monitor for more than 
1 repeat measurement to be permitted. In particular, RAAS inhibitors affect protein excretion and eGFR. If, in the 
Investigator’s opinion, withdrawal of RAAS inhibitor may alter these variables sufficiently to meet eligibility 
criteria, the patient may, if willing, undergo RAAS inhibitor washout and be retested for UP/C and/or eGFR to 
assess eligibility prior to potential randomization. 
Criteria for the Double-blind Period 
Inclusion Criteria: 
A patient will meet all of the following criteria to be eligible for this study. 
1. The patient or parent/legal guardian (as appropriate) is willing and able to provide signed informed 
consent, and where required, the patient is willing to provide assent, prior to any screening procedures. 
2. The patient has biopsy-proven FSGS lesion(s) or documentation of a genetic mutation in a podocyte 
protein associated with FSGS. The biopsy may have been performed at any time in the past. The patient 
will be enrolled based on light microscopy diagnosis of FSGS and supportive findings on either electron 
microscopy (EM) or immunofluorescence (IF) analysis (preferably both). In exceptional cases, the 
patient may be enrolled based on light microscopy diagnosis of FSGS lesion(s) in the absence of EM 
and/or IF analysis, provided the history and/or the course of the disease are indicative of primary FSGS 
and the case has been reviewed by the Medical Monitor and Investigator. 
3. 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. 
4. The patient has a UP/C ≥1.5 g/g (170 mg/mmol) at screening. 
5. The patient has an eGFR ≥30 mL/min/1.73 m2 at screening. 
6. The patient has a mean seated blood pressure ≥100/60 mmHg and ≤160/100 mmHg (patients ≥18 years 
of age) or between the 5th and 95th percentile for age, sex, and height (patients <18 years of age; 
Banker 2016). 
7. Women of childbearing potential (WOCBP), beginning at menarche, must agree to the use of 1 highly 
reliable (ie, can achieve a failure rate of <1% per year) method of contraception from 7 days prior to the 
first dose of study medication until 90 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 inhibition of ovulation, or an intrauterine device in place for at least 3 months. 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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NAME OF COMPANY: 
Travere Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
One additional barrier method must also be used during sexual activity, such as a diaphragm or 
diaphragm with spermicide (preferred) or male partner’s use of male condom or male condom with 
spermicide (preferred) from Day 1/Randomization until 90 days after the last dose of study medication. 
Women of childbearing potential are defined as those who are fertile, following menarche and until 
becoming postmenopausal unless permanently sterile; permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as 
amenorrhea for more than 24 consecutive months without an alternative medical cause; women on 
hormone replacement therapy must have a documented plasma follicle-stimulating hormone level 
>40 mIU/mL. All WOCBP must have a negative serum pregnancy test at Screening (Visit 1) and a 
negative urine pregnancy test, with positive results confirmed by serum, at every study visit from 
Randomization (Visit 3) and after.  
NOTE: Prior to menarche, pregnancy testing and contraceptive use are not required. However, the 
patient and their parent/guardian must be advised that, immediately upon menarche, the patient will be 
required to begin pregnancy testing and initiate contraceptive use. This requirement cannot be avoided. 
Exclusion Criteria: 
A patient who meets any of the following criteria will be excluded from this study. 
1. The patient has FSGS secondary to another condition. 
2. The patient is ≥18 years of age and has positive findings on serological tests that, in the Investigator’s 
opinion, are diagnostic of another primary or secondary glomerular disease. These may include 
antinuclear antibody, anti-double stranded deoxyribonucleic acid (DNA) antibodies, complement C3 and 
C4, anti-neutrophil cytoplasmic antibody, rheumatoid factor, anti-glomerular basement membrane 
antibodies, any clinically significant abnormalities identified by serum and urine protein electrophoresis 
or immunofixation, or serum kappa and lambda free light chains. At the Investigator’s discretion, these 
tests may be performed in patients <18 years of age under clinically relevant circumstances. 
3. The patient has a history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus (hemoglobin 
A1c [HbA1c] >8%), or non-fasting blood glucose >180 mg/dL (10.0 mmol/L) at screening. 
4. The patient has undergone any organ transplantation, with the exception of corneal transplants. 
5. The patient requires any of the prohibited concomitant medications (see Section 15.2.1). 
6. The patient has been treated with rituximab, cyclophosphamide, or abatacept within ≤3 months prior to 
screening. If a patient is taking other chronic immunosuppressive medications, the dosage must be stable 
for ≥1 month prior to screening and during the screening period. 
7. The patient has a documented history of heart failure (New York Heart Association Class II-IV) and/or 
previous hospitalization for heart failure or unexplained dyspnea, orthopnea, paroxysmal nocturnal 
dyspnea, ascites, and/or peripheral edema. 
8. The patient has 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, coronary angiogram revealing stenosis, or a coronary 
revascularization procedure) within 6 months prior to screening. 
9. The patient has hemodynamically significant valvular disease. 
10. The patient has jaundice, hepatitis, or known hepatobiliary disease (excluding asymptomatic 
cholelithiasis), or alanine aminotransferase and/or aspartate aminotransferase >2 times the upper limit of 
the normal range at screening. 
11. The patient is positive at screening for the human immunodeficiency virus or markers indicating acute or 
chronic hepatitis B virus (HBV) infection (acute HBV is defined as a positive hepatitis B surface antigen 
[HBsAg], hepatitis B “e” antigen [HBeAg], HBV DNA in blood or liver, or immunoglobulin M hepatitis 
B core antibody; chronic HBV is defined as a positive HBsAg and/or HBeAg and/or HBV DNA) or 
hepatitis C virus (HCV) infection (defined as reactive anti-HCV antibody and HCV RNA). 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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NAME OF COMPANY: 
Travere Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
12. The patient has a history of malignancy other than adequately treated basal cell or squamous cell skin 
cancer or cervical carcinoma within the past 2 years. 
13. The patient has a screening hematocrit value <27% (0.27 L/L) or hemoglobin value <9 g/dL (90 g/L). 
14. The patient has a screening potassium value of >5.5 mEq/L (5.5 mmol/L). 
15. The patient is extremely obese (ie, ≥18 years of age with a body mass index [BMI] >40 kg/m2 or 
<18 years of age with a BMI in the 99th percentile plus 5 units at screening), in whom, in the 
Investigator’s opinion, there is a causal relationship between obesity and development of the FSGS 
lesion. For patients with moderate or severe edema, BMI will be calculated based on remission or 
premorbid weight measured within 3 months prior to screening, if available. If not available, BMI will 
be calculated based on the estimated dry weight, based on the Investigator’s clinical judgment. 
16. The patient has a history of alcohol or illicit drug use disorder (as defined in the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition), or a reported habitual alcohol intake greater than 
21 units/week within 2 years prior to screening. 
17. The patient has a history of serious side effect or allergic response to any angiotensin II antagonist or 
endothelin receptor antagonist, including sparsentan or irbesartan, or has a hypersensitivity to any of the 
excipients in the study medications. 
18. The female patient is pregnant, plans to become pregnant during the course of the study, or is 
breastfeeding. 
19. The patient has participated in a study of another investigational product within 28 days prior to 
screening or plans to participate in such a study during the course of this study. 
20. The patient has had prior exposure to sparsentan. 
21. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of the study, 
including the ability to swallow the study medication capsules whole. 
Patients with a medical condition or abnormal clinically significant laboratory screening value not listed above 
that may interfere with the evaluation of sparsentan efficacy or safety will be reviewed with the Medical Monitor 
before consideration of the patient for enrollment. Patients who fail screening may be re-screened up to 
2 additional times. Patients who are re-screened will undergo all screening procedures and will be assigned a new 
patient number. Patients will also repeat the informed consent procedure each time they are re-screened. 
Criteria for the Open-label Extension 
Inclusion Criteria for the Open-label Extension: 
Based on assessments at the Week 108 visit, a patient will meet all of the following criteria to be eligible for the 
open-label extension. 
1. The patient completed participation in the double-blind period, including the Week 112 visit. 
2. The patient or parent/legal guardian (as appropriate) is willing and able to provide signed informed 
consent for participation in the open-label extension. 
3. The patient received blinded study medication throughout the duration of the double-blind period (ie, did 
not permanently discontinue study medication; see Section 6.4.2). 
Exclusion Criteria for the Open-label Extension: 
Based on assessments at the Week 108 and Week 112 visits, a patient who meets any of the following criteria will 
be excluded from the open-label extension. 
1. The patient has progressed to end-stage renal disease (ESRD) requiring renal replacement therapy 
(RRT). 
2. The patient developed criteria for discontinuation as defined in Section 6.4.2 or Section 6.5 between 
Week 108 and Week 112. 

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Confidential and Proprietary 
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NAME OF COMPANY: 
Travere Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
3. The patient was unable to initiate, or developed contraindications to, treatment with RAAS inhibitors 
between Week 108 and Week 112. 
4. The patient has an eGFR ≤20 mL/min/1.73 m2 at Week 108. NOTE: If in the Investigator’s opinion, the 
eGFR value at Week 108 is deemed unlikely to be representative of the patient’s true status, the 
Investigator may repeat the eGFR measurement prior to Week 112 through the central laboratory to 
assess patient eligibility. Patients with an eGFR <30 mL/min/1.73 m2 will require close monitoring of 
eGFR and serum potassium throughout the open-label extension. 
5. The female patient is pregnant, plans to become pregnant during the course of the study, or is 
breastfeeding. 
DOSE FORM (TEST ARTICLE): 
For the double-blind period, sparsentan will be dispensed as 200 mg tablets over-encapsulated (blinded) with 
size 00 capsules. For the open-label extension, sparsentan will be dispensed as 200 or 400 mg tablets. 
DOSE FORM (REFERENCE TREATMENT): 
Irbesartan will be the active control in the double-blind period. Irbesartan will be dispensed as 75 mg tablets 
over-encapsulated (blinded) with size 00 capsules. Irbesartan will not be used in the open-label extension. 
DOSE/ROUTE/REGIMEN (TEST ARTICLE AND REFERENCE TREATMENT): 
A dose adjustment will be made for patients whose body weight is ≤50 kg at screening; these patients will receive 
one-half the otherwise specified doses of study medication (weight will be measured at each visit and the dose 
increased at the Investigator’s discretion if the patient’s weight reaches >50 kg). 
Double-blind Period 
The full daily dose for both sparsentan (active) and irbesartan (control) will preferably be taken prior to the 
morning meal, with the exception of the day of a study visit. On the day of a study visit, the patient will take their 
study medication at the clinic. At the visits specified in Section 15.1, study medication will be administered at the 
clinic after the pre-dose pharmacokinetic (PK) blood sample has been obtained. Allowed doses during the 
double-blind period are shown in Table 2. 
Patients will receive the initial dose (ie, one-half the target dose) based on screening body weight for the first 
2 weeks. The Investigator will evaluate dose tolerance in a blinded manner prior to titrating up to the target dose; 
tolerance is defined as blood pressure measurements >100/60 mmHg (patients ≥18 years of age) or above the 
5th percentile for sex and height (patients <18 years of age; Banker 2016) after 2 weeks and no adverse events 
(AEs) or laboratory findings interfering with the patient’s continuation on study medication. Patients who display 
asymptomatic blood pressure values ≤100/60 mmHg (patients ≥18 years of age) or ≤90/50 mmHg or are below 
the 5th percentile for sex and height (whichever is lower in patients <18 years of age) or who present with clinical 
symptoms of orthostatic hypotension but otherwise tolerate the initial dose will continue after the Week 2 visit 
without titrating up to the target dose (see Section 8.1 and Section 8.3.2). 
At the Investigator’s discretion, patients weighing >50 kg who do not tolerate the initial dose for any reason 
(including changes in laboratory parameters assessed at Week 2) may continue at one-half the initial dose. 
Patients weighing ≤50 kg who do not tolerate the initial dose for any reason (including changes in laboratory 
parameters assessed at Week 2) will be discontinued from the study. 
Open-label Extension 
The full daily dose will preferably be taken prior to the morning meal. Allowed doses during the open-label 
extension are shown in Table 3. 
Patients who are taking 2 capsules of study medication (ie, 400 mg sparsentan or 150 mg irbesartan) at the end of 
the double-blind period will initiate treatment in the open-label extension at 200 mg sparsentan for the first 
2 weeks of the open-label extension. Likewise, patients who are taking 4 capsules of study medication 
(ie, 800 mg sparsentan or 300 mg irbesartan) at the end of the double-blind period will initiate treatment in the 
open-label extension at 400 mg sparsentan for the first 2 weeks of the open-label extension. Following 2 weeks 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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NAME OF COMPANY: 
Travere Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
(ie, Week 114) at one-half the double-blind dose, the Investigator will evaluate dose tolerance, as defined above 
for the double-blind period, prior to titrating up to the target dose. If the patient is tolerating the initial dose, the 
patient will titrate to the target dose at this time. Patients who display asymptomatic blood pressure values 
≤100/60 mmHg (patients ≥18 years of age) or ≤90/50 mmHg or are below the 5th percentile for sex and height 
(whichever is lower in patients <18 years of age) or who present with clinical symptoms of orthostatic 
hypotension but otherwise tolerate the initial dose will continue without titrating up to the target dose after the 
Week 114 visit. 
Patients who are taking 1 capsule of study medication (ie, 200 mg sparsentan or 75 mg irbesartan) at the end of 
the double-blind period will initiate treatment in the open-label extension at 200 mg sparsentan for the first 
2 weeks of the open-label extension. Following 2 weeks at 200 mg sparsentan (ie, Week 114), the Investigator 
will evaluate dose tolerance, as defined above for the double-blind period. Patients who are tolerating the initial 
dose will continue on 200 mg sparsentan at this time, including those who display asymptomatic blood pressure 
values ≤100/60 mmHg (patients ≥18 years of age) or ≤90/50 mmHg or are below the 5th percentile for sex and 
height (whichever is lower in patients <18 years of age) or who present with clinical symptoms of orthostatic 
hypotension but otherwise tolerate the initial dose. 
For patients who enter the open-label extension with an eGFR value <30 mL/min/1.73 m2 (ie, at Week 108), any 
dose titration at Week 114 will be at the Investigator’s discretion based on the results of the Week 114 
assessments. Patients who do titrate to a higher dose at Week 114 will be contacted by the Investigator at 
Week 116 to assess tolerance of the higher dose; at the Investigator’s discretion, these patients may also come in 
for an additional visit at this time. 
Doses may be modified at any time throughout the open-label extension for safety/tolerability reasons at the 
Investigator’s discretion. In addition, after titration to the target dose, increases above the target doses of 200 or 
400 mg sparsentan may be considered for patients who, in the Investigator’s opinion (and following consultation 
with the Medical Monitor), would benefit from an increased dose. 
ENDPOINTS: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the slope of eGFR over approximately 2 years of randomized treatment assessed 
at the final analysis. The slope of eGFR is evaluated following the initial acute effect of randomized treatment 
(ie, from Week 6 to Week 108; chronic slope over 2 years) in non-US countries and following initiation of 
randomized treatment (ie, from Day 1 to Week 108; total slope over 2 years) in the US. 
The surrogate efficacy endpoint is the proportion of patients achieving a UP/C ≤1.5 g/g (170 mg/mmol) and a 
>40% reduction from baseline of the double-blind period (ie, Day 1) in UP/C at Week 36. 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints in non-US countries are: 
• 
The percent change from Week 6 in eGFR at Week 108 
• 
The percent change in eGFR from baseline of the double-blind period to 4 weeks post-cessation of 
randomized treatment at Week 112 
• 
The slope of eGFR following the initiation of randomized treatment (ie, from Day 1 to Week 108; total slope 
over 2 years) 
The secondary efficacy endpoints in the US are: 
• 
The slope of eGFR following the initial acute effect of randomized treatment (ie, from Week 6 to Week 108; 
chronic slope over 2 years) 
• 
The change in eGFR from baseline of the double-blind period to 4 weeks post-cessation of randomized 
treatment at Week 112 

Travere Therapeutics, Inc. 
sparsentan (RE-021) 
021FSGS16010 (DUPLEX) Protocol Amendment 9 
 
Confidential and Proprietary 
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NAME OF COMPANY: 
Travere Therapeutics, Inc. 
NAME OF FINISHED PRODUCT: 
sparsentan tablets 
Exploratory Endpoints: 
• 
The slopes of eGFR over approximately 1 year of randomized treatment evaluated following the initial acute 
effect of randomized treatment (ie, from Week 6 to Week 60; chronic slope over 1 year) and after initiation 
of randomized treatment (ie, from Day 1 to Week 60; total slope over 1 year) 
• 
The absolute and percent change from baseline of the double-blind period in eGFR at each visit 
• 
The percent change from Week 6 in eGFR at each visit 
• 
The proportion of patients achieving a UP/C ≤1.5 g/g (170 mg/mmol) and a >40% reduction from baseline of 
the double-blind period in UP/C at each visit 
• 
The percent change from baseline of the double-blind period in UP/C at each visit 
• 
The time to achieve the target reduction in UP/C (ie, ≤1.5 g/g [170 mg/mmol] and a >40% reduction) 
• 
The proportion of patients reaching a confirmed 40% reduction in eGFR, ESRD, or death (ESRD is defined 
as initiation of RRT or sustained eGFR <15 mL/min/1.73 m2 during the study). 
• 
The proportion of patients reaching a confirmed 30% reduction in eGFR, ESRD, or death 
• 
Changes from baseline of the double-blind period in blood pressure at each visit 
• 
The proportion of patients requiring initiation of or intensification in immunosuppressive medication during 
the study 
• 
The proportion of patients undergoing reduction in immunosuppressive medication during the study 
• 
The time to initiation or intensification of immunosuppressive medication during the study 
• 
Changes from baseline of the double-blind period in quality of life (QoL), measured via patient-reported 
outcome (PRO) at each visit beginning with Week 12 
• 
Frequency and duration of hospitalizations (for any reason and for reasons related to the kidney) 
• 
Trough plasma PK concentrations during the double-blind period 
Safety Endpoints: 
Safety endpoints include: 
• 
Changes from baseline of the double-blind period in body weight, vital signs, physical examinations, 
peripheral edema, 12-lead electrocardiogram (ECG), and clinical laboratory parameters 
• 
Changes from baseline of the double-blind period in lipid profile (total cholesterol and triglycerides, 
low-density lipoprotein cholesterol [LDL-C], very low-density lipoprotein cholesterol [VLDL-C], and 
high-density lipoprotein cholesterol [HDL-C]) 
• 
Changes from baseline of the double-blind period in serum albumin and serum potassium at each visit 
• 
The incidence of treatment-emergent adverse events (TEAEs) during the double-blind period 
Open-label Endpoints: 
Endpoints for the open-label extension include, but are not necessarily limited to: 
• 
The absolute and percent change from Week 112 in eGFR at each visit 
• 
The percent change from Week 112 in UP/C at each visit 
• 
Changes from Week 112 in QoL at each visit 
• 
Changes from Week 112 in body weight, vital signs, physical examinations, peripheral edema, and clinical 
laboratory parameters 
• 
Changes from Week 112 in lipid profile (total cholesterol and triglycerides, LDL-C, and HDL-C) 
• 
The incidence of TEAEs during the open-label extension 

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NAME OF COMPANY: 
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sparsentan tablets 
STATISTICAL METHODS: 
Power and Sample Size: 
Approximately 300 patients will be randomized and allocated 1:1 to receive sparsentan or irbesartan. This sample 
size takes into consideration enrollment feasibility in this rare disease setting and was evaluated using 
simulations. 
For the surrogate endpoint, at the time of the interim analysis (which is planned for after 36 weeks following 
randomization of at least 190 patients [approximately 95 per treatment group]), the power to detect a difference in 
response proportions between treatment groups is more than 90%, assuming the response proportions are 50% for 
sparsentan and 20% for irbesartan, with a 2-sided α of 0.05. 
For the primary endpoint (slope of eGFR) at the final analysis, the study has at least 90% power to differentiate 
between treatments if the underlying eGFR slope difference is at least 2.5 mL/min/1.73 m2 per year for the 
chronic slope over 2 years (non-US) or at least 2.1 mL/min/1.73 m2 per year for the total slope over 2 years (US). 
The calculations assume that the separate tests for US and non-US countries are performed at a 2-sided α of 0.05 
and that statistically significant difference is demonstrated at the interim analysis of the surrogate endpoint. 
Analysis Sets: 
Full Analysis Set (FAS): All patients who are randomized and take at least 1 dose of double-blind study 
medication will be included in the FAS. All analyses of the FAS will be based on each patient’s randomized 
assigned treatment. If a patient is incorrectly stratified (ie, randomized according to the incorrect stratification), 
the patient will be analyzed under the randomized treatment for the stratum recorded in the randomization system. 
All efficacy analyses for the double-blind period will be based on the FAS. 
Per Protocol (PP) Analysis Set: The PP Analysis Set will include all patients in the FAS who meet the study 
eligibility requirements and have no major protocol deviations that affect the validity of the efficacy 
measurements. Patients will be analyzed according to their randomized treatment. The PP Analysis Set will be 
used for a sensitivity analysis of the primary efficacy endpoint. The criteria for inclusion in the PP Analysis Set 
will be finalized prior to study unblinding and detailed in the Statistical Analysis Plan. 
Safety Analysis Set: All patients who are randomized and take at least 1 dose of double-blind study medication 
will be included in the Safety Analysis Set. Safety analyses will be based on randomized treatment. 
Open-Label Extension Full Analysis Set (OLEFAS): All patients who received at least 1 dose of open-label 
sparsentan in the open-label extension will be included in the OLEFAS. All efficacy and safety analyses during 
the open-label extension will be based on the OLEFAS. 
Demographics and Baseline Characteristics: 
Demographic data and baseline characteristics for the FAS, PP, and Safety Analysis Sets will be summarized by 
treatment group using descriptive statistics. Demographic data include sex, age (years), categorical age (<18 years 
and ≥18 years), race/ethnicity, weight (kg), height (cm), and calculated BMI. Baseline characteristics also include 
reproductive status (for females only), HbA1c, baseline eGFR, and current use of: steroids, calcineurin inhibitors, 
mycophenolate mofetil and other immunosuppressive agents, RAAS inhibitors (ie, angiotensin-converting 
enzyme inhibitors, ARBs, aldosterone blockers, and aliskiren) prior to the 2-week washout, diuretics, additional 
antihypertensive treatments, and statins. 
Likewise, demographic data and baseline characteristics for the OLEFAS will be summarized overall using 
descriptive statistics. 
Efficacy: 
All efficacy analyses during the double-blind period will be performed based on the FAS. The primary endpoint 
analysis will also be conducted using the PP Analysis Set. 

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The eGFR during the screening period will be determined using the Chronic Kidney Disease Epidemiology 
(CKD-EPI) equation for adults (Levey 2009) and the Modified Schwartz formula (Schwartz 2009a; 
Schwartz 2009b) for children <18 years of age. 
The eGFR for each timepoint (visit) during the double-blind period will be determined using the CKD-EPI 
equation for adults (Levey 2009) and children ≥16 years of age at screening for the double-blind period, and the 
Modified Schwartz formula for children <16 years of age at screening for the double-blind period 
(Schwartz 2009a; Schwartz 2009b). For the double-blind period, UP/C will be determined using first morning 
void urine samples and will be calculated as the average of 3 first morning void urine samples collected within 
5 days prior to each visit at which UP/C is assessed. 
The eGFR for each timepoint (visit) during the open-label extension will be determined using the CKD-EPI 
equation for adults (Levey 2009) and children ≥16 years of age at Week 108, and the Modified Schwartz formula 
for children <16 years of age at Week 108 (Schwartz 2009a; Schwartz 2009b). For the open-label extension, 
UP/C will be determined using 1 first morning void sample collected within 5 days prior to each visit at which 
UP/C is assessed. 
As UP/C is a highly-skewed variable, analyses will be performed on log-transformed data; however, for ease of 
interpretation, results will be presented in the original units. 
To control the overall type I error for this study when conducting significance tests for the primary and secondary 
efficacy endpoints, a hierarchical (gate-keeping) testing procedure will be used. 
The surrogate efficacy endpoint (UP/C response at Week 36) will first be tested at the interim analysis at 2-sided 
α = 0.05. If the test is not significant, hypothesis testing stops. If the test is significant, then the following 
country-specific hierarchical testing will be performed. 
For non-US countries, the hierarchy for the hypothesis testing will be as follows, if the test of the surrogate 
efficacy endpoint (UP/C response at Week 36) is significant: 
1. test the primary efficacy endpoint (eGFR chronic slope over 2 years) at the final analysis at 2-sided α = 0.05. 
If the test is not significant, hypothesis testing stops. If the test is significant, 
2. test the 3 secondary efficacy endpoints using a Bonferroni-Holm procedure to control for family-wise error 
rate at 2-sided α = 0.05. 
For the US, the hierarchy for the hypothesis testing will be as follows, if the test of the surrogate efficacy 
endpoint (UP/C response at Week 36) is significant: 
1. test the primary efficacy endpoint (eGFR total slope over 2 years) at the final analysis at 2-sided α = 0.05. If 
the test is not significant, hypothesis testing stops. If the test is significant, 
2. test the efficacy endpoint of eGFR chronic slope over 2 years at the final analysis at 2-sided α = 0.05. If the 
test is not significant, hypothesis testing stops. If the test is significant, 
3. test the efficacy endpoint of change in eGFR from baseline of the double-blind period to 4 weeks 
post-cessation of randomized treatment at Week 112 at the final analysis at 2-sided α = 0.05. 
For the primary endpoint of slope of eGFR evaluated following the initial acute effect of randomized treatment 
(ie, from Week 6 to Week 108; chronic slope over 2 years), a mixed-effects model with linear spline (knot or 
change point at Week 6) will be fitted to the available eGFR data. The response variable is the eGFR measured at 
post-baseline assessments for each patient during the double-blind period. The model will include fixed effects 
for treatment, both stratification factors for randomization, baseline eGFR (continuous), time (in weeks) from 
baseline (continuous), and time (in weeks) from the change point (ie, timek = max(time – 6, 0)), 
time-by-treatment, and timek-by-treatment interactions. The model will also include a random intercept and 
random slopes (time and timek) for each patient. The mixed model will utilize restricted maximum likelihood 
estimation with Kenward-Roger method used to compute the denominator degrees of freedom for tests of fixed 
effects. The model will assume an unstructured covariance matrix. If the model does not converge under the 
unstructured covariance matrix, the autoregressive-1 covariance structure will be used. The primary efficacy 

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hypothesis of interest is whether eGFR slopes over the blinded treatment period (after adjusting for early 
hemodynamic effects) are different between the 2 treatment groups, ie: 
H0: (βtime*treatment + βtime k*treatment) = 0 versus H1: (βtime*treatment + βtime k*treatment) ≠ 0 
This hypothesis will be tested using the mixed model by testing whether the time-by-treatment interaction 
parameters least-squares (LS) mean estimate is equal to zero. Sensitivity analyses are planned to assess the 
potential impact of major protocol deviations, premature treatment discontinuations, changes in 
immunosuppressive medications, and the choice of the change point. 
For the primary endpoint of slope of eGFR evaluated following initiation of randomized treatment (ie, from 
Day 1 to Week 108; total slope over 2 years), a mixed-effects model will be fitted to the available eGFR data. The 
response variable is the eGFR measured at post-baseline assessments for each patient during the double-blind 
period. The model will include fixed effects for treatment, both stratification factors for randomization, baseline 
eGFR (continuous), time (in weeks) from baseline (continuous), and time-by-treatment interaction. The model 
will also include a random intercept and random slope for each patient. The mixed model will utilize restricted 
maximum likelihood estimation with Kenward-Roger method used to compute the denominator degrees of 
freedom for tests of fixed effects. The model will assume an unstructured covariance matrix. If the model does 
not converge under the unstructured covariance matrix, the autoregressive-1 covariance structure will be used. 
The hypothesis of interest is whether eGFR slopes over the blinded treatment period (after adjusting for early 
hemodynamic effects) are different between the 2 treatment groups, ie: 
H0: βtime*treatment = 0 versus 
H1: βtime*treatment ≠ 0. 
This hypothesis will be tested using the mixed model by testing whether the time-by-treatment interaction 
parameter LS mean estimate is equal to zero. Sensitivity analyses are planned to assess the potential impact of 
major protocol deviations, premature treatment discontinuations, changes in immunosuppressive medications, and 
the choice of the change point. 
For the analysis of eGFR absolute change from baseline by visit, a Mixed Model Repeated Measures (MMRM) 
model will be fitted to the available eGFR data, incorporating all post-baseline visits at which eGFR was 
measured for each patient during the double-blind period. The model will include treatment, both stratification 
factors for randomization, baseline eGFR, visit (categorical), and visit-by-treatment interaction as fixed effects. In 
addition, patient will be included as a random effect. An unstructured within-patient covariance structure will be 
assumed. If the model does not converge under the unstructured covariance matrix, the autoregressive-1 
covariance structure will be used. The LS mean estimate for βWKj*treatment (ie, the treatment effect at the visit j of 
interest) from the MMRM model will be used to perform treatment group comparisons by visit. 
The percent change from baseline to 4 weeks post-cessation of randomized treatment at Week 112 in eGFR will 
be analyzed via analysis of covariance (ANCOVA). The dependent variable will be the natural log(eGFR) of 
analysis visit Week 112, with treatment and baseline eGFR in log scale included as fixed effects. The analysis 
will be stratified by the randomization strata. The treatment effect will be the contrast between sparsentan and 
irbesartan LS means. The LS means, treatment effect estimate, 95% confidence interval (CI), and p-value will be 
presented. Estimates and CIs will be converted to percentage. 
The change from baseline to 4 weeks post-cessation of randomized treatment at Week 112 in eGFR will be 
analyzed via analysis of covariance (ANCOVA). The dependent variable will be the eGFR at analysis visit 
Week 112, with treatment and baseline eGFR included as fixed effects. The analysis will be stratified by the 
randomization strata. The treatment effect will be the contrast between sparsentan and irbesartan LS means. The 
LS means, treatment effect estimate, 95% confidence interval (CI), and p-value will be presented. 
For the analysis of eGFR percent change from baseline by visit, a MMRM approach analogous to the model 
described for the absolute change from baseline will be used, except that the response variable will be natural 

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log(eGFR) and corresponding baseline value natural log(baseline eGFR). Estimates and CIs will be converted to 
percentages via the following transformation: 
[exp (LS mean change from baseline in natural log(eGFR)) – 1] × 100. 
For the analysis of eGFR percent change from Week 6 by visit, the estimates from the MMRM model used in the 
analysis of eGFR relative percent change from baseline by visit described above will be utilized. However, for 
this analysis, the statistical significance of the treatment difference at visit j (eg, Week 108 for the secondary 
endpoint) will be assessed by testing the following hypothesis: 
H0: (βWKj*treatment – βWK6*treatment) = 0 versus H1: (βWKj*treatment – βWK6*treatment) ≠ 0, 
where βWKj*treatment is the treatment effect at the visit j of interest and βWK6*treatment is the treatment effect at Week 6. 
The LS mean estimate from the MMRM model will be used to perform treatment group comparisons by visit. 
Estimates and CIs will be converted to percentages via the following transformation: 
[exp(LS mean change from Week 6 in natural log(eGFR)) – 1] × 100. 
Analyses of the proportion of patients achieving a UP/C ≤1.5 g/g (170 mg/mmol) and a >40% reduction from 
baseline at each visit (including the surrogate efficacy endpoint at Week 36) will be performed using a 
generalized linear model with logit link function to model the probability of achieving UP/C ≤1.5 g/g 
(170 mg/mmol) and a >40% reduction from baseline and to compare sparsentan with irbesartan. The response 
variable will be a binary indicator of achievement of UP/C ≤1.5 g/g (170 mg/mmol) and a >40% reduction from 
baseline at each post-baseline visit. Missing response variables will be imputed using the multiple imputation 
(MI) procedure before analysis. Fixed effects in the model will include baseline UP/C, treatment, time 
(categorical, in weeks), and treatment-by-time interaction. Analysis will be stratified by a randomization 
stratification variable (4 levels based on Screening eGFR and UP/C). An unstructured covariance matrix within 
patient will be assumed. If convergence issues arise, the autoregressive-1 covariance structure will be used. At 
each post-baseline visit included in the model, the probability of achieving UP/C ≤1.5 g/g (170 mg/mmol) and a 
>40% reduction from baseline (risk) for each treatment group, treatment effect (risk difference), standard errors 
of risk and risk difference, 95% CIs of risks and risk difference, and p-values will be extracted from the model. 
Relative risk ratios and odds ratios, along with standard errors and 95% CIs, will also be presented. This analysis 
will be performed at the interim analysis (ie, surrogate efficacy endpoint). Sensitivity analyses will be performed 
using a Cochran-Mantel-Haenszel (CMH) test at Week 36, tipping point analysis, and analysis using observed 
cases (ie, no MI). 
Change from baseline to all post-baseline visits during the double-blind period in natural log(UP/C) will be 
analyzed using a MMRM model analogous to the one described for percent change from baseline in eGFR. 
Estimates and CIs will be converted to percentages via the following transformation: 
[exp (least-squares mean change from baseline in natural log(UP/C)) – 1] × 100 
The time to achieve the target reduction in UP/C during the double-blind period will be analyzed using Cox 
proportional hazards model, stratified by randomization stratification variables, with a comparison between 
treatment groups. Patients who discontinue from treatment during the double-blind period prior to achieving the 
target reduction will be censored at the time of treatment discontinuation. Patients who never meet target during 
the double-blind period will be censored at the time of analysis. 
The following endpoints will be summarized descriptively for the double-blind period and compared between 
treatment groups using a CMH test controlling for the randomization stratification variables: the proportion of 
patients reaching a confirmed 40% reduction in eGFR, ESRD, or death; the proportion of patients requiring 
initiation or intensification of immunosuppressive medication during the study; and the proportion of patients 
with reduction in immunosuppressive medication during the study. Changes from baseline to all post-baseline 
visits during the double-blind period with respect to QoL scores and blood pressure (systolic and diastolic) values 
will be analyzed using a MMRM model analogous to the one described for changes from baseline in eGFR. 

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sparsentan tablets 
Safety: 
All safety analyses for the double-blind period will be conducted based on the Safety Analysis Set. 
Safety data will include AEs, physical examination results, vital signs, ECG results, and clinical laboratory 
measurements. Observed data will be listed by patient and summarized using descriptive statistics by treatment 
group for the double-blind period. 
Interim Analysis: 
An unblinded interim analysis will be performed after 36 weeks following randomization of at least 190 patients 
to evaluate the surrogate endpoint. 
Open-label Analyses: 
Analyses of the endpoints for the open-label extension will be performed using the methods described above as 
appropriate. 
Efficacy and safety endpoints for the open-label extension will be summarized using descriptive statistics and 
presented overall and by original randomized treatment based on the OLEFAS. Analyses using baselines other 
than Week 112 (eg, prior to first dose of study medication in the double-blind period) may be explored. 

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2. 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
STUDY CONTACT INFORMATION ...........................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS ...........................................................................................17 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
4. 
INTRODUCTION ......................................................................................................27 
4.1. 
Summary of Potential Risks .......................................................................................30 
4.2. 
Summary of Potential Benefits ...................................................................................31 
4.3. 
Rationale for the Study ...............................................................................................31 
5. 
STUDY OBJECTIVES ..............................................................................................33 
5.1. 
Efficacy Objective ......................................................................................................33 
5.2. 
Safety Objective ..........................................................................................................33 
5.3. 
Open-Label Objective .................................................................................................33 
6. 
INVESTIGATIONAL PLAN .....................................................................................34 
6.1. 
Endpoints ....................................................................................................................34 
6.1.1. 
Efficacy Endpoints ......................................................................................................34 
6.1.1.1. 
Primary Efficacy Endpoint .........................................................................................34 
6.1.1.2. 
Secondary Efficacy Endpoints ....................................................................................34 
6.1.1.3. 
Exploratory Endpoints for the Double-Blind Period ..................................................34 
6.1.2. 
Safety Endpoints .........................................................................................................35 
6.1.3. 
Open-Label Endpoints ................................................................................................35 
6.2. 
Study Design ...............................................................................................................36 
6.2.1. 
Double-Blind Period Design.......................................................................................36 
6.2.2. 
Open-Label Extension Design ....................................................................................38 
6.3. 
Patient Completion and Overall Study Completion ...................................................40 
6.3.1. 
Patient Completion of the Double-Blind Period .........................................................40 
6.3.2. 
Patient Completion of the Open-Label Extension ......................................................40 
6.3.3. 
Overall Study Completion ..........................................................................................40 
6.4. 
Discontinuation of Study Medication .........................................................................40 
6.4.1. 
Temporary Interruption of Study Medication .............................................................41 
6.4.2. 
Permanent Discontinuation of Study Medication .......................................................41 

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6.5. 
Discontinuation of the Patient from the Study ...........................................................42 
6.6. 
Lost to Follow-up .......................................................................................................42 
7. 
PATIENT POPULATION AND SELECTION .........................................................44 
7.1. 
Criteria for the Study ..................................................................................................44 
7.1.1. 
Inclusion Criteria ........................................................................................................44 
7.1.2. 
Exclusion Criteria .......................................................................................................45 
7.2. 
Criteria for the Open-Label Extension .......................................................................47 
7.2.1. 
Inclusion Criteria for the Open-Label Extension ........................................................47 
7.2.2. 
Exclusion Criteria for the Open-Label Extension ......................................................47 
8. 
TREATMENTS ..........................................................................................................49 
8.1. 
Treatments Administered ............................................................................................49 
8.1.1. 
Treatments Administered During the Double-Blind Period .......................................49 
8.1.2. 
Treatments Administered During Open-Label Extension ..........................................50 
8.2. 
Study Medication ........................................................................................................51 
8.2.1. 
Packaging and Labeling ..............................................................................................51 
8.2.2. 
Storage ........................................................................................................................52 
8.2.3. 
Preparation and Administration of the Study Medication ..........................................52 
8.3. 
Dosing Considerations ................................................................................................52 
8.3.1. 
Dose Selection Rationale ............................................................................................52 
8.3.2. 
Dose Modification, Reduction, or Discontinuation ....................................................53 
8.4. 
Prior and Concomitant Medications and Therapeutic Procedures .............................54 
8.5. 
Method of Assigning Patients to Treatment (Randomization) ...................................54 
8.6. 
Blinding and Emergency Unblinding .........................................................................54 
8.7. 
Assignment of Site and Patient Numbers ...................................................................55 
8.8. 
Treatment Compliance ................................................................................................55 
9. 
STUDY ASSESSMENTS ..........................................................................................56 
9.1. 
Schedule of Study Events ...........................................................................................56 
9.2. 
Study Fasting Requirements .......................................................................................57 
9.3. 
Screening Assessments ...............................................................................................57 
9.4. 
Medical History and Demographics ...........................................................................57 
9.5. 
Physical Examination .................................................................................................57 
9.6. 
Vital Signs ..................................................................................................................57 
9.7. 
Electrocardiogram .......................................................................................................58 

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9.8. 
Clinical Laboratory Assessments ...............................................................................58 
9.9. 
Contraception Requirements and Pregnancy Testing .................................................59 
9.10. 
Patient-reported Outcomes .........................................................................................60 
9.11. 
Pharmacokinetic Assessments ....................................................................................61 
9.12. 
Biorepository Samples ................................................................................................61 
9.13. 
Genotyping .................................................................................................................61 
9.14. 
Safety Assessments .....................................................................................................61 
10. 
ADVERSE EVENT REPORTING ............................................................................62 
10.1. 
Adverse Event (AE) ....................................................................................................62 
10.1.1. 
COVID-19 Adverse Events ........................................................................................62 
10.2. 
Serious Adverse Event (SAE) ....................................................................................62 
10.3. 
Adverse Events of Interest (AEOI) .............................................................................63 
10.3.1. 
Abnormal Liver Function Test Results.......................................................................63 
10.4. 
Acute Kidney Injury ...................................................................................................64 
10.5. 
Serious Renal Conditions ...........................................................................................65 
10.6. 
Evaluation of Adverse Events/Serious Adverse Events .............................................65 
10.6.1. 
Causality Assessment .................................................................................................65 
10.6.2. 
Severity .......................................................................................................................66 
10.6.3. 
Outcome ......................................................................................................................66 
10.6.4. 
Action Taken Regarding the Study Medication .........................................................66 
10.6.5. 
Assessment of Expectedness ......................................................................................67 
10.7. 
Reporting Adverse Events and Serious Adverse Events ............................................67 
10.7.1. 
Reporting Adverse Events ..........................................................................................67 
10.7.2. 
Reporting Serious Adverse Events .............................................................................67 
10.7.3. 
Follow-up of Adverse Events and Serious Adverse Events .......................................68 
10.7.4. 
Reporting to Regulatory Authorities, Investigators and Institutional Review 
Boards/Independent Ethics Committees .....................................................................69 
10.8. 
Pregnancy Reporting ..................................................................................................69 
11. 
DATA COLLECTION, QUALITY ASSURANCE, AND MANAGEMENT ..........71 
11.1. 
Recording of Data .......................................................................................................71 
11.2. 
Data Quality Assurance ..............................................................................................71 
11.3. 
Data Management .......................................................................................................71 
12. 
STATISTICAL METHODS AND PLANNED ANALYSES ...................................72 

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12.1. 
General Considerations ...............................................................................................72 
12.2. 
Determination of Sample Size ....................................................................................72 
12.2.1. 
Surrogate Endpoint: Proportion of Patients Achieving Target UP/C ≤1.5 g/g 
(170 mg/mmol) and a >40% Reduction in UP/C at Week 36 ....................................72 
12.2.2. 
Primary Endpoint: Slope of eGFR ..............................................................................72 
12.3. 
Analysis Sets ...............................................................................................................73 
12.3.1. 
Full Analysis Set .........................................................................................................73 
12.3.2. 
Per Protocol Analysis Set ...........................................................................................73 
12.3.3. 
Safety Analysis Set .....................................................................................................73 
12.3.4. 
Open-Label Extension Full Analysis Set ....................................................................73 
12.4. 
Demographics and Baseline Characteristics ...............................................................74 
12.5. 
Patient Accountability ................................................................................................74 
12.6. 
Study Treatment Usage and Compliance ...................................................................74 
12.7. 
Efficacy Analysis ........................................................................................................75 
12.7.1. 
Primary Efficacy Analysis ..........................................................................................75 
12.7.1.1. 
Primary Efficacy Endpoint: Slope of eGFR at the Final Analysis .............................75 
12.7.1.2. 
Surrogate Efficacy Endpoint: Proportion of Patients Achieving a UP/C 
≤1.5 g/g (170 mg/mmol) and a >40% Reduction from Baseline at Week 36 ............76 
12.7.2. 
Secondary Efficacy Analyses .....................................................................................77 
12.7.3. 
Additional Efficacy Analyses .....................................................................................77 
12.8. 
Safety Analyses ..........................................................................................................79 
12.8.1. 
Physical Examination and Vital Signs ........................................................................79 
12.8.2. 
Clinical Laboratory Tests ...........................................................................................79 
12.8.3. 
Adverse Events ...........................................................................................................79 
12.8.4. 
Other Safety Assessments ...........................................................................................80 
12.9. 
Other Analyses ............................................................................................................80 
12.9.1. 
Prior Medications, Concomitant Medications, and Concomitant Medical 
Procedures ...................................................................................................................80 
12.9.2. 
Pharmacokinetics ........................................................................................................80 
12.10. 
Other Statistical Issues ................................................................................................80 
12.10.1. 
Significance Levels .....................................................................................................80 
12.10.2. 
Multiple Comparisons/Multiplicity ............................................................................80 
12.10.3. 
Missing Data ...............................................................................................................81 

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12.11. 
Interim Analysis ..........................................................................................................81 
12.12. 
Analyses for the Open-Label Extension .....................................................................82 
13. 
SPECIAL REQUIREMENTS AND PROCEDURES................................................83 
13.1. 
Institutional and Ethics Review ..................................................................................83 
13.2. 
Data Monitoring Committee .......................................................................................83 
13.3. 
Changes to the Conduct of the Study or Protocol .......................................................84 
13.4. 
Investigator's Responsibilities ....................................................................................84 
13.4.1. 
Patient Informed Consent ...........................................................................................85 
13.4.2. 
Case Report Forms .....................................................................................................85 
13.4.3. 
Record Retention ........................................................................................................85 
13.4.4. 
Monitoring ..................................................................................................................86 
13.4.5. 
Study or Site Termination ...........................................................................................86 
13.4.6. 
Study Medication Control...........................................................................................87 
13.4.6.1. 
Receipt of Study Medication ......................................................................................87 
13.4.6.2. 
Disposition of Unused Study Medication ...................................................................87 
13.4.6.3. 
Product Handling and Complaints Reporting .............................................................88 
13.4.7. 
Insurance .....................................................................................................................88 
13.4.8. 
Data Confidentiality ....................................................................................................88 
13.4.9. 
Clinical Study Report .................................................................................................88 
14. 
REFERENCES ...........................................................................................................89 
15. 
APPENDICES ............................................................................................................92 
15.1. 
Appendix A: Schedule(s) of Study Events .................................................................92 
15.2. 
Appendix B: Supplemental Study Information ........................................................103 
15.2.1. 
Concomitant Medication Considerations .................................................................103 
15.2.2. 
Recommendations for Management of Hyperkalemia .............................................109 
15.2.3. 
Peripheral Edema Assessment Guidance ..................................................................110 
15.2.4. 
Clinical Laboratory Assessments Performed During the Study ...............................111 
15.3. 
Appendix C: Germany-Specific Requirements ........................................................113 
15.4. 
Appendix D: Protocol History ..................................................................................120 
 

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LIST OF TABLES 
Table 1: 
Study 021FSGS16010 Double-Blind Study Visits .....................................................38 
Table 2: 
Sparsentan and Active Control Irbesartan Doses Allowed During the 
Double-Blind Period ...................................................................................................49 
Table 3: 
Sparsentan Doses Allowed During the Open-Label Extension ..................................50 
Table 4: 
Double-Blind Period: Schedule of Events from Screening Through Week 12 ..........92 
Table 5: 
Double-Blind Period: Schedule of Events from Week 24 Through End of the 
Double-Blind Period ...................................................................................................96 
Table 6: 
Open-Label Extension: Schedule of Events from Week 114 through 
Week 184 ....................................................................................................................99 
Table 7: 
Open-Label Extension: Schedule of Events from Week 196 through End of 
Study .........................................................................................................................101 
Table 8: 
Clinical Laboratory Assessments During the Double-Blind Period .........................111 
Table 9: 
Clinical Laboratory Assessments During the Open-Label Extension ......................112 
Table 10: Germany Summary of Changes ................................................................................114 
 
LIST OF FIGURES 
Figure 1: 
Study 021FSGS16010 Overview Flow Chart of the Double-Blind Period ................37 
Figure 2: 
Study 021FSGS16010 Overview Flow Chart of the Open-Label Extension .............39 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations used throughout the protocol should not be used by the site when documenting 
adverse events, medical history, etc. on source documents. 
Abbreviation 
Definition 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
AEOI 
Adverse event of interest 
AKI 
Acute kidney injury 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AngII 
Angiotensin II 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
AT1 
Angiotensin II type 1 receptor 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology (equation) 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus disease 2019 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DUET 
Study RET-D-001, NCT01613118, EudraCT 2014-002358-38: Efficacy and 
Safety of Sparsentan (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 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
eGFR 
Estimated glomerular filtration rate 
EM 
Electron microscopy 
EOS 
End of Study 
EOT 
End of treatment 

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Abbreviation 
Definition 
EQ-5D-5L 
EuroQol, 5-dimension quality of life instrument, version 5L 
EQ-5D-Y 
EuroQol, 5-dimension quality of life instrument, version Y 
ERA 
Endothelin receptor antagonist 
ESRD 
End-stage renal disease 
ET 
Early termination 
ETA 
Endothelin receptor subtype A 
ETB 
Endothelin receptor subtype B 
 
 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSGS 
Focal segmental glomerulosclerosis 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GMP 
Good Manufacturing Practice 
HbA1c 
Hemoglobin A1c (glycosylated hemoglobin) 
HBeAg 
Hepatitis B “e” antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IF 
Immunofluorescence 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IWRS 
Interactive web response system 
KDIGO 
Kidney Disease Improving-Global Outcomes 

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Abbreviation 
Definition 
KDQOL 
Kidney Disease Quality of Life (instrument)  
LDL-C 
Low-density lipoprotein cholesterol 
LOCF 
Last observation carried forward 
LS 
Least-squares 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
Mixed Model Repeated Measures 
NSAID 
Non-steroidal anti-inflammatory drug 
OLEFAS 
Open-label Extension Full Analysis Set 
PedsQL 
Pediatrics Quality of Life Inventory 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol (analysis set) 
PRO 
Patient-reported outcome 
QoL 
Quality of life 
RAAS 
Renin-angiotensin-aldosterone system 
REML 
Restricted maximum likelihood 
RNA 
Ribonucleic acid 
RRT 
Renal replacement therapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Systems 
SD 
Standard deviation 
SOP 
Standard operating procedure 
SUSAR 
Suspected, unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TRPC 
Transient receptor potential canonical 
UK 
United Kingdom 
ULN 
Upper limit of normal 
UP/C 
Urine protein/creatinine ratio 

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Abbreviation 
Definition 
US 
United States 
VLDL-C 
Very low-density lipoprotein cholesterol 
WBC 
White blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
WOCBP 
Women of childbearing potential 
 

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4. 
INTRODUCTION 
Focal Segmental Glomerulosclerosis 
Focal segmental glomerulosclerosis (FSGS) is a renal histological lesion characterized by 
segmental accumulation of glomerular extracellular matrix resulting in glomerular scarring and 
capillary obliteration. A variety of heterogeneous clinical conditions may lead to FSGS-type 
lesions, which could be classified as primary, genetic, or secondary forms. Primary FSGS has no 
identifiable cause but may result from the actions of putative circulating permeability factors that 
cause podocyte injury. Genetic causes include mutations in genes encoding proteins required for 
normal podocyte structure and/or function. In contrast, secondary forms of FSGS are caused by 
loss of renal parenchyma, metabolic derangements, other antecedent diseases, drugs, or 
infections (D’Agati 2011). 
The presentation of primary and genetic FSGS varies, but can include severe proteinuria, arterial 
hypertension, edema, and nephrotic syndrome (Coppo 2013; Ponticelli 2013; Sethna 2014), with 
the potential for progression to end-stage renal disease (ESRD) and the consequent need for 
dialysis and kidney transplant. 
Primary FSGS is a leading and growing cause of nephrotic syndrome (D’Agati 2011), and 
accounts for 3% to 4% of the prevalence of ESRD (Kitiyakara 2003). In most case series 
presented in the literature, primary FSGS is associated with a 10-year kidney survival in the 
range of 40% to 70% (Cameron 1978; Cattran 1998; Korbet 1986; Wehrmann 1990). 
Patients with primary FSGS who present with nephrotic-range proteinuria have poor prognosis 
without treatment and typically progress to ESRD over the course of 3 to 6 years (Korbet 2002; 
Korbet 2003). Similarly, lack of response to disease-modifying treatments such as steroids has 
been identified as a negative prognostic sign (Korbet 2002). For patients with genetic FSGS, a 
rarer form than primary FSGS, kidney survival rates are comparably poor, with the rate of 
progression to ESRD tending to vary depending on mutation type. Treatment options are limited 
as genetic FSGS patients are generally resistant to immunosuppressive therapy. Taken together, 
clinical data show primary and genetic FSGS to be a serious condition associated with significant 
mortality and morbidity. 
Sparsentan is a first-in-class, potent, orally active, dual-acting angiotensin receptor blocker 
(ARB; angiotensin II type 1 [AT1]) plus endothelin type A (ETA) receptor blocker. The selective, 
dual antagonistic actions of sparsentan have been demonstrated by in vitro binding assays 
(Kowala 2004). 
Role and Pathophysiology of Angiotensin II and Endothelin in FSGS 
To date, no studies focusing specifically on the mechanism of action of sparsentan on the kidney 
have been performed. However, considering known pharmacological actions of dual blockade of 
AT1 and ETA, sparsentan’s actions on the renal system can be inferred from literature reports 
describing separate effects of AT1 or ETA receptor inhibition. 
Angiotensin II (AngII) and endothelin 1 (
 affect practically all renal compartments and cell 
types (Kohan 2014; Rüster 2011; Wennmann 2012), being implicated in processes involved in 
the pathophysiology of chronic kidney disease (CKD). There are overlaps in the actions of both 
peptides on the renal system that may act in an additive or synergistic manner in the pathogenesis 
of CKD, thus providing a strong rationale for dual blockade (Komers 2016). 

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Both AngII (Carmines 1990) and 
 are vasoactive peptides that exert renal hemodynamic 
effects. They promote cell growth, oxidative stress, and increased expression and activity of 
well-established proinflammatory and profibrotic signaling molecules and mediators 
(Gerstung 2007; Lenoir 2014; Watson 2010; Saleh 2011a; Saleh 2011b; Saleh 2010; 
Sasser 2007; Simonson 2011; Zoja 1999; Gagliardini 2009; Boffa 2001). The 
prosclerotic/fibrogenic and inflammatory actions of 
 may occur as part of AngII signaling 
(Rüster 2011) or as a direct consequence of stimulation of ETA receptors (Saleh 2010; 
Simonson 2011). 
Relevant to the pathogenesis and treatment of primary FSGS, both AngII and 
 affect 
podocytes, which are an integral part of the glomerular filtration barrier that prevents the passage 
of proteins into the urinary space. Both peptides play a role in the pathogenesis of proteinuria, 
being involved in a variety of processes that directly result in podocytic dysfunction and 
structural alterations. For example, the podocyte-specific overexpression of AT1 receptors in rats 
is sufficient to cause proteinuria that eventually results in FSGS-type lesions. At the cellular 
level, the stimulation of AT1 leads to activation of ion channels (transient receptor potential 
canonical [TRPC]5 and TRPC6), increases in cytosolic calcium, and activation of signaling 
pathways that ultimately induce membrane ruffling and the loss of stress fibers (Greka 2011). 
The impact on the cytoskeleton is similar to the depletion of synaptopodin, an important 
podocytic structural protein. Studies with renin-angiotensin-aldosterone-system (RAAS) 
inhibitors also implicate AngII in the loss of slit diaphragm proteins such as nephrin 
(Langham 2002). 
Similarly, 
 is involved in podocyte alterations, apoptosis, and loss of podocytic structural 
proteins. Nephrin shedding, the loss of synaptopodin, and cytoskeletal rearrangement result in 
foot process effacement, which is a hallmark of podocytopathies (Barton 2012; Buelli 2014; 
Lenoir 2014; Saleh 2011b) including FSGS (Buelli 2014; Daehn 2014). Podocytes are not only 
targets of 
 actions, but are also a source of the peptide, resulting in deleterious effects on 
adjacent glomerular endothelial cells and causing mitochondrial dysfunction and production of 
reactive oxygen species (Daehn 2014). 
In addition, 
 acting via ETA receptors, increases glomerular permeability to albumin both in 
vitro and in vivo in a blood pressure-independent manner (Saleh 2010; Saleh 2012). These 
actions contribute to the proteinuric effects of 
 Treatment with endothelin receptor 
antagonists (ERAs; or more recently by genetic deletion of endothelin receptors) ameliorated 
cytoskeletal changes, restored podocyte structural integrity, and reduced proteinuria in models of 
podocyte injury and FSGS (Buelli 2014; Daehn 2014; Opocenský 2004). Both experimental and 
clinical evidence suggests that dual blockade of AngII and 
 has more prominent 
antiproteinuric effects than inhibition of either peptide alone (Komers 2016). However, data 
demonstrating the superior effect of a dual blockade on the long-term preservation of kidney 
function are not yet available. 
Sparsentan Clinical Development 
The purpose of sparsentan clinical development is to combine the potentially synergistic action 
of AngII receptor blockade with 
 receptor antagonism for clinical use in treating FSGS. 
Sparsentan has been evaluated in a clinical development program targeted at the treatment of 
hypertension. That program consisted of 7 Phase 1 studies in 160 healthy volunteers and 

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2 Phase 2 studies in over 200 hypertensive patients. Dose-proportional pharmacokinetics (PK) 
and adequate oral exposure have been well defined. In a clinical pharmacodynamic study, 
sparsentan doses of 250 and 500 mg were shown to block the AngII pressor response in a healthy 
volunteer challenge test. 
A Phase 2a study in hypertensive patients demonstrated clinically meaningful blood pressure 
reduction. A Phase 2b study that included a head-to-head comparison of sparsentan to irbesartan 
demonstrated superior efficacy of sparsentan at a dose of 800 mg/day compared to irbesartan at 
irbesartan’s maximal approved dose of 300 mg/day. Progressive dose-dependent blood pressure 
reduction occurred through the highest sparsentan dose of 800 mg. Phase 1 Clinical Trials in 
healthy volunteers, and Phase 2 studies in hypertensive patients have shown a favorable safety 
profile with no drug-related serious adverse events (SAEs), changes in vital signs, or major 
clinically significant abnormalities in laboratory tests. 
Sparsentan is currently being investigated in the ongoing open-label treatment period of the 
Phase 2 DUET study in patients with primary FSGS (RET-D-001; NCT01613118; 
EudraCT 2014-002358-38). The study aim is to determine the change in proteinuria after 
8 weeks of double-blind treatment in primary FSGS patients receiving sparsentan over a range of 
dose levels (200 mg, 400 mg, and 800 mg) when compared to treatment with 300 mg irbesartan 
as active control. 
In brief, patients 8 to 75 years of age with biopsy-proven FSGS (or documentation of a genetic 
mutation in a podocyte protein associated with the disease) were enrolled and assigned to 1 of 
5 cohorts, representing 3 escalating sparsentan doses (200 mg, 400 mg, and 800 mg). Within 
each cohort, patients were randomized to sparsentan or a fixed maximal dose of active control 
(irbesartan) for an 8-week double-blind period. Patients weighing ≤50 kg received one-half of 
the randomized dose of either sparsentan or irbesartan. Following the double-blind period, 
patients were offered open-label sparsentan treatment in the study for an additional 208 weeks. 
The primary efficacy objective of the DUET study was to determine the level of proteinuria 
reduction in patients with primary FSGS; the primary endpoint was the change in proteinuria 
after 8 weeks of double-blind treatment in patients receiving sparsentan over a range of dose 
levels (200 mg, 400 mg, and 800 mg) compared with treatment with irbesartan as the active 
control. Proteinuria was quantified using the urine protein/creatinine ratio (UP/C). The primary 
safety objective of the DUET study was to assess the safety and tolerability of sparsentan over a 
range of doses by comparing the safety profile of patients treated with sparsentan with that of 
patients treated with irbesartan (active control). This study also provided full PK profiles at 
Day 1 and Week 8, along with trough drug plasma concentrations at all other visits. 
The first patient was screened for the DUET study on 13 Mar 2014 and was randomized on 
07 Apr 2014. A total of 109 patients have been enrolled, including 23 pediatric FSGS patients 
(aged 8 to 18 years). Preliminary results are available from an interim analysis of data using a 
cutoff date of 09 Jun 2016. This analysis includes all safety and efficacy data collected through 
the double-blind period, as well as all open-label data available as the cutoff date. The 
preliminary results from this analysis outlined below indicate the greater antiproteinuric potential 
of sparsentan as compared to the ARB irbesartan. 

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• The DUET study met its primary efficacy endpoint: 
− The mean percentage reduction in UP/C from baseline in all sparsentan-treated 
patients (ie, 200 mg, 400 mg, and 800 mg groups combined; n = 64) to the end of 
the 8-week double-blind treatment phase was 44.8%, compared to a mean 
percentage reduction in irbesartan-treated patients (n = 32) of 18.5% (p = 0.006). 
− The mean percentage reduction in UP/C from baseline in all patients treated with 
400 mg or 800 mg sparsentan (ie, 400 mg and 800 mg groups combined; n = 51) 
to the end of the 8-week double-blind treatment phase was 47.4%, compared to a 
mean percentage reduction in irbesartan-treated patients in these 2 dose cohorts 
(n = 25) of 19.0% (p = 0.011). 
− The comparison of UP/C reduction in the individual sparsentan doses to 
irbesartan showed clear signals of improvement but did not reach statistical 
significance. 
• For DUET’s secondary efficacy endpoint, the proportion of patients experiencing a 
UP/C ratio ≤1.5 g/g and a >40% reduction from baseline in UP/C at Week 8 was 
greater among sparsentan-treated patients (28.1%) compared with irbesartan-treated 
patients (9.4%; p = 0.040). 
• Based on the preliminary results of the interim analysis, sparsentan has been 
well-tolerated thus far in the DUET study, with the majority (96.3%) of 
treatment-emergent adverse events (TEAEs) being mild or moderate. The most 
common TEAEs among sparsentan-treated patients were headache, dizziness, 
hypotension, nausea, diarrhea, vomiting, and peripheral edema/edema. 
4.1. 
Summary of Potential Risks 
The potential risks for patients treated with sparsentan are a consequence of its dual antagonist 
properties of both angiotensin and endothelin receptor blockade. Due to its ARB properties, 
sparsentan imparts a potential risk of acute kidney injury (AKI) due to reductions in 
intracapillary glomerular pressure, and a risk of hyperkalemia due to lower glomerular filtration 
rate (GFR) and aldosterone inhibition. In addition, syncope has been identified as a risk due to 
sparsentan’s antihypertensive properties. These risks are accentuated in patients with reduced 
kidney function, volume depletion, and those being treated with non-steroidal anti-inflammatory 
drugs (NSAIDs). Studies have also shown that treatment with ERAs is associated with increased 
rates of edema and congestive heart failure (CHF) in patients with diabetic nephropathy 
(Mann 2010). 
Selective and nonselective endothelin ETA/endothelin receptor subtype B (ETB) receptor 
antagonists are expected to cause fetal harm (harm to a developing embryo) if given to pregnant 
women. Similarly, ARBs have been shown to reduce fetal renal function and increase fetal and 
neonatal morbidity and death during the second and third trimesters of pregnancy. However, a 
recently completed, thorough, scientific evidence-based review of all available toxicology data 
evaluating the risk of genotoxic and teratogenic effects of sparsentan in male patients and their 
female partners indicates that, similar to marketed ERAs and ARBs, the requirement for 
contraception in male study patients is not warranted. 

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Because of these potential risks, sparsentan should be used with caution in patients with CKD 
Stages 3 and 4 and with extreme caution in patients with CKD Stage 5 and patients at risk of 
AKI. Moreover, sparsentan should be avoided in patients with CHF Stages 2 through 4, and in 
women who are or may become pregnant or who are breastfeeding. 
For details regarding all nonclinical and clinical data on sparsentan, as well as warnings, 
precautions, and contraindications, the Investigator should refer to the appropriate section of the 
Investigator’s Brochure. 
4.2. 
Summary of Potential Benefits 
Treatment-associated reduction in proteinuria in patients with primary FSGS may translate into a 
long-term nephroprotective effect. Sparsentan’s antiproteinuric effect in patients with primary 
FSGS was observed in the DUET study (see Section 4). The current study will provide additional 
and essential long-term efficacy data to determine the durability of sparsentan’s antiproteinuric 
effect over time, as well as its ability to slow the progression of primary FSGS, as measured by 
change in estimated glomerular filtration rate (eGFR) compared to standard-of-care therapies. 
4.3. 
Rationale for the Study 
The preliminary results from the interim analysis of data from the DUET study (see Section 4) 
indicate that sparsentan has a markedly stronger antiproteinuric effect than irbesartan over a 
period of 8 weeks in patients with primary FSGS. Although most nephrologists accept that even 
a short-term treatment-associated reduction in proteinuria results in better long-term renal 
outcomes, this hypothesis must be investigated further in a long-term study focusing on the 
durability of sparsentan’s effect over a longer time period, and also on kidney function as 
measured by eGFR. 
Despite its progressive course, which may result in some patients reaching ESRD within 5 to 
10 years, primary FSGS is characterized by relatively slow decline in GFR in most patients. 
Consequently, utilization of the “hard” endpoints recognized by regulatory agencies for long-
term interventional studies in kidney diseases (ie, doubling of serum creatinine, ESRD or renal 
replacement therapy [RRT], or death) is not practical for investigating appropriate treatments for 
FSGS. To address this issue, the current study (Protocol 021FSGS16010; also referred to as 
DUPLEX) will utilize the slope of eGFR decline as the primary endpoint to explore treatment 
differences between sparsentan and irbesartan. It is assumed that the stronger antiproteinuric 
effect seen with sparsentan leads to better preservation of kidney function, and consequently to 
less steep decline in GFR compared with irbesartan. 
GFR will be estimated in this study every 3 months to obtain sufficient data for generation of 
reliable GFR slopes over a period of 2 years. Changes in kidney function will be evaluated in 
parallel with measurements of antiproteinuric effects of both sparsentan and irbesartan to further 
support the role of treatment-induced changes in proteinuria as a surrogate for long-term kidney 
survival. 
Because pediatric patients comprise a substantial proportion of patients with FSGS, this study 
will include patients 8 years of age and older. As with the adult population, the goal of treatment 
for the pediatric population (aged 8 to 18 years) is reduction of proteinuria and preservation of 
kidney function; treatment-induced change in proteinuria has been associated with markedly 

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better long-term kidney survival and reduced need for RRT in both populations. Therefore, the 
study endpoints chosen are relevant for both pediatric and adult patients. 
Current experience with sparsentan treatment in patients with FSGS does not indicate specific 
safety concerns for pediatric patients. In this study, pediatric patients with a screening body 
weight >50 kg will be treated with the same dose as adult patients, whereas both adult and 
pediatric patients with a screening body weight ≤50 kg will receive one-half the target dose of 
sparsentan or active control. 
For details regarding all nonclinical and clinical data on sparsentan, as well as warnings, 
precautions, and contraindications, the Investigator should refer to the appropriate section of the 
Investigator’s Brochure. 

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5. 
STUDY OBJECTIVES 
5.1. 
Efficacy Objective 
The efficacy objective of the study is to determine the long-term nephroprotective potential of 
treatment with sparsentan as compared with an ARB in patients with primary and genetic FSGS. 
5.2. 
Safety Objective 
The safety objective of the study is to assess the safety and tolerability of sparsentan by 
double-blind monitoring of safety endpoints. 
5.3. 
Open-Label Objective 
The open-label objective of the study is to assess the long-term efficacy, safety, and tolerability 
of open-label sparsentan in patients with FSGS. 

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6. 
INVESTIGATIONAL PLAN 
6.1. 
Endpoints 
6.1.1. 
Efficacy Endpoints 
6.1.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the slope of eGFR over approximately 2 years of randomized 
treatment assessed at the final analysis. The slope of eGFR is evaluated following the initial 
acute effect of randomized treatment (ie, from Week 6 to Week 108; chronic slope over 2 years) 
in non-United States (US) countries and following initiation of randomized treatment (ie, from 
Day 1 to Week 108; total slope over 2 years) in the US. 
The surrogate efficacy endpoint is the proportion of patients achieving a UP/C ≤1.5 g/g 
(170 mg/mmol) and a >40% reduction from baseline of the double-blind period in UP/C at 
Week 36. 
6.1.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are assessed at the final analysis and are part of a hierarchical 
(gate-keeping) testing procedure (see Section 12.10.2). Secondary efficacy endpoints in non-US 
countries include: 
• The percent change from Week 6 in eGFR at Week 108 
• The percent change in eGFR from baseline of the double-blind period to 4 weeks 
post-cessation of randomized treatment at Week 112 
• The slope of eGFR following the initiation of randomized treatment (ie, from Day 1 
to Week 108; total slope over 2 years) 
The secondary efficacy endpoints in the US are: 
• The slope of eGFR following the initial acute effect of randomized treatment 
(ie, from Week 6 to Week 108; chronic slope over 2 years) 
• The change in eGFR from baseline of the double-blind period to 4 weeks 
post-cessation of randomized treatment at Week 112 
6.1.1.3. 
Exploratory Endpoints for the Double-Blind Period 
• The slopes of eGFR over approximately 1 year of randomized treatment evaluated 
following the initial acute effect of randomized treatment (ie, from Week 6 to 
Week 60; chronic slope over 1 year) and after initiation of randomized treatment 
(ie, from Day 1 to Week 60; total slope over 1 year) 
• The absolute and percent change from baseline of the double-blind period in eGFR at 
each visit 
• The percent change from Week 6 in eGFR at each visit 
• The proportion of patients achieving a UP/C ≤1.5 g/g (170 mg/mmol) and a 
>40% reduction from baseline of the double-blind period in UP/C at each visit 

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• The percent change from baseline of the double-blind period in UP/C at each visit 
• The time to achieve the target reduction in UP/C (ie, ≤1.5 g/g [170 mg/mmol] and a 
>40% reduction) 
• The proportion of patients reaching a confirmed 40% reduction in eGFR, ESRD, or 
death. (ESRD is defined as initiation of RRT or sustained eGFR <15 mL/min/1.73 m2 
during the study). 
• The proportion of patients reaching a confirmed 30% reduction in eGFR, ESRD, or 
death 
• Changes from baseline of the double-blind period in blood pressure at each visit 
• The proportion of patients requiring initiation of or intensification in 
immunosuppressive medication during the study 
• The proportion of patients undergoing reduction in immunosuppressive medication 
during the study 
• The time to initiation or intensification of immunosuppressive medication during the 
study 
• Changes from baseline of the double-blind period in quality of life (QoL), measured 
via patient-reported outcome (PRO) at each visit beginning with Week 12 
• Frequency and duration of hospitalizations (for any reason and for reasons related to 
the kidney) 
• Trough plasma PK concentrations during the double-blind period 
6.1.2. 
Safety Endpoints 
Safety endpoints include: 
• Changes from baseline of the double-blind period in body weight, vital signs, 
physical examinations, peripheral edema, 12-lead electrocardiogram (ECG), and 
clinical laboratory parameters 
• Changes from baseline of the double-blind period in lipid profile (total cholesterol 
and triglycerides, low-density lipoprotein cholesterol [LDL-C], very low-density 
lipoprotein cholesterol [VLDL-C], and high-density lipoprotein cholesterol [HDL-C]) 
• Changes from baseline of the double-blind period in serum albumin and serum 
potassium at each visit 
• The incidence of TEAEs during the double-blind period 
6.1.3. 
Open-Label Endpoints 
Endpoints for the open-label extension include, but are not necessarily limited to: 
• The absolute and percent change from Week 112 in eGFR at each visit 
• The percent change from Week 112 in UP/C at each visit 
• Changes from Week 112 in QoL at each visit 
• Changes from Week 112 in body weight, vital signs, physical examinations, 
peripheral edema, and clinical laboratory parameters 

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• Changes from Week 112 in lipid profile (total cholesterol and triglycerides, LDL-C, 
and HDL-C) 
• The incidence of TEAEs during the open-label extension 
6.2. 
Study Design 
This is a 112-week, randomized, multicenter, double-blind, parallel, active-control study, with an 
open-label extension of up to 156 weeks, for a total study duration of up to 268 weeks. 
Approximately 300 patients aged 8 to 75 years, inclusive (US and United Kingdom [UK]) and 
18 to 75 years, inclusive (countries other than the US and UK), weighing ≥20 kg, will be 
enrolled in the study. 
6.2.1. 
Double-Blind Period Design 
Patients who meet inclusion criteria during screening who are taking RAAS inhibitors will 
undergo a 2-week washout period from these agents prior to Day 1/Randomization. 
Following screening (and the washout period for patients taking RAAS inhibitors), all patients 
will undergo comprehensive baseline evaluations and clinical laboratory tests, and will be 
randomly assigned in a 1:1 ratio to receive either sparsentan (initial dose of 400 mg daily for 
2 weeks, titrating up to a target dose of 800 mg daily) or an active control (irbesartan; initial dose 
of 150 mg daily for 2 weeks, titrating up to a target dose of 300 mg daily) (see Section 8.1). 
Randomization will include stratification by screening eGFR and UP/C values. The strata will be 
as follows: 
• eGFR strata: 
− ≥30 to <60 mL/min/1.73 m2 (all patients) 
− ≥60 mL/min/1.73 m2 (all patients) 
• UP/C strata: 
− ≤3.5 g/g (396 mg/mmol; patients ≥18 years of age) or ≤2 g/g (226 mg/mmol; 
patients <18 years of age) 
− >3.5 g/g (396 mg/mmol; patients ≥18 years of age) or >2 g/g (226 mg/mmol; 
patients <18 years of age) 
Sparsentan and irbesartan concentrations in plasma will be evaluated. At applicable visits 
(see Section 15.1), 1 trough sample will be obtained pre-dose in the clinic. 
Unless otherwise specified, endpoints will use pretreatment values obtained prior to 
randomization as baseline. The follow-up visits to obtain measurements will be conducted at 
3-month intervals unless otherwise specified. 
Additional antihypertensive agents are allowed during the double-blind period to maintain blood 
pressure ≤130/80 mmHg (patients ≥18 years of age) or ≤ the 75th percentile (patients <18 years 
of age; Banker 2016), with the exception of those agents that inhibit the RAAS and endothelin 
systems (see Section 15.2.1 for concomitant medication considerations). 
An unblinded analysis will be performed after 36 weeks following randomization of at least 
190 patients (approximately 95 per treatment group) to evaluate the surrogate efficacy 

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endpoint (ie, the proportion of patients achieving a UP/C ≤1.5 g/g [170 mg/mmol] and a 
>40% reduction in UP/C at Week 36). 
Following a 108-week blinded treatment period, treatment with study medication will be 
discontinued, and patients may be evaluated for eligibility in the open-label extension using 
values from the Week 108 visit as screening assessments (see Section 6.2.2). At this time, the 
Investigator should resume standard-of-care treatment, including treatment with RAAS inhibitors 
provided there are no contraindications for their use. If the patient was treated with irbesartan at 
study entry, an alternative ARB at an equivalent dose is required from Week 108 to Week 112. 
The Investigator may make additional adjustments in antihypertensive medications as necessary 
to adequately control the patient’s blood pressure. 
Patients will return to the site for the final visit of the double-blind period 4 weeks after study 
medication has been discontinued (ie, Week 112; see Figure 1). 
Figure 1: 
Study 021FSGS16010 Overview Flow Chart of the Double-Blind Period 
 
a Screening may begin after informed consent has been signed. The screening window begins on the day of the 
patient’s first in-clinic study procedure. Patients should be screened within the 6-week screening period; however, 
under extenuating circumstances the screening period may be extended by a maximum of 2 weeks. 
b For patients who are undergoing washout from RAAS inhibitors. 
c Patients whose body weight is ≤50 kg at screening will receive one-half the otherwise specified doses of either 
sparsentan or irbesartan (active control). Weight will be measured at each visit and the dose increased at the 
Investigator’s discretion if the patient’s weight reaches >50 kg. 
d Day 1 events shown will occur in the order in which they are listed. 
e Randomization will be stratified by eGFR value (≥30 to <60 mL/min/1.73 m2 and ≥60 mL/min/1.73 m2 for all 
patients) and UP/C (≤3.5 g/g and >3.5 g/g [396 mg/mmol; patients ≥18 years of age] or ≤2 g/g and >2 g/g 
[226 mg/mmol; patients <18 years of age]) at screening. 
f Following the 108-week blinded treatment period, treatment with study medication will be discontinued and 
patients may be evaluated for eligibility in the open-label extension. At this time, the Investigator should resume 
standard-of-care treatment, including treatment with RAAS inhibitors provided there are no contraindications for 
their use. If the patient was treated with irbesartan at study entry, an alternative ARB at an equivalent dose is 
required from Week 108 to Week 112. The Investigator may make additional adjustments in antihypertensive 
medications as necessary to adequately control the patient’s blood pressure. 

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Table 1: 
Study 021FSGS16010 Double-Blind Study Visits 
Visit: 
Visit 1a 
Visit 2 
(± 3 days) 
Visit 3d 
Visit 4 
(± 3 days) 
Visit 5 
(± 3 days) 
Visit 6 
(± 7 days) 
Visit 7 
(± 7 days) 
Visit 8 
(± 7 days) 
Screening  
All 
Patients  
Washout 
Patientsb 
Blinded Treatment  
Week
: 
W -6  
W -
2b 
W-1c 
Day 1 
(Randomizatio
n) 
W2 
W4  
W6 
W8 
W12 
 
Visit: 
Visit 9 
(± 7 
days) 
Visit 10 
(± 7 
days) 
Visit 11 
(± 7 
days) 
Visit 12 
(±7 days) 
Visit 13 
(±7 
days) 
Visit 14 
(±7 days) 
Visit 15 
(±7 days) 
Visit 16e 
(±7 days) 
Visit 17 
(-7 to +14 days) 
Blinded Treatment 
End of 
Double-Blind 
Period Visit 
Week
: 
W24 
W36 
W48 
W60 
W72 
W84 
W96 
W108 
W112 
a The screening period for all patients is 6 weeks (42 days) prior to Day 1. Under extenuating circumstances, the 
screening period may be extended by a maximum of 2 weeks. 
b Patients taking RAAS inhibitors at screening (Visit 1) will complete a 2-week (14-day) washout from these 
medications prior to Day 1 (Randomization). The washout should begin no later than 4 weeks (28 days) after Visit 1. 
c Patients undergoing washout will return to the clinic for a follow-up visit to assess safety and blood pressure control 
approximately 1 week after the start of the washout period. 
d The Day 1 (Randomization) Visit will occur no later than 6 weeks (42 days) after Visit 1 (8 weeks if the screening 
period was extended). All eligible patients will be randomized via interactive web response system (IWRS) and the 
first dose will be administered in the clinic. 
e Visit 16 is the End of Treatment visit. 
6.2.2. 
Open-Label Extension Design 
Patients may be evaluated for eligibility in the open-label extension using values from the 
Week 108 visit as screening assessments. Patients with an eGFR <30 (but >20) mL/min/1.73 m2 
will be eligible for participation in the open-label extension at the discretion of the Investigator, 
but will require close monitoring of eGFR and serum potassium (see Section 7.2.2). 
For patients who agree to participate in the open-label extension and meet eligibility criteria (see 
Section 7.2), the Week 112 visit will also serve as the baseline visit for the open-label extension. 
Standard-of-care treatment (ACEI and/or ARB therapy) will be discontinued before the 
Week 112 visit. The final dose of an ACEI and/or ARB should be taken on the day before the 
Week 112 visit. At this visit, patients will sign a new informed consent (if not completed 
previously) for the open-label extension and begin taking open-label sparsentan. All Week 112 
evaluations must be completed prior to the first dose of open-label sparsentan. 
Patients who are taking 2 or 4 capsules of study medication (ie, 400 mg or 800 mg sparsentan 
or 150 mg or 300 mg irbesartan) at the end of the double-blind period will initiate treatment in 
the open-label extension at one-half the corresponding dose of open-label sparsentan for the first 
2 weeks (ie, 200 mg or 400 mg sparsentan, respectively), then titrate to the target dose after 
confirmation of tolerability at Week 114. Patients who are taking 1 capsule of study medication 
(ie, 200 mg sparsentan or 75 mg irbesartan) at the end of the double-blind period will initiate 
treatment in the open-label extension at 200 mg open-label sparsentan and continue on that dose 

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throughout the open-label extension. For details regarding dose titration in the open-
label- extension, see Section 8.1.2; for details regarding dose modifications, see Section 8.3.2. 
As in the double-blind period, additional antihypertensive agents are allowed during the 
open-label extension to maintain blood pressure ≤130/80 mmHg (patients ≥18 years of age) or 
≤ the 75th percentile (patients <18 years of age; Banker 2016), with the exception of those that 
inhibit the RAAS and endothelin systems (see Section 15.2.1 for concomitant medication 
considerations). 
Patients will participate in the open-label extension for up to 156 weeks (see Figure 2), for a total 
of 268 weeks in the study (ie, double-blind and open-label periods). If the product becomes 
commercially available during the open-label extension period, eligible patients may transition 
out of the study and onto commercial product before the end of the open-label extension period. 
After the patient completes the study (Week 268), if sparsentan is not commercially available, 
patients may potentially receive sparsentan via alternative means depending upon regulations 
and commercial status in each country. 
Figure 2: 
Study 021FSGS16010 Overview Flow Chart of the Open-Label Extension 
 
a See Section 7.2 for eligibility criteria for the open-label extension. 
b The blinded dose the patient is on at Week 108 is dependent on randomization, weight, and ability to tolerate study 
medication during the double-blind period. 
c Dose for the open-label extension will be based on tolerability as determined at Week 114. Any dose titration for 
patients who enter the open-label extension with an eGFR value <30 mL/min/1.73 m2 will be at the Investigator’s 
discretion based on the results of the Week 114 assessments. Doses may be modified at any time throughout the 
open-label extension for safety/tolerability reasons at the Investigator’s discretion. In addition, after titration to the 
target dose, increases above the target doses of 200 mg or 400 mg sparsentan may be considered for patients who, 
in the Investigator’s opinion (and following consultation with the Medical Monitor), would benefit from an 
increased dose. 
d Patients who enter the open-label extension with an eGFR value <30 mL/min/1.73 m2 and titrate at Week 114 will 
be contacted by the Investigator at Week 116 to assess tolerance of the higher dose; at the Investigator’s discretion, 
these patients may also come in for an additional visit at this time. 

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6.3. 
Patient Completion and Overall Study Completion 
6.3.1. 
Patient Completion of the Double-Blind Period 
Each patient will participate in the double-blind period of the study for approximately 6 weeks 
during the screening phase, followed by 108 weeks of double-blind treatment. At the end of the 
108-week treatment period, study medication will be discontinued and replaced with 
standard-of-care therapy treatment, including treatment with RAAS inhibitors provided there are 
no contraindications for their use. If the patient was treated with irbesartan at study entry, an 
alternative ARB at an equivalent dose is required from Week 108 to Week 112. The Investigator 
may make additional adjustments in antihypertensive medications as necessary to adequately 
control the patient’s blood pressure. 
Patients will return to the site for the final (Week 112) visit 4 weeks later. Thus, patients will 
participate in the double-blind period for a total of approximately 118 weeks or about 30 months. 
A patient will be considered as having completed the double-blind period, regardless of whether 
the patient is on or off study medication, if the patient is followed until Week 112. The need for 
additional intervention for the treatment of FSGS or the occurrence of safety endpoints do not 
constitute completion of the double-blind period and are not criteria for withdrawal from the 
study or study medication. 
Patients who successfully complete the final Week 112 Visit will complete the assessments listed 
in the schedule of events (Section 15.1). Patients who received blinded study medication 
throughout the duration of the double-blind- period (ie, did not permanently discontinue study 
medication) may be eligible to enroll in the open-label extension (see Section 7.2). 
6.3.2. 
Patient Completion of the Open-Label Extension 
Eligible patients may participate in the open-label extension for up to 156 weeks. If the product 
becomes commercially available during the open-label extension period, eligible patients may 
transition out of the study and onto commercial product before the end of the open-label 
extension period. After the patient completes the study (Week 268), if sparsentan is not 
commercially available, patients may potentially receive sparsentan via alternative means 
depending upon regulations and commercial status in each country. 
6.3.3. 
Overall Study Completion 
The study will be considered complete when the last patient completes their final visit. 
6.4. 
Discontinuation of Study Medication 
A patient/patient’s parents or guardians is/are free to withdraw assent/consent and/or discontinue 
the patient’s participation in the study at any time, without prejudice to subsequent 
standard-of-care treatment. As part of the informed consent process, only patients who fully 
understand and agree to full and long-term participation should be consented to participate. In all 
cases of impending study medication discontinuation, Investigators should discuss options of 
continuing in the study with the patient (see Section 6.4.1 and Section 6.4.2). In general, patients 
should be encouraged to both stay on study medication and remain in the study until study 
termination. 

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6.4.1. 
Temporary Interruption of Study Medication 
Patients who temporarily interrupt study medication prior to completion of the study will 
continue with study visits and assessments according to the Schedule of Study Events 
(Section 15.1). Unless contraindicated, treatment should be resumed (titrated at the Investigator’s 
discretion according to Section 8.3.2) whenever possible (including between visits), and 
treatment resumption should be considered at every visit following study medication 
interruption. 
6.4.2. 
Permanent Discontinuation of Study Medication 
During the course of this long-term study, it is anticipated that patients may permanently 
discontinue study medication (sparsentan or irbesartan) for any of the following reasons: 
• Receipt of kidney transplant or initiation of RRT 
• Any SAE, AE of interest (AEOI; see Section 10.3), clinically significant laboratory 
abnormality, intercurrent illness, or other medical condition that indicates to the 
Investigator that continuation on study medication is not in the best interest of the 
patient 
• Significant protocol deviation (ie, patient failed to meet entry criteria or did not 
comply with protocol requirements resulting in an unacceptable risk to the patient’s 
health) 
• Investigator discretion 
• Patient (or parent/legal guardian) decision to stop study medication 
• Patient pregnancy 
• Diagnosis of Class II-IV CHF 
• Hyperkalemia resistant to treatment (see Appendix B, Section 15.2.2 for 
hyperkalemia management guidelines) 
• Termination of the study by the Sponsor, US Food and Drug Administration (FDA), 
or other regulatory authorities (see Section 13.4.5) 
• Lost to follow-up 
Therapy to treat relapse (that is a new or substantial change in immunosuppression) during the 
study is not a reason for permanent study medication discontinuation. 
Patients who permanently discontinue study medication during the double-blind period should be 
encouraged to continue study visits through Week 112 for continued collection of safety and 
efficacy data despite stopping study medication, but may withdraw consent at any time (see 
Section 6.5). Patients who agree to continue regularly scheduled study visits will complete the 
End of Treatment (EOT) assessments listed in the schedule of events (Section 15.1) as close as 
possible to the patient’s last dose of study medication. The visit data, including the primary 
reason for discontinuation of study medication, will be recorded on the EOT electronic case 
report form (eCRF). Subsequent study visit data will be recorded on the visit-specific eCRF, and 
the patient’s final study visit will be recorded on the End of Study (EOS) eCRF. 

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For patients who permanently discontinue study medication during the double-blind period, the 
Investigator should resume standard-of-care treatment, including treatment with appropriate 
medications, as deemed necessary. If the patient was treated with irbesartan at study entry, an 
alternative ARB or angiotensin-converting enzyme (ACE) inhibitor must be resumed. 
Patients permanently discontinuing study medication who are not willing to continue with 
regular study visits, but who are willing to continue to provide their information for use in the 
study will be encouraged to remain in the study. The Investigator will contact the Sponsor’s 
designee to determine the best approach based on the patient’s situation. 
Patients who permanently discontinue study medication during the open-label extension are 
encouraged to return to the site for a final visit. No other study visits are necessary. If an EOT 
visit is completed, study medication cannot be resumed. 
6.5. 
Discontinuation of the Patient from the Study 
Patients are free to withdraw consent and/or discontinue participation in the study at any time 
without prejudice to subsequent standard-of-care treatment. A patient’s participation in the study 
may also be discontinued at any time at the discretion of the Investigator or Sponsor. Patients 
may also be discontinued from the study if the study is terminated (see Section 13.4.5). 
Patients may be permanently discontinued from the study for any of the following reasons: 
• Death 
• Voluntary withdrawal of patient/guardian assent/consent (complete withdrawal of 
consent requires a patient’s/parent’s/guardian’s refusal of ALL methods of follow-up 
noted in the informed consent form [ICF]) 
• Termination of the study by the Sponsor, US FDA, or other regulatory authorities 
(see Section 13.4.5) 
• Lost to follow-up 
In general, patients should be encouraged to remain in the study until they complete the 
double-blind period. A patient who permanently discontinues from the study during the 
double-blind- period will complete the early termination (ET) assessments listed in the schedule 
of events (Section 15.1) as close as possible to the patient’s last dose of study medication. The 
visit data, including the primary reason for premature discontinuation from the study, will be 
recorded on the EOS eCRF. 
6.6. 
Lost to Follow-up 
The Investigator must make every effort to contact patients who fail to return for scheduled visits 
so that they will not be declared “lost to follow-up.” Patients will be considered “lost to follow-
up” only after reasonable, documented attempts to reach the patient prove unsuccessful. These 
attempts include, but are not limited to, the following: 
1. Contact all telephone numbers for the patient and their listed contacts (to be collected in 
the source at the patient’s entry into the study), as applicable. 

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2. Contact the patient’s primary care physician, referring specialist, or other healthcare 
professional, as applicable. 
3. Send email, text, and postal mail with certified letters to all the patient’s addresses and 
contacts, as applicable. 
4. Review available medical records/notes for details of hospitalizations, clinic visits, or 
other procedures that may indicate the status of the patient, as applicable. 
5. Utilize the internet to search for additional contact information, as applicable. 
6. Check local, regional, and national public records to locate the patient or search for 
mortality status as allowed by law, as applicable. 
The information and dates of attempted contact must be recorded in the patient’s records and the 
patient’s final status recorded in the appropriate eCRF. Once these actions have been exhausted 
and documented, the Sponsor or Sponsor’s designee should be contacted for additional guidance. 

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7. 
PATIENT POPULATION AND SELECTION 
Eligibility must be confirmed, and signed/dated informed consent obtained, prior to any 
study-related procedure. Where applicable, this includes the patient beginning the 2-week 
washout from RAAS inhibitors. 
For patients who require RAAS inhibitor washout, certain evaluations at Visit 3 (randomization) 
may no longer fall within the limits set by the inclusion/exclusion criteria. These patients will 
remain eligible for the study based on their screening results, unless at Visit 3 they have a 
positive pregnancy test (positive urine pregnancy tests will be confirmed by a serum test) or have 
experienced the occurrence of any medical condition or circumstance that, in the opinion of the 
Investigator, exposes them to substantial risk and/or does not allow them to adhere to the 
requirements of the protocol. 
If in the Investigator’s opinion, a laboratory value at screening is deemed unlikely to be 
representative of the patient’s true status, the Investigator may repeat the measurement on that 
variable through the central laboratory to assess patient eligibility. The Investigator is required to 
consult with the Medical Monitor for more than 1 repeat measurement to be permitted. In 
particular, RAAS inhibitors affect protein excretion and eGFR. If, in the Investigator’s opinion, 
withdrawal of RAAS inhibitor may alter these variables sufficiently to meet eligibility criteria, 
the patient may, if willing, undergo RAAS inhibitor washout and be retested for UP/C and/or 
eGFR to assess eligibility prior to potential randomization. 
7.1. 
Criteria for the Study 
7.1.1. 
Inclusion Criteria 
A patient will meet all of the following criteria to be eligible for this study. 
1. The patient or parent/legal guardian (as appropriate) is willing and able to provide signed 
informed consent, and where required, the patient is willing to provide assent, prior to 
any screening procedures. 
2. The patient has biopsy-proven FSGS lesion(s) or documentation of a genetic mutation in 
a podocyte protein associated with FSGS. The biopsy may have been performed at any 
time in the past. The patient will be enrolled based on light microscopy diagnosis of 
FSGS and supportive findings on either electron microscopy (EM) or 
immunofluorescence (IF) analysis (preferably both). In exceptional cases, the patient may 
be enrolled based on light microscopy diagnosis of FSGS lesion(s) in the absence of EM 
or IF analysis, provided the history and/or the course of the disease are indicative of 
primary FSGS and the case has been reviewed by the Medical Monitor and Investigator. 
3. 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. 
4. The patient has a UP/C ≥1.5 g/g (170 mg/mmol) at screening. 
5. The patient has an eGFR ≥30 mL/min/1.73 m2 at screening. 

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6. The patient has a mean seated blood pressure ≥100/60 mmHg and ≤160/100 mmHg 
(patients ≥18 years of age) or between the 5th and 95th percentile for age, sex, and height 
(patients <18 years of age; Banker 2016). 
7. Women of childbearing potential (WOCBP), beginning at menarche, must agree to the 
use of 1 highly reliable (ie, can achieve a failure rate of <1% per year) method of 
contraception from 7 days prior to the first dose of study medication until 90 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 inhibition of ovulation, or an intrauterine device (IUD) in place for at least 
3 months. One additional barrier method must also be used during sexual activity, such as 
a diaphragm or diaphragm with spermicide (preferred), or male partner’s use of male 
condom or male condom with spermicide (preferred), from Day 1/Randomization until 
90 days after the last dose of study medication. WOCBP are defined as those who are 
fertile, following menarche and until becoming postmenopausal unless permanently 
sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy, 
and bilateral oophorectomy. A postmenopausal state is defined as amenorrhea for more 
than 24 consecutive months without an alternative medical cause; women on hormone 
replacement therapy must have a documented plasma follicle-stimulating hormone level 
>40 mIU/mL. All WOCBP must have a negative serum pregnancy test at Screening 
(Visit 1), and a negative urine pregnancy test, with positive results confirmed by serum, 
at every study visit from Randomization (Visit 3) and after. 
NOTE: Prior to menarche, pregnancy testing and contraceptive use are not required. 
However, the patient and their parent/guardian must be advised that, immediately upon 
menarche, the patient will be required to begin pregnancy testing and initiate 
contraceptive use. This requirement cannot be avoided. 
7.1.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this study. 
1. The patient has FSGS secondary to another condition. 
2. The patient is ≥18 years of age and has positive findings on serological tests that, in the 
Investigator’s opinion, are diagnostic of another primary or secondary glomerular 
disease. These may include: antinuclear antibody, anti-double stranded deoxyribonucleic 
acid (DNA) antibodies, complement C3 and C4, anti-neutrophil cytoplasmic antibody, 
rheumatoid factor, anti-glomerular basement membrane antibodies, any clinically 
significant abnormalities identified by serum and urine protein electrophoresis or 
immunofixation, or serum kappa and lambda free light chains. At the Investigator’s 
discretion, these tests may be performed in patients <18 years of age under clinically 
relevant circumstances. 
3. The patient has a history of type 1 diabetes mellitus, uncontrolled type 2 diabetes mellitus 
(hemoglobin A1c [HbA1c] >8%), or non-fasting blood glucose >180 mg/dL 
(10.0 mmol/L) at screening. 
4. The patient has undergone any organ transplantation, with the exception of corneal 
transplants. 

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5. The patient requires any of the prohibited concomitant medications (see Section 15.2.1). 
6. The patient has been treated with rituximab, cyclophosphamide, or abatacept 
within ≤3 months prior to screening. If a patient is taking other chronic 
immunosuppressive medications, the dosage must be stable for ≥1 month prior to 
screening and during the screening period. 
7. The patient has a documented history of heart failure (New York Heart Association Class 
II-IV) and/or previous hospitalization for heart failure or unexplained dyspnea, 
orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema. 
8. The patient has 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, coronary angiogram 
revealing stenosis, or a coronary revascularization procedure) within 6 months prior to 
screening. 
9. The patient has hemodynamically significant valvular disease. 
10. The patient has jaundice, hepatitis, or known hepatobiliary disease (excluding 
asymptomatic cholelithiasis), or alanine aminotransferase (ALT) and/or aspartate 
aminotransferase (AST) >2 times the upper limit of the normal range at screening. 
11. The patient is positive at screening for the human immunodeficiency virus (HIV) or 
markers indicating acute or chronic hepatitis B virus (HBV) infection (acute HBV is 
defined as a positive hepatitis B surface antigen [HBsAg], hepatitis B “e” antigen 
[HBeAg], HBV DNA in blood or liver, or immunoglobulin M hepatitis B core antibody; 
chronic HBV is defined as a positive HBsAg and/or HBeAg and/or HBV DNA) or 
hepatitis C virus (HCV) infection (defined as reactive anti-HCV antibody and HCV 
RNA). 
12. The patient has a history of malignancy other than adequately treated basal cell or 
squamous cell skin cancer or cervical carcinoma within the past 2 years. 
13. The patient has a screening hematocrit value <27% (0.27 L/L) or hemoglobin value 
<9 g/dL (90 g/L). 
14. The patient has a screening potassium value of >5.5 mEq/L (5.5 mmol/L). 
15. The patient is extremely obese (ie, ≥18 years of age with a body mass index 
[BMI] >40 kg/m2, or <18 years of age with a BMI in the 99th percentile plus 5 units at 
screening), in whom, in the Investigator’s opinion, there is a causal relationship between 
obesity and development of the FSGS lesion. For patients with moderate or severe 
edema, BMI will be calculated based on remission or premorbid weight measured within 
3 months prior to screening, if available. If not available, BMI will be calculated based on 
the estimated dry weight, based on the Investigator’s clinical judgment. 
16. The patient has a history of alcohol or illicit drug use disorder (as defined in the 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), or a reported habitual 
alcohol intake greater than 21 units/week within 2 years prior to screening. 

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17. The patient has a history of serious side effect or allergic response to any AngII 
antagonist or ERA, including sparsentan or irbesartan, or has a hypersensitivity to any of 
the excipients in the study medications. 
18. The female patient is pregnant, plans to become pregnant during the course of the study, 
or is breastfeeding. 
19. The patient has participated in a study of another investigational product within 28 days 
prior to screening or plans to participate in such a study during the course of this study. 
20. The patient has had prior exposure to sparsentan. 
21. The patient, in the opinion of the Investigator, is unable to adhere to the requirements of 
the study, including the ability to swallow the study medication capsules whole. 
Patients with a medical condition or abnormal clinically significant laboratory screening value 
not listed above that may interfere with the evaluation of sparsentan efficacy or safety will be 
reviewed with the Medical Monitor before consideration of the patient for enrollment. Patients 
who fail screening may be re-screened up to 2 additional times. Patients who are re-screened will 
undergo all screening procedures and will be assigned a new patient number. Patients will also 
repeat the informed consent procedure each time they are re-screened. 
7.2. 
Criteria for the Open-Label Extension 
7.2.1. 
Inclusion Criteria for the Open-Label Extension 
Based on assessments at the Week 108 visit, a patient will meet all of the following criteria to be 
eligible for the open-label extension. 
1. The patient completed participation in the double-blind period, including the Week 112 
visit. 
2. The patient or parent/legal guardian (as appropriate) is willing and able to provide signed 
informed consent for participation in the open-label extension. 
3. The patient received blinded study medication throughout the duration of the 
double-blind period (ie, did not permanently discontinue study medication; see 
Section 6.4.2). 
7.2.2. 
Exclusion Criteria for the Open-Label Extension 
Based on assessments at the Week 108 and Week 112 visits, a patient who meets any of the 
following criteria will be excluded from the open-label extension. 
1. The patient has progressed to ESRD requiring RRT. 
2. The patient developed criteria for discontinuation as defined in Section 6.4.2 or 
Section 6.5 between Week 108 and Week 112. 
3. The patient was unable to initiate, or developed contraindications to, treatment with 
RAAS inhibitors between Week 108 and Week 112. 

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4. The patient has an eGFR ≤20 mL/min/1.73 m2 at Week 108. NOTE: If, in the 
Investigator’s opinion, the eGFR value at Week 108 is deemed unlikely to be 
representative of the patient’s true status, the Investigator may repeat the eGFR 
measurement prior to Week 112 through the central laboratory to assess patient 
eligibility. Patients with an eGFR <30 mL/min/1.73 m2 will require close monitoring of 
eGFR and serum potassium throughout the open-label extension. 
5. The female patient is pregnant, plans to become pregnant during the course of the study, 
or is breastfeeding. 

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8. 
TREATMENTS 
8.1. 
Treatments Administered 
For the purposes of this protocol, sparsentan is the investigational product, and irbesartan is the 
active control. When referring to either investigational product (sparsentan) or active control 
(irbesartan), the term “study medication” is used. 
The investigational product doses to be administered in the double-blind period of the study will 
be dispensed as 200 mg sparsentan tablets over-encapsulated (blinded) with size 00 capsules. 
The active control doses to be administered in the double-blind period of the study will be 
dispensed as 75 mg irbesartan tablets over-encapsulated (blinded) with size 00 capsules. The 
open-label sparsentan doses to be administered in the open-label extension will be dispensed as 
200 mg or 400 mg sparsentan tablets. 
A dose adjustment will be made for patients whose body weight is ≤50 kg at screening; these 
patients will receive one-half the otherwise specified doses of either sparsentan or irbesartan 
(weight will be measured at each visit and the dose increased at the Investigator’s discretion if 
the patient’s weight reaches >50 kg). 
8.1.1. 
Treatments Administered During the Double-Blind Period 
Allowed doses during the double-blind period, and the number of capsules to be used for those 
doses, are shown in Table 2. The full daily dose of study medication will preferably be taken 
prior to the morning meal, with the exception of the day of a study visit. On the day of a study 
visit, the patient will take their study medication at the clinic. At the visits specified in 
Section 15.1, study medication will be administered at the clinic after the pre-dose PK blood 
sample has been obtained. 
Table 2: 
Sparsentan and Active Control Irbesartan Doses Allowed During the 
Double-Blind Period 
Screening Weight 
Initial (or Reduced) Dose 
Target Dose 
One-Half Initial  
(or Double Reduced) Dose 
Number of 
Capsulesa 
Dose (mg) 
Number of 
Capsulesa 
Dose (mg) 
Number of 
Capsulesa 
Dose (mg) 
Randomized to Sparsentan 
>50 kg 
2 
400 
4 
800 
1 
200 
20 to ≤50 kg 
1 
200 
2 
400 
N/A 
N/A 
Randomized to Irbesartan 
>50 kg 
2 
150 
4 
300 
1 
75 
20 to ≤50 kg 
1 
75 
2 
150 
N/A 
N/A 
a Within each weight category, the number of capsules for each dose category (ie, initial [reduced], target, or 
one-half initial [double reduced]) are the same for patients randomized to sparsentan and irbesartan, to maintain 
study blind. 
Patients will receive the initial dose (ie, one-half the target dose) based on screening body weight 
for the first 2 weeks. The Investigator will evaluate dose tolerance in a blinded manner prior to 

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titrating up to the target dose; tolerance is defined as blood pressure 
measurements >100/60 mmHg (patients ≥18 years of age) or above the 5th percentile for sex and 
height (patients <18 years of age; Banker 2016) after 2 weeks and no adverse events (AEs) or 
laboratory findings interfering with the patient’s continuation on study medication. Patients who 
display asymptomatic blood pressure values ≤100/60 mmHg (patients ≥18 years of age) 
or ≤ 90/50 mmHg or below the 5th percentile for sex and height (whichever is lower in 
patients <18 years of age), or who present with clinical symptoms of orthostatic hypotension but 
otherwise tolerate the initial dose will continue after the Week 2 visit without titrating up to the 
target dose. At the Investigator’s discretion and in consultation with the Medical Monitor, 
patients weighing >50 kg who do not tolerate the initial dose for any reason (including changes 
in laboratory parameters assessed at Week 2) may continue at one-half the initial dose. Patients 
weighing ≤50 kg who do not tolerate the initial dose for any reason (including changes in 
laboratory parameters assessed at Week 2) will be discontinued from the study. 
The Week 2 PK sample will be drawn prior to escalating the patient to the target dose. 
Dose modification is permitted as presented in Section 8.3.2. 
8.1.2. 
Treatments Administered During Open-Label Extension 
Allowed doses during the open-label extension are shown in Table 3. 
Table 3: 
Sparsentan Doses Allowed During the Open-Label Extension 
Number of Capsules Taken 
During Double-Blind Period 
Initial Dose in Open-Label 
Extension 
Target Dose (Week 114)a 
1 
200 
200 
2 
200 
400 
4 
400 
800 
a Tolerability to the initial dose will be assessed after 2 weeks. Patients who tolerate the initial dose will titrate to the 
target dose after 2 weeks, and patients who do not tolerate the initial dose may continue at the initial dose at the 
Investigator’s discretion. Doses may be modified at any time throughout the open-label extension for 
safety/tolerability reasons at the Investigator’s discretion. 
Patients who are taking 2 capsules of study medication (ie, 400 mg sparsentan or 150 mg 
irbesartan) at the end of the double-blind period will initiate treatment in the open-label 
extension at 200 mg sparsentan for the first 2 weeks of the open-label extension. Likewise, 
patients who are taking 4 capsules of study medication (ie, 800 mg sparsentan or 300 mg 
irbesartan) at the end of the double-blind period will initiate treatment in the open-label 
extension at 400 mg sparsentan for the first 2 weeks of the open-label extension. Following 
2 weeks at one-half the double-blind dose (ie, Week 114), the Investigator will evaluate dose 
tolerance (as defined in Section 8.1.1) prior to titrating up to the target dose. If the patient is 
tolerating the dose, the patient will titrate to the target dose at this time. Patients who display 
asymptomatic blood pressure values ≤100/60 mmHg (patients ≥18 years of age) 
or ≤90/50 mmHg or are below the 5th percentile for sex and height (whichever is lower in 
patients <18 years of age) or who present with clinical symptoms of orthostatic hypotension but 
otherwise tolerate the initial dose will continue without titrating up to the target dose after the 
Week 114 visit. Patients who completed the double-blind period on 4 capsules of study 
medication (ie, 800 mg sparsentan or 300 mg irbesartan) and initiate treatment in the open-label 

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extension on 400 mg sparsentan but do not tolerate this dose will be able to reduce their dose 
down to 200 mg sparsentan. These patients will be able to titrate up to 400 mg sparsentan or 
800 mg sparsentan if the Investigator feels the patient can tolerate these doses. Only 1 level of 
titration up will be allowed at each visit. 
Patients who are taking 1 capsule of study medication (ie, 200 mg sparsentan or 75 mg 
irbesartan) at the end of the double-blind period will initiate treatment in the open-label 
extension at 200 mg sparsentan for the first 2 weeks of the open-label extension. Following 
2 weeks at 200 mg sparsentan (ie, Week 114), the Investigator will evaluate dose tolerance (as 
defined in Section 8.1.1). Patients who are tolerating the initial dose will continue on 200 mg 
sparsentan at this time, including those who display asymptomatic blood pressure values 
≤100/60 mmHg (patients ≥18 years of age) or ≤90/50 mmHg or are below the 5th percentile for 
sex and height (whichever is lower in patients <18 years of age) or who present with clinical 
symptoms of orthostatic hypotension but otherwise tolerate the initial dose. 
For patients who enter the open-label extension with an eGFR value <30 mL/min/1.73 m2 (ie, at 
Week 108), any dose titration at Week 114 will be at the Investigator’s discretion based on the 
results of the Week 114 assessments. Patients who do titrate to a higher dose at Week 114 will be 
contacted by the Investigator at Week 116 to assess tolerance of the higher dose; at the 
Investigator’s discretion, these patients may also come in for an additional visit at this time. 
Dose modification is permitted during the open-label extension as presented in Section 8.3.2. 
8.2. 
Study Medication 
8.2.1. 
Packaging and Labeling 
For the double-blind period, blinded size 00 capsules will be provided in country-specific labeled 
150-cc wide-mouth, round, white, high-density polyethylene bottles with polypropylene caps. 
Each 68-count bottle will have a label that will contain, but will not be limited to, the following: 
Sponsor’s name and address, protocol number, packaging job/lot number, name and strength 
(mg) of study medication (in a blinded manner), medication identification number, patient 
information, caution statement, directions for use, and storage conditions. 
For the open-label extension, sparsentan 200 mg tablets will be provided in country-specific 
labeled 150-cc wide-mouth, round, white, high-density polyethylene bottles with polypropylene 
caps. Each 68-count or 30-count bottle will have a label that will contain, but will not be limited 
to, the following: Sponsor’s name and address, protocol number, packaging job/lot number, 
name and strength (mg) of study medication, medication identification number, patient 
information, caution statement, directions for use, and storage conditions. 
Sparsentan 400 mg tablets may also be used in the open-label extension. 
For the open-label extension, at some point during the study, the supply of sparsentan 200 mg 
and 400 mg tablets will be provided in country-specific labeled 40-cc wide-mouth, round, white, 
high-density polyethylene bottles with polypropylene caps. Each 30-count bottle will have a 
label that will contain, but will not be limited to, the following: Sponsor’s name and address, 
protocol number, packaging job/lot number, name and strength (mg) of study medication, 
medication identification number, patient information, caution statement, directions for use, and 
storage conditions. 

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All study medication used in this study will be prepared, packaged, and labeled in accordance 
with the standard operating procedures (SOPs) of the Sponsor or its designee, Good 
Manufacturing Practice guidelines, International Council for Harmonisation (ICH) guidelines for 
Good Clinical Practice (GCP), and applicable national regulations. All labels on the packaging 
will be in accordance with local regulations. Additional details can be found in the study 
reference manuals. 
8.2.2. 
Storage 
Over-encapsulated sparsentan and irbesartan tablets and open-label sparsentan tablets will be 
shipped and stored between 20-25°C (68-77°F); excursions between 15-30°C (59-86°F) are 
allowed. All study medication must be stored at the site in a secure location with limited access. 
Further guidance will be provided by the Sponsor in a Pharmacy Manual. 
8.2.3. 
Preparation and Administration of the Study Medication 
Patients will be instructed to take the appropriate quantity of capsules/tablets for their assigned 
oral dose at approximately the same time each day, preferably prior to the morning meal, except 
on the day of a study visit during the double-blind period. On the day of each study visit in the 
double-blind period, including the Day 1/Randomization visit, the patient will take their study 
medication in the clinic. At the visits (both during the double-blind period and open-label period) 
specified in Section 15.1, study medication will be administered after the pre-dose PK and 
biorepository (for biomarker assessments) blood samples have been obtained. 
Patients will be instructed to swallow the capsules/tablets whole, and not to open, break, chew, 
crush, or split the capsule/tablet prior to taking. Patients will also be instructed to avoid drinking 
or eating anything that contains grapefruit, Seville oranges (bitter oranges often used as 
marmalade), or starfruit (carambola) throughout the study. 
If an on-site visit by the patient is not feasible due to challenges related to the coronavirus 
disease 2019 (COVID-19) pandemic or other unexpected circumstances, study medication may 
be transported directly to a patient via a traceable courier and/or shipping provider to ensure 
uninterrupted treatment, if necessary. Before doing this, sites will be instructed to acquire verbal 
agreement from the patient, verification of correct shipping address, and the patient’s availability 
to receive the shipment. Confirmation of receipt and the shipping process will be documented in 
the site source documentation. The patient’s identity and personal information will continue to be 
kept confidential and will not be shared with the Sponsor. Refer to the Pharmacy Manual for 
additional details. 
Patients will be instructed that if they miss a dose of study medication prior to the morning meal, 
they should take the missed dose the same day as soon as it is discovered that they missed the 
dose. If study medication is missed for the entire day, they will be asked to note the date of the 
missed dose. Patients should not take 2 doses on any one day. 
8.3. 
Dosing Considerations 
8.3.1. 
Dose Selection Rationale 
The most relevant data for sparsentan dose selection are provided by the Phase 2 studies in 
patients with essential hypertension and by the ongoing DUET trial in patients with FSGS. 

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In the hypertension studies, a clear dose response related to blood pressure was observed in 
hypertensive patients who achieved blood pressure control after 12 weeks of treatment with 
sparsentan (200 mg, 400 mg, and 800 mg). In these Phase 2 studies, the 800 mg/day sparsentan 
dose was significantly more effective in lowering blood pressure and achieving blood pressure 
control than the maximal dose of the active control (irbesartan 300 mg/day). Treatment with 
sparsentan up to 800 mg daily for up to 12 weeks was also found to be generally safe and well 
tolerated in both healthy adults and patients with stage 1 and 2 hypertension. 
Preliminary results from the DUET trial are described in more detail in Section 4. In the DUET 
study, the highest sparsentan dose (800 mg/day) tended to have the most prominent 
antiproteinuric effect while maintaining an acceptable safety profile. 
The PK profiles seen at the end of the double-blind treatment period in DUET have been utilized 
to examine the effect of sparsentan exposure on the primary efficacy endpoint (ie, the change in 
UP/C from baseline to the end of the 8-week double-blind treatment phase) and on the change in 
mean seated blood pressure. These results showed that UP/C decreased with increased 
sparsentan exposure, while variability in UP/C increased with decreasing sparsentan exposure. In 
contrast, change in mean seated blood pressure with change in sparsentan exposure appeared 
minimal. Thus, with less interpatient variability and fewer patients exhibiting a lack of benefit 
(based on change in UP/C), along with no meaningful difference in blood pressure effect, a dose 
of 800 mg/day is preferred for the current study. 
At the beginning of the blinded treatment period, patients will initially receive one-half of the 
targeted dose (defined as the initial dose) of both sparsentan and the active control, irbesartan. In 
addition, patients entering into the open-label extension (following a 4-week interval in which no 
study medication is taken) will initially receive one-half of the targeted open-label dose. This 
approach follows common clinical practice to initiate treatment with RAAS inhibitors at doses 
lower than the maximum dose to prevent adverse reactions and potentially harmful elevations in 
serum potassium and reductions in GFR. 
8.3.2. 
Dose Modification, Reduction, or Discontinuation 
Patients who display asymptomatic blood pressure values ≤100/60 mmHg (patients ≥18 years of 
age) or ≤90/50 mmHg or are below the 5th percentile for sex and height (whichever is lower in 
patients <18 years of age), or who present with clinical symptoms of orthostatic hypotension (see 
Section 9.6) but otherwise tolerate the initial dose will continue after the Week 2 visit (or the 
Week 114 visit for the open-label extension) without titrating up to the target dose. Patients who 
do not titrate up to the target dose at Week 2 (or Week 114) may titrate up to that dose at any 
time, based on evaluation of the Investigator, in consultation with the Medical Monitor as 
needed. Reductions from the target dose back to the initial dose are permitted at any time after 
titrating up to the target dose. 
Patients weighing >50 kg at screening who do not tolerate the initial dose for any reason may 
continue at one-half the initial dose at the Investigator’s discretion and in consultation with the 
Medical Monitor, as needed. Patients weighing ≤50 kg at screening who do not tolerate the 
initial dose for any reason will be discontinued from the study. 

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In patients with temporary dose interruptions, treatment should be resumed whenever possible 
(including between visits), and treatment resumption should be considered at every visit 
following study medication interruption. 
Doses may be modified at any time throughout the open-label extension for safety/tolerability 
reasons at the Investigator’s discretion. In addition, after titration to the target dose for the 
open-label extension, increases above the target doses of 200 mg or 400 mg sparsentan may be 
considered for patients who, in the Investigator’s opinion (and following consultation with the 
Medical Monitor), would benefit from an increased dose. 
8.4. 
Prior and Concomitant Medications and Therapeutic Procedures 
For enrolled patients, concomitant medications and concomitant therapies will be collected from 
the 3 months prior to screening through the patient’s final study visit. In addition, a lifetime 
history of medications previously used for treatment of FSGS, including systemic corticosteroids 
or other systemic immunotherapeutic agents, will be collected. Prohibited concomitant 
medications and other concomitant medication considerations during study participation are 
outlined in Section 15.2.1. 
8.5. 
Method of Assigning Patients to Treatment (Randomization) 
This study will be conducted in a double-blind, active-controlled manner. Enrolled patients will 
be randomly assigned in a 1:1 ratio to sparsentan or the active control (irbesartan) based on a 
predefined randomization code (generated by the Sponsor or designee) via the IWRS at the 
Day 1/Randomization visit. Randomization will include stratification by screening eGFR and 
UP/C values. The strata will be as follow: 
• eGFR strata: 
− ≥30 to <60 mL/min/1.73 m2 (all patients) 
− ≥60 mL/min/1.73 m2 (all patients) 
• UP/C strata: 
− ≤3.5 g/g (396 mg/mmol; patients ≥18 years of age) or ≤2 g/g (226 mg/mmol; 
patients <18 years of age) 
− >3.5 g/g (396 mg/mmol; patients ≥18 years of age) or >2 g/g (226 mg/mmol; 
patients <18 years of age) 
8.6. 
Blinding and Emergency Unblinding 
The patient’s treatment allocation will remain blinded to all parties involved with the study 
throughout its course (including during the open-label extension), with the exception of the Data 
Monitoring Committee (DMC; see Section 13.2), study medication supply, the SAE reporting 
contact, and the independent statistical team responsible for the interim analysis (see 
Section 12.11). Double-blind treatment will not be unblinded for initiation of open-label 
treatment. The randomization schedule for treatment allocation will be securely maintained and 
will not be disclosed until after database lock for the entire study. 

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Doses allowed during the study are shown in Table 2 and Table 3, and dose modifications are 
discussed in Section 8.3.2. 
For emergency unblinding only, randomization codes and corresponding treatment assignments 
will be made available to the Investigator through the IWRS system. When possible, the Medical 
Monitor should be consulted if a medical emergency necessitates unblinding (ie, in situations 
where knowledge of the unblinded treatment is necessary for further medical management of the 
patient). If it is not reasonable to inform the Medical Monitor in advance of unblinding, the 
Investigator must promptly document the case in the patient’s study record. Subsequently, the 
Investigator should contact the Medical Monitor to explain any premature unblinding of 
treatment assignment (eg, accidental unblinding or unblinding due to an SAE). Procedures for 
unblinding a patient’s treatment will be provided separately to the Investigator. Similarly, if the 
Medical Monitor breaks the blind to evaluate an emergent safety issue or for regulatory reporting 
purposes, the Medical Monitor will document within study correspondence the rationale, 
circumstances, and the person(s) being informed about the unblinding. 
Access to randomization codes and corresponding treatment assignments will be made available 
through the IWRS system to the appropriate, named individual(s) responsible for unblinding 
suspected, unexpected serious adverse reactions (SUSARs) for reporting to regulatory 
authorities. 
8.7. 
Assignment of Site and Patient Numbers 
Each study site selected to participate in this study will be assigned a site number by the Sponsor 
or designee. The site number will be used to categorize patient data and to identify the site and/or 
Investigator within study documents. This number will be recorded in the eCRF. 
At screening, each patient will be registered in the IWRS and assigned a unique identification 
number which will stay the same throughout the study, including the open-label extension. 
Patients who are re-screened will be assigned a new patient number. 
8.8. 
Treatment Compliance 
The Investigator or designee should assess the patient’s compliance with study medication 
dosing at each visit after Day 1. Study medication compliance is defined as the ratio of the 
number of actual capsules/tablets taken over the number of capsules/tablets that should have 
been taken during the dosing period multiplied by 100. Patients will be asked to return all unused 
study medication and used and unused packaging at each visit. If the Investigator has concerns 
about a patient’s dosing compliance, he/she should reiterate the dosing requirements to the 
patient, and the discussion should be documented in the source documents. 

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9. 
STUDY ASSESSMENTS 
9.1. 
Schedule of Study Events 
The schedule of study events is located in Section 15.1. 
If an on-site visit by the patient is not feasible due to challenges related to the COVID-19 
pandemic or other unexpected circumstances, Investigators/appropriately designated study staff 
will be allowed to perform study visits as remote study visits (eg, conducted via telephone, video 
conference). These contacts will be allowed at all protocol-required visits and at any time during 
the conduct of the study. However, Screening (Week 6), Washout (Week 1), and Day 1 
(Randomization) visits must be conducted at the study site. The sites will discuss the patient’s 
current health status, AEs, concomitant medications, and medication compliance during the 
telephone and video contacts. Patients will be instructed to contact the site personnel with any 
health concerns. Results of these patient contacts will be fully documented in the patient source 
documents/health records. Patients will return for an on-site visit as soon as the site and the 
patient determine that it is appropriate and safe. 
Given the importance of ongoing laboratory and clinical tests for safety evaluations and to 
reduce the burden on the patient to come to the clinical site, the Sponsor is contracting with a 
home care agency to assist with study visits. Dictated by local public health authority 
requirements and if an Investigator agrees with the patient to utilize the home care services, a 
signed consent/assent form for home care visits will be obtained at the next site visit. Due to the 
challenges related to the COVID-19 pandemic or other unexpected circumstances, a verbal 
consent/assent may be obtained if allowed by local regulations prior to the home care visit and 
the signed consent/assent form obtained at the next site visit. A licensed nurse will contact the 
patient or parent/legal guardian via telephone to schedule the home visits in accordance with the 
Service Request Form provided by the Investigator. In order to conduct the home visits, the 
home care nurse, the home care agency, and the home care service provider will have access to 
the patient’s personal data including their individually identifiable protected health information, 
such as the patient’s name, address, or telephone number. This type of information will only be 
used, as necessary, to schedule and conduct the home visits and will not be provided to the 
Sponsor, the contract research organization, or any other study vendors. Service providers will 
complete the services ordered by the Investigator, including collection of laboratory samples, and 
document the service provided in the source documents. Study procedure instructions for the 
service provider will be provided in the home care visit training manual. Source documentation 
will be expedited by courier to the study site. 
Home care visits may also be utilized for patient retention during the double-blind and the 
open-label extension periods in any situation that interrupts safety oversight. 
Study sites may implement home blood pressure monitoring to allow for further safety 
assessment. If requested by the Investigator, the Sponsor will supply blood pressure cuffs to the 
study site to be provided to the patients for monitoring of blood pressure at home. The 
Investigator will be responsible for instructing the patient about how to monitor and record blood 
pressure at home. 

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9.2. 
Study Fasting Requirements 
Beginning on Day 1, all patients must be instructed to arrive at the study site for their next visit 
in a fasted state (ie, fasting for at least 8 hours prior to the visit). Water is permitted during the 
fasting period. 
9.3. 
Screening Assessments 
Screening Visit assessments for the double-blind period must be performed within 6 weeks prior 
to Day 1/Randomization; the screening window begins on the day of the patient’s first in-clinic 
study procedure. Each patient will be registered in the IWRS at screening for the double-blind 
period and assigned a unique identification number which will stay the same throughout the 
study (including the open-label extension; see Section 8.7). Patients who fail screening for any 
reason may be re-screened up to 2 additional times. Patients who are re-screened will repeat all 
screening procedures and will be re-registered in the IWRS and assigned a new patient number. 
Patients will also repeat the informed consent procedure at each re-screening. 
9.4. 
Medical History and Demographics 
A complete medical history will be obtained from the patient at screening, along with 
concomitant medications/therapies (including all immunosuppressive therapies the patient has 
taken in their lifetime) at enrollment. Demographic characteristics will include age, race, 
ethnicity, and sex. Race is being collected to accurately calculate eGFR (a primary endpoint). 
9.5. 
Physical Examination 
Physical examinations will be performed according to the schedule of study events in 
Section 15.1. Physical examinations will include assessment of the following body systems: 
abdomen; cardiovascular; ear, nose, and throat; eyes; hair and skin; lymph nodes; mental status; 
musculoskeletal; neurological; peripheral edema; and respiratory. Peripheral edema will be 
assessed using the semi-quantitative scale in Appendix B (Section 15.2.3). 
9.6. 
Vital Signs 
Vital signs, including blood pressure, heart rate, temperature, respiration rate, weight, and height, 
will be performed according to the schedule of study events in Section 15.1. Height will only be 
recorded at screening for patients ≥18 years of age. For patients <18 years of age, height will be 
measured every 6 months after screening until the patient turns 18. Vital signs will be measured 
prior to phlebotomies for clinical laboratory evaluations. 
At all protocol-specified time points, blood pressure will be measured after the patient has been 
sitting comfortably in a chair for at least 5 minutes prior to obtaining 3 readings, using the same 
arm for each reading, and the mean of the last 2 readings will be recorded. At the 
Day 1/Randomization visit, vital signs will be obtained prior to dosing and at 1, 2, 3, and 4 hours 
after the first dose of study medication. 
Measurements of blood pressure intended to detect possible orthostatic hypotension will also be 
performed at each visit according to US Centers for Disease Control and Prevention guidelines 
(US CDC 2017). This should be done after the sitting BP measurements have been taken. 
Briefly, blood pressure will be measured 3 times: 1 time after the patient has been in a supine 

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position for 5 minutes, 1 time after the patient has been standing for 1 minute, and 1 time after 
the patient has been standing for 3 minutes. Heart rate will also be collected each time blood 
pressure is taken. A decrease in systolic blood pressure of ≥20 mmHg or diastolic blood pressure 
of ≥10 mmHg, or the presence of lightheadedness or dizziness during the test is considered 
abnormal and may justify a change in study drug dose at the Investigator’s discretion. 
9.7. 
Electrocardiogram 
Twelve-lead ECGs should be conducted after the patient has been resting in a supine position for 
at least 5 minutes. Assessments will be performed according to the schedule of study events in 
Section 15.1. ECGs will be performed prior to phlebotomies for clinical laboratory evaluations. 
Copies of the ECGs may be required to be sent to a central repository for third party review and 
analysis. 
9.8. 
Clinical Laboratory Assessments 
For the double-blind period (with the exception of the Screening Visit [Visit 1]), patients will be 
instructed to attend each study visit in a fasted state (ie, fasting for at least 8 hours prior to the 
visit; water is permitted during the fasting period), preferably in the morning, and patients should 
remain fasted until their blood samples have been collected. For visits that require fasting, the 
Investigator or designee will document that the patient has fasted in the source documents. If the 
patient reports having eaten within 8 hours, the Investigator or designee will document 
accordingly in the source documents and eCRF and remind the patient that fasting is required 
before all study visits. 
For the open-label extension, it is strongly recommended that patients come to the study visit in a 
fasted state, and patients should remain fasted until their blood samples have been collected. 
However, if fasting for 8 hours prior to the visit is not possible, the visit should occur as 
scheduled and it should be documented in the eCRF that the patient was not fasting. 
Routine blood and urine samples for laboratory assessments will be collected at the visits 
specified in the schedule of study events in Section 15.1. The Investigator will receive the results 
of this testing from the central laboratory and must determine the clinical significance of any 
results that are outside of the normal range. All randomized patients with clinically significant 
abnormal test results will be followed regularly until the values return to normal ranges or until 
further follow-up is deemed medically unnecessary. 
Full instructions concerning the number and type of laboratory samples to be collected at each 
visit, the necessary collection supplies, required sample volumes, sample collection methods, 
sample processing, sample labeling, and sample shipping will be provided by the central 
laboratory, and will be appropriately assembled for the specific evaluations required at each visit. 
Patients will be provided kits for the home collection of quantitative urinalysis samples. They 
will also receive full instructions regarding the proper collection of those samples. If necessary, 
due to challenges related to the COVID-19 pandemic or other unexpected circumstances, a 
patient or parent/legal guardian may transport the first morning void samples to the site via 
courier service for processing and shipment to the central laboratory. If a patient cannot come to 
the site, safety labs may be tested at a local laboratory. It is the responsibility of the Investigator 
to document this process in the patient’s source documents. 

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The eGFR during screening period will be determined using the Chronic Kidney Disease 
Epidemiology (CKD-EPI) equation for adults (Levey 2009) and the Modified Schwartz formula 
(Schwartz 2009a; Schwartz 2009b) for children <18 years of age. 
The eGFR for each timepoint (visit) during the double-blind period will be determined using the 
CKD-EPI equation for adults (Levey 2009) and children ≥16 years of age at screening for the 
double-blind period, and the Modified Schwartz formula for children <16 years of age at 
screening for the double-blind period (Schwartz 2009a; Schwartz 2009b). The eGFR for each 
timepoint (visit) during the open-label extension will be determined using the CKD-EPI equation 
for adults (Levey 2009) and children ≥16 years of age at Week 108, and the Modified Schwartz 
formula for children <16 years of age at Week 108 (Schwartz 2009a; Schwartz 2009b). 
UP/C will be determined using first morning void urine samples. For the double-blind period, 
UP/C will be calculated as the average of 3 first morning void urine samples collected within 
5 days prior to the visit. If 1 of the samples is missing, the average of the other 2 samples will be 
used. For the open-label extension, UP/C will be based on a single first morning void sample 
collected within 5 days prior to the visit. 
The list of clinical laboratory analytes to be tested is presented in Section 15.2.4. 
9.9. 
Contraception Requirements and Pregnancy Testing 
Women of childbearing potential are defined as females who are fertile, following menarche and 
until becoming postmenopausal unless permanently sterile; permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal 
state is defined as amenorrhea for more than 24 consecutive months without an alternative 
medical cause; women on hormone replacement therapy must have a documented plasma 
follicle-stimulating hormone level >40 mIU/mL. 
Double-blind: 
Women of childbearing potential must not become pregnant, and so beginning at menarche must 
agree to the use of 1 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. Highly reliable 
contraception methods are defined as those that can achieve a failure rate of <1% per year; 
examples of these methods include: 
• stable oral, implanted, transdermal, or injected contraceptive hormones associated 
with inhibition of ovulation, or 
• an IUD in place for at least 3 months 
Open-label Extension: 
Women of childbearing potential must not become pregnant, and so beginning at menarche must 
agree to the use of 1 highly reliable method of contraception from 7 days prior to the first dose of 
study medication until 30 days after the last dose of study medication. Highly reliable 
contraception methods are defined as those that can achieve a failure rate of <1% per year; 
examples of these methods include: 
• stable oral, implanted, transdermal, or injected contraceptive hormones associated 
with inhibition of ovulation, or 

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• an IUD in place for a duration defined as effective in product labeling. 
One additional barrier method must also be used during sexual activity from 
Day 1/Randomization until 30 days after the last dose of study medication. Examples of barrier 
methods include: 
• diaphragm 
• diaphragm with spermicide (preferred) 
• male partner’s use of male condom 
• male partner’s use of condom with spermicide (preferred) 
Serum pregnancy tests will be performed on WOCBP at screening. Urine pregnancy tests will be 
performed at all other study visits, as well as monthly between visits (see next paragraph). A 
positive urine pregnancy test during the study must be confirmed with a serum pregnancy test. 
Urine pregnancy tests will be dispensed to WOCBP to conduct pregnancy testing at home 
between study visits, beginning at the Week 12 visit, and continuing through the open-label 
extension. Patients will receive enough tests to conduct pregnancy testing once monthly until the 
next scheduled study visit. Sites will contact patients monthly to confirm that the pregnancy test 
has been performed and the results are negative. If the urine pregnancy test is positive, study 
medication will be immediately discontinued, and a serum pregnancy test will be performed to 
confirm the result. If the serum pregnancy test is positive, the Sponsor will be notified, and the 
patient will be followed to pregnancy outcome as outlined in Section 10.8. At every visit and 
monthly, sites will verify that WOCBP are continuing to use highly reliable contraception 
methods as defined in this protocol. 
Prior to menarche, pregnancy testing and contraceptive use is not required. However, the patient 
and their parent/guardian must be advised that immediately upon menarche, the patient will be 
required to begin pregnancy testing and initiate contraceptive use. Upon menarche, study 
medication should be stopped until highly reliable contraception per protocol specifications has 
been started and is considered to be effective. These requirements cannot be avoided. 
9.10. 
Patient-reported Outcomes 
The following PROs will be used to evaluate the effects of sparsentan (as compared to 
irbesartan) on improvements in health-related QoL: 
• Patients ≥18 years of age: 
− Kidney Disease Quality of Life (KDQOL) instrument 
− EuroQol, 5-dimension QoL instrument, version 5L (EQ-5D-5L) 
• Patients <18 years of age: 
− Pediatric Quality of Life Inventory (PedsQL) questionnaire. The PedsQL 
instrument consists of 2 developmentally appropriate modules; the Child 
Self-Report for ages 8-12 and Child Self-Report for ages 13-18. 
− EuroQol, 5-dimension QoL instrument, version Y (EQ-5D-Y). 

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If the questionnaires were NOT completed at baseline of the double-blind period (ie, Day 1), the 
patient should not complete them for the rest of the double-blind period. Patients participating in 
the open-label extension who did not complete the questionnaires at Day 1 should complete them 
at Week 112 (as baseline assessments for the open-label extension) and through the 
Week 268/End of Study visit. If the questionnaires were not completed at Week 112, the patient 
should not complete them for the rest of the open-label extension. Once a patient enters the open-
label extension portion of the study, questionnaires will continue to be collected through the 
Week 268/End of Study visit. 
9.11. 
Pharmacokinetic Assessments 
Samples enabling assessment of sparsentan and irbesartan in plasma will be taken during the 
double-blind period according to the schedule of study events in Section 15.1. At applicable 
visits, 1 sample will be taken pre-dose in the clinic. 
9.12. 
Biorepository Samples 
With patient consent (or assent as appropriate), serum, plasma, and urine samples will be 
collected for assessment of biomarkers that could help better understand the mechanisms of 
disease and treatment. Additional biomarkers may be identified during or after the study and be 
considered for assessment in the future. 
Samples will be collected at visits specified in the schedule of events during both the double-
blind- and open-label periods of the study, as specified in Section 15.1. 
Patients may withdraw consent for use of biorepository samples at any time, as described in the 
ICF. Biorepository samples will not be used for genetic testing. Samples will be shipped and 
stored according to instructions in the Laboratory Manual. The samples will be destroyed 5 years 
after the clinical study report is finalized. 
9.13. 
Genotyping 
Blood samples for genotyping of FSGS and nephrotic syndrome-associated genes, and 
apolipoprotein1 polymorphisms will be taken at Day1/Randomization. Test results, if available, 
may be provided to Investigators after study completion. Samples will be used only for this 
purpose and will be destroyed once the sample analysis is complete. 
9.14. 
Safety Assessments 
The safety and tolerability of sparsentan will be evaluated by AEs and by vital signs, physical 
examinations, clinical laboratory parameters, and 12-lead ECGs. 

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10. 
ADVERSE EVENT REPORTING 
10.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence associated with the use of the study medication 
(active or placebo, biologic, or device) in a clinical investigation patient, but does not necessarily 
have a causal relationship with the study medication. An AE can, therefore, be any unfavorable 
and unintended sign (eg, an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a study medication, whether or not considered related to the study 
medication. 
Adverse events may include: 
• Symptoms described by the patient 
• Clinically significant changes in the patient’s physical examination or other signs 
observed by the Investigator or medical staff 
• Test abnormalities (laboratory tests, ECG, X-rays, etc.) that reflect a change from 
baseline (Day 1 for the double-blind period or Week 112 for the open-label 
extension) and/or that may result in changes in administration of study medication or 
in an alteration in medical care (diagnostic or therapeutic) 
• Conditions present at baseline (Day 1 for the double-blind period or Week 112 for the 
open-label extension) that have either worsened or recurred following resolution 
The patient will be evaluated for new AEs and the status of existing AEs at each study visit, 
including screening or washout periods, or at any time contact is made with the patient outside of 
a scheduled visit. The Investigator may elicit symptoms using an open-ended question, followed 
by appropriate questions that clarify the patient’s verbatim description of AEs or change in 
concomitant medications. 
10.1.1. 
COVID-19 Adverse Events 
If a patient is diagnosed with COVID-19 by a positive test result and any of the SAE criteria 
(Section 10.2) are met, report the event as an SAE. If a patient has a positive test result for 
COVID-19 and is asymptomatic, or is symptomatic but not meeting SAE criteria, it should be 
reported as an AE. 
As with all SAE reporting, the SAE should be reported, per protocol, within 24 hours of 
becoming aware of the event. If the 24-hour reporting deadline is not met, then a note should be 
added to the SAE Report Form stating the reason the timeline was not adhered to. 
10.2. 
Serious Adverse Event (SAE) 
An SAE is an AE that results in any of the following: 
• Death: The patient died as the result of the event. 
• Is life-threatening: An AE that places the patient, in the view of the Investigator or the 
Sponsor, at immediate risk of death from the AE as it occurred; ie, does not include 
an AE that, had it occurred in a more severe form, might have caused death. 

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• Requires in-patient hospitalization or prolongation of an existing hospitalization:  
Note: Planned or elective hospital admissions for treatment/procedures for a 
condition/disease that existed prior to signing the informed consent will be recorded 
in the patient’s screening documents and will not be captured as SAEs. If, however, 
the admission or procedure occurs other than planned due to a worsening of the 
condition, the event will be recorded as an SAE. 
• Persistent or significant disability/incapacity: An AE that results in a substantial 
disruption of a person’s ability to conduct normal life functions. 
• Congenital anomaly/birth defect: A congenital anomaly/birth defect that occurs in the 
offspring of a patient exposed to the study medication. 
• Other medically important serious events: An AE that may not result in death, be 
life-threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, the event may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Voluntary admission to the hospital (eg, for elective surgery) will not be considered an SAE. 
10.3. 
Adverse Events of Interest (AEOI) 
10.3.1. 
Abnormal Liver Function Test Results 
Abnormal liver function tests that meet the below criteria will be considered AEOIs and must be 
reported to the Sponsor’s Medical Monitor within 24 hours of awareness if one of the following 
conditions are met: 
• The abnormality represents a new elevation in ALT or AST >3 times the upper limit 
of normal (ULN), with or without an elevation of total serum bilirubin >2 times ULN; 
or 
• The abnormality represents a 2-fold increase in ALT or AST above the baseline value 
for the double-blind period (ie, Day 1) in patients who had elevated values prior to 
starting study medication, or a 2-fold increase in ALT or AST above the baseline 
value for the open-label extension (ie, Week 112) in patients who had elevated values 
prior to starting open-label sparsentan. 
In such instances, the following steps should be taken: 
1. Temporarily discontinue study medication. 
2. Perform repeat testing of ALT, AST, and total bilirubin, and test liver alkaline 
phosphatase isoenzyme within 48 to 72 hours to confirm the abnormalities. 
3. If the abnormality is confirmed by repeat results: 
a. Complete an AEOI Report Form that documents both the liver function test findings 
and any associated signs or symptoms and report by email to the SAE contact on the 
Study Contact Information page of this protocol. 
b. Monitor liver enzymes and serum bilirubin 2 or 3 times weekly. The frequency of 
re-testing can decrease to once weekly or less if the abnormalities stabilize and the 
patient is asymptomatic. 

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c. Perform additional testing to evaluate liver function, as appropriate (eg, international 
normalized ratio [INR], direct bilirubin). 
4. Do not resume study medication until monitoring indicates abnormalities have resolved 
or stabilized. 
Patients are not allowed to resume study medication if they have: 
• ALT or AST >8 times ULN 
• ALT or AST >5 times ULN for more than 2 weeks 
• ALT or AST >3 times ULN and total bilirubin >2 times ULN or INR >1.5 
• ALT or AST >3 times ULN with symptoms of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5% eosinophils) 
Additionally, patients who demonstrate elevated liver enzymes a second time after 
re-introduction of the study medication may continue in the clinical trial; however, they will not 
receive study medication for the remainder of the trial. 
Management of such patients should be closely coordinated with the Sponsor’s Medical Monitor. 
In addition to monitoring liver function tests, the Investigator should perform other relevant 
clinical and laboratory measurements to identify potential causes of the abnormalities (eg, acute 
viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic 
steatohepatitis; biliary tract disease or exposure to hepatotoxic medications or environmental 
chemical agents). 
Cases of increased liver function tests will always be considered serious (ie, medically 
important) if they meet both the following criteria: 
• Study medication is suspected to have caused hepatocellular injury, generally shown 
by a confirmed elevation of 3-fold or greater above ULN in ALT or AST; and 
• The ALT or AST elevations are accompanied by a total bilirubin >2 times the ULN 
or INR >1.5, without initial findings of cholestasis (elevated serum liver alkaline 
phosphatase isoenzyme) 
10.4. 
Acute Kidney Injury 
The Kidney Disease: Improving-Global Outcomes (KDIGO) guidelines for diagnosing AKI are: 
• Increased serum creatinine ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours; or 
• Increased serum creatinine ≥1.5 times baseline (that is known or presumed to have 
occurred within the prior 7 days); or 
• Urine volume <0.5 mL/kg/hour for 6 hours or more (KDIGO 2013). 
These KDIGO guidelines typically apply to hospital settings, where baseline values within given 
timeframes (ie, the preceding 48 hours to 7 days) are available. However, in interventional trials 
such as the current study, values this recent will not likely be available in most cases. In such 
instances, at the Investigator’s discretion, diagnosis of AKI may be based on the most recently 
available serum creatinine level preceding the event, provided this creatinine measurement was 

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conducted at or after the last study visit prior to the event (ie, was within 3 months prior to the 
event). 
The Investigator should always take into consideration whether the event is true acute 
deterioration of kidney function due to an identified etiology, or whether the event represents 
natural progression of the underlying kidney disease. In cases of AKI where an etiology is 
identified, the reported AE term should reflect the etiology for the impairment of renal function 
(eg, AKI due to hypovolemia). 
10.5. 
Serious Renal Conditions 
The following conditions should always be reported as SAEs: 
• Progression of CKD leading to chronic dialysis: For patients who undergo transition 
to chronic maintenance dialysis, the verbatim SAE term should be reported as 
“progression of CKD leading to chronic dialysis.” The term “chronic dialysis” should 
also be captured on the Concomitant Procedure page of the eCRF. 
• Medical conditions requiring transient acute dialysis: For patients who undergo 
transient acute dialysis, the verbatim SAE term should record the condition for which 
the dialysis is required. For example, if a patient requires acute dialysis due to 
hyperkalemia, the verbatim SAE term would be reported as “hyperkalemia requiring 
transient acute dialysis.” The “acute dialysis” should also be captured on the 
Concomitant Procedure page of the eCRF. 
• Kidney transplantation: For patients receiving a kidney transplant, the reason for the 
transplant should be recorded as the verbatim SAE (eg, “progression of CKD 
requiring kidney transplant”). The term “kidney transplant” should also be captured 
on the Concomitant Procedure page of the eCRF. 
10.6. 
Evaluation of Adverse Events/Serious Adverse Events 
10.6.1. 
Causality Assessment 
Assessment of the relationship between the AE and exposure to the study medication is 
important for regulatory reporting and assists in the overall analysis of the safety information. 
For each AE/SAE the Investigator will determine whether, based on available evidence, there is 
a reasonable possibility that the study medication caused the event. Causal relationship will be 
classified according to the following criteria: 
• Not Related: There is no suspicion of a causal relationship between exposure and the 
AE. 
• Unlikely Related: There is no evidence for a causal relationship between exposure 
and the AE; however, such a relationship cannot be ruled out. 
• Possibly Related: There is some evidence supporting the possibility of a causal 
relationship between exposure and the AE. 
• Related: There is strong evidence that there is a causal relationship between exposure 
and the AE. 

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A causality assessment will be provided for each AE/SAE recorded, even if there is only limited 
information at the time. 
Upon receipt of follow-up information, the Investigator may change their assessment of causality 
and amend the AE/SAE report accordingly. 
10.6.2. 
Severity 
Severity indicates the intensity of the event and should not be confused with seriousness (ie, 
Section 10.2), which is an event outcome applied for the purpose of event classification and 
regulatory reporting. 
The Investigator will assess the severity of all AEs/SAEs as mild, moderate, or severe, based on 
the following definitions. 
• Mild: A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
• Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research patient. 
• Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
10.6.3. 
Outcome 
Outcome describes the status of the AE. The Investigator will provide information regarding the 
patient outcome of each AE. Definitions for possible results of an AE outcome include: 
• Recovered/Resolved: The event has improved, or the patient recuperated. 
• Recovering/Resolving: The event is improving. 
• Not Recovered/Not Resolved: The event has not improved, or the patient has not 
recuperated. 
• Recovered/Resolved with sequelae: The patient recuperated but retained pathological 
conditions directly resulting from the disease or injury. 
• Fatal: Termination of life as a result of an AE. There should be only 1 AE marked 
with this outcome. 
• Unknown: Not known, not observed, not recorded, or refused. 
10.6.4. 
Action Taken Regarding the Study Medication 
The action taken with regard to the study medication in response to the AE will be provided at 
the time the event is reported. Options for action taken include the following: 
• Drug Withdrawn: Medication schedule was modified by permanently terminating a 
prescribed regimen of medication. 

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• Dose Reduced: Medication schedule was modified by subtraction, either by changing 
the frequency, strength or amount. 
• Dose Increased: Medication schedule was modified by addition; either by changing 
the frequency, strength or amount. 
• Dose Not Changed: Medication schedule was maintained. 
• Drug Interrupted: Medication schedule was modified by temporarily terminating a 
prescribed regimen of medication. 
• Unknown: Not known, not observed, not recorded or refused. 
• Not Applicable: Determination of a value is not relevant in the current context, for 
example, if the AE began and ended prior to treatment or after discontinuation of 
treatment. 
10.6.5. 
Assessment of Expectedness 
The expectedness of an SAE will be determined by the Sponsor in accordance with the 
sparsentan Reference Safety Information (which is contained in the Investigator’s Brochure) or 
the irbesartan product label, as applicable. 
10.7. 
Reporting Adverse Events and Serious Adverse Events 
10.7.1. 
Reporting Adverse Events 
Adverse events (including SAEs) will be captured from the time informed consent is signed to 
the patient’s final visit. 
For patients who prematurely discontinue study treatment (see Section 8.3.2) but who are not 
withdrawn from the study, AEs will continue to be recorded until the patient completes the study 
(see Section 6.3.1 for definition of patient completion). 
If a patient initiates RRT after premature discontinuation of study treatment, only AEs and SAEs 
considered related or possibly related to study treatment need to be recorded. 
Adverse events will be recorded using appropriate medical terminology. When recording, it is 
preferable to provide a diagnosis. In the absence of a diagnosis, each sign and symptom will be 
captured as a unique AE. Sufficient information should be sought to assist the Investigator both 
in determining the diagnosis and in making a causality assessment. 
Reporting should not be delayed pending receipt of all required information. If information is 
unavailable at the time of the initial report, the Investigator is expected to follow-up until the 
required information has been obtained. 
10.7.2. 
Reporting Serious Adverse Events 
The necessity and time requirements for reporting of SAEs to the Sponsor or its designee and/or 
regulatory agencies are as follows: 
• All SAEs will be reported by email to the SAE contact on the Study Contact 
Information page of this protocol or by fax to the number in the Investigator Site File 

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within 24 hours of the Investigator’s first knowledge of the event, regardless of causal 
relationship. 
• For the double-blind portion of the study (Day 1 through Week 112) and the 
open-label extension portion of the study (Week 112 and after), a completed SAE 
Report Form containing a detailed written description of the event along with 
available supporting documents (eg, discharge summary, autopsy report, diagnostic 
test results, etc.) will be provided by email to the SAE contact on the Study Contact 
Information page or by fax to the number in the Investigator Site File. For complete 
instructions, refer to SAE Report Form completion guidelines. 
• Additional information that is not available at the time the initial SAE Report Form 
was completed will be promptly reviewed and provided by email to the SAE contact 
on the Study Contact Information page or by fax to the number in the Investigator 
Site File within 48 hours of receipt. Full supporting documentation should be 
solicited by the investigative site even if the SAE occurred at another institution. Such 
documentation may include copies of relevant patient/hospital records, discharge 
summaries, laboratory/test results or autopsy reports. 
• If at any time after the patient has completed participation in the study (as defined in 
Section 6.3.1 and Section 6.3.2), the Investigator or study staff becomes aware of an 
SAE that they suspect is related to the study medication (see Section 10.6.1), the 
event and any known details will be reported promptly by email to the SAE contact 
on the Study Contact Information page or by fax to the number in the Investigator 
Site File, following the reporting instructions in this section. 
10.7.3. 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs will be followed until resolution, until the condition stabilizes, or until completion of the 
patient’s participation or study termination, whichever occurs first. 
Serious AEs will be followed until resolution, until the condition stabilizes, or until the 
Investigator and the Sponsor agree that follow-up is no longer necessary. 
All AEs/SAEs documented at a previous visit/contact where event outcome is designated as not 
recovered/not resolved, recovering/resolving or unknown will be reviewed by the Investigator at 
subsequent visits/contacts. SAEs that are ongoing after completion of the last scheduled visit will 
continue to be followed to determine the final outcome. 
Rules for AE/SAE follow-up apply to all patients, to the extent allowed by the patient’s consent. 
The Investigator will ensure that follow-up includes further investigations consistent with 
appropriate medical management to understand the nature and/or causality of the AE/SAE. The 
Sponsor, its designee, or regulatory authorities may also request additional information regarding 
an SAE at any time. 
All follow-up information will be promptly reviewed by the Investigator and provided by email 
to the SAE contact on the Study Contact Information page of this protocol or by fax to the 
number in the Investigator Site File within the specified timelines. Additional AEs/SAEs may be 
identified during the review of follow-up information and will be processed in accordance with 
requirements defined throughout Section 10. 

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10.7.4. 
Reporting to Regulatory Authorities, Investigators and Institutional Review 
Boards/Independent Ethics Committees 
The Sponsor will ensure that processes are in place for provision of SAEs and Expedited SAE 
reports (SUSARs) to Regulatory Authorities, Investigators, and Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) as required, within the specified timelines. 
The Sponsor will submit SAE and/or SUSAR reports to regulatory authorities and the 
Investigator as required. In the US, Investigators will report SAEs and SUSARs to their IRB in 
accordance with applicable SOPs and/or local reporting requirements. In Europe, the Sponsor or 
its designee will notify the IEC of any SUSARs. In regions/countries other than the US/Europe, 
reporting of events to IECs or local authorities will be performed by the Investigator/Sponsor or 
its designee and will be done in accordance with local procedures/regulations. 
Investigators will forward copies of the IRB/IEC notification to the Sponsor or its designee, 
when applicable. 
10.8. 
Pregnancy Reporting 
Although not an AE in itself, exposure to study medication during pregnancy must be reported; 
therefore, all pregnancies in female patients will be recorded on the AE eCRF. If a patient 
becomes pregnant during the study, study medication will be immediately discontinued, and 
pregnancy will be documented as the reason for study medication discontinuation. If a urine 
pregnancy test is positive, study medication will be immediately discontinued until a serum 
pregnancy test confirms the result. 
If the Investigator suspects that a pregnancy was the result of an interaction between the study 
medication and the contraceptive method, in addition to the pregnancy, the study medication 
interaction will also be captured as a separate AE. 
The Investigator will report any pregnancy associated with exposure to study medication, from 
the time of first dose until at least 90 days after final study medication administration (including 
open-label sparsentan). When a site becomes aware that a patient is pregnant, they are to contact 
the Medical Monitor immediately (within 24 hours of the site becoming aware of the event), 
complete an initial Pregnancy Notification Form, and send the form by email to the SAE contact 
on the Study Contact Information page of this protocol or by fax to the number in the 
Investigator Site File. 
Sites will contact patients monthly to confirm that the required pregnancy test has been 
performed and the results are negative. Female patients will be instructed to notify the 
Investigator immediately if they discover they are pregnant. 
If the Investigator learns of a report of pregnancy after signing informed consent, the Investigator 
will complete the Pregnancy forms and submit them to the study contact on the Study Contact 
Information page of this protocol or by fax to the number in the Investigator Site File. 
All pregnancies in female patients will be followed to outcome (ie, delivery, elective termination, 
spontaneous abortion). Infants should be followed for a minimum of 8 weeks. In certain cases, it 
may be necessary to follow-up on the long-term outcome of an AE using the pregnancy 
follow-up form. The Investigator will inform the patient that the Sponsor or its designee is 
required to gather information regarding the course and outcome of the pregnancy after exposure 

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to the study medication. All study-related visits/contacts involving a known pregnancy will 
include pregnancy status assessment until pregnancy outcome is known. The Investigator should 
further obtain follow-up information no later than 1 month after the gestational period to obtain 
maternal/fetal/neonatal outcome and any other relevant information (after obtaining consent from 
the patient). Upon obtaining pregnancy outcome, the Investigator will complete the pregnancy 
outcome form and submit it to the study contact on the Study Contact Information page of this 
protocol or by fax to the number in the Investigator Site File. 
All information related to the pregnancy and its outcome will be assessed for the occurrence of 
an AE or SAE. Spontaneous abortions and stillbirths will always be reported as SAEs. Should an 
AE or SAE occur in the patient and the patient decides to continue in the study after permanently 
discontinuing study medication, the event will be processed per routine study 
guidelines. However, if the patient decides not to continue in the study, all AEs and SAEs will be 
documented and provided directly to the SAE contact on the Study Contact Information page of 
this protocol. Likewise, if the pregnancy results in the birth of a child and an AE or SAE occurs 
in the child, the data will be documented and provided directly to the SAE contact. 

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11. 
DATA COLLECTION, QUALITY ASSURANCE, AND 
MANAGEMENT 
11.1. 
Recording of Data 
The study will use eCRFs for data collection. The data will be entered by trained site personnel 
only. The Investigator is responsible for ensuring that all sections of each eCRF are completed 
promptly and correctly and that the data can be verified against source data. 
AEs, medical history, and concomitant medical procedures will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Similarly, prior and concomitant medications 
and concomitant therapies will be coded using the World Health Organization Drug Dictionary 
(WHO-DD). 
11.2. 
Data Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or its 
designee may conduct a quality assurance audit. 
11.3. 
Data Management 
Data management will be performed by a qualified vendor under their SOPs. The Sponsor will 
provide oversight. 

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12. 
STATISTICAL METHODS AND PLANNED ANALYSES 
12.1. 
General Considerations 
The statistical principles applied in the design and planned analyses of this study are consistent 
with the ICH Guideline E9 (Statistical Principles for Clinical Trials). 
All statistical analyses will be performed using Version 9.2 or later of Statistical Analysis 
Systems (SAS®). 
Data summaries will use descriptive statistics (n, mean, standard deviation [SD], median, 
minimum, and maximum) for continuous variables, and frequency and percentage for categorical 
and ordinal variables. Where there are missing values, the number missing will be presented 
without a percentage. All data collected will be included in by patient data listings. 
12.2. 
Determination of Sample Size 
Approximately 300 patients will be randomized and allocated 1:1 to receive sparsentan or 
irbesartan. This sample size takes into consideration enrollment feasibility in this rare disease 
setting and was evaluated using simulations. A sample size reassessment procedure is planned 
when the first 50 randomized patients have completed the Week 60 visit. This procedure will be 
conducted and overseen by the DMC and will be fully described in the Statistical Analysis Plan 
(SAP). 
12.2.1. 
Surrogate Endpoint: Proportion of Patients Achieving Target UP/C ≤1.5 g/g 
(170 mg/mmol) and a >40% Reduction in UP/C at Week 36 
Based on the results at Week 8 of the sparsentan Phase 2 DUET study and projected to Week 36, 
it is assumed that sparsentan will result in approximately 50% of patients achieving the response 
(p1), and that irbesartan will result in approximately 20% of patients achieving the response (p2). 
For the surrogate endpoint, at the time of the interim analysis (which is planned for after 
36 weeks following randomization of at least 190 patients [approximately 95 per treatment 
group]), the power to detect a difference in response proportions (p1 – p2) between treatment 
groups is more than 90%, assuming the response proportions are 50% for sparsentan and 20% for 
irbesartan, with a 2-sided α of 0.05. The minimum treatment difference that could be declared 
statistically significant is approximately 13% with approximately 190 patients. 
12.2.2. 
Primary Endpoint: Slope of eGFR 
For the final analysis of the primary endpoint (eGFR slope) evaluated following the initial acute 
effect of randomized treatment (ie, eGFR chronic slope over 2 years) in non-US countries and 
following the initiation of randomized treatment (ie, eGFR total slope over 2 years) in the US, 
the ability of the study to distinguish between treatment groups was evaluated using the projected 
treatment difference in eGFR slopes given the treatment difference on the surrogate efficacy 
endpoint. The calculations assume that treatment difference in eGFR slope is equal to the 
treatment difference in UP/C response proportions multiplied by the difference in eGFR slopes 
among patients who achieved the UP/C response (ie, UP/C responders) and those who do not 
(ie, UP/C non-responders). Available data from the DUET and disease registry studies were used 
to model this relationship. 

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Using the available data, the modeling exercise yielded an estimated difference in eGFR slopes 
between UP/C responders and non-responders of approximately 8.4 mL/min/1.73 m2 per year 
based on the eGFR chronic slope. With the assumed treatment difference in response proportions 
of 30%, the projected treatment difference in eGFR slopes is approximately 
2.52 mL/min/1.73 m2 per year. The model also estimated the residual variability (SD) to be 
approximately 10.80 mL/min/1.73 m2 per year. Power calculations follow the approach 
described in Dupont and Plummer (Dupont 1998). 
Based on the eGFR total slope, the modeling exercise yielded a projected treatment difference in 
eGFR slopes of approximately 2.1 mL/min/1.73 m2 per year, assuming a treatment difference in 
response proportions of 30% for the surrogate endpoint. With 300 patients (approximately 
150 patients per treatment group) and a 2-sided α of 0.05, the study has at least 90% power to 
differentiate between treatments. This power calculation is based on the Wald statistic using a 
standard deviation of the eGFR total slope of 5.50 mL/min/1.73 m2 per year estimated from 
blinded interim data from the current study. 
It should be noted that statistical testing can only be performed at the final analysis if a 
statistically significant difference is demonstrated at the interim analysis of the surrogate 
endpoint. 
12.3. 
Analysis Sets 
12.3.1. 
Full Analysis Set 
All patients who are randomized and take at least one dose of double-blind study medication will 
be included in the Full Analysis Set (FAS). All analyses of the FAS will be based on each 
patient’s randomized assigned treatment. If a patient is incorrectly stratified (ie, randomized 
according to the incorrect stratification), the patient will be analyzed under the randomized 
treatment for the stratum recorded in the randomization system. All efficacy analyses for the 
double-blind period will be based on the FAS. 
12.3.2. 
Per Protocol Analysis Set 
The Per Protocol (PP) Analysis Set will include all patients in the FAS who meet the study 
eligibility requirements and have no major protocol deviations that affect the validity of the 
efficacy measurements. Patients will be analyzed according to their randomized treatment. The 
PP Analysis Set will be used for a sensitivity analysis of the primary efficacy endpoint. The 
criteria for inclusion in the PP Analysis Set will be finalized prior to study unblinding and 
detailed in the SAP. 
12.3.3. 
Safety Analysis Set 
All patients who are randomized and take at least 1 dose of double-blind study medication will 
be included in the Safety Analysis Set. Safety analyses will be based on randomized treatment. 
12.3.4. 
Open-Label Extension Full Analysis Set 
All patients who received at least 1 dose of open-label sparsentan in the open-label extension 
will be included in the OLEFAS. All efficacy and safety analyses during the open-label 
extension will be based on the OLEFAS. 

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12.4. 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics for the FAS, PP, and Safety Analysis Sets will be 
summarized by treatment group using descriptive statistics. Demographic data include sex, age 
(years), categorical age (<18 years and ≥18 years), race/ethnicity, weight (kg), height (cm), and 
calculated BMI. Baseline characteristics also include reproductive status (for females only), 
HbA1c, baseline eGFR, and current use of: steroids, calcineurin inhibitors, mycophenolate 
mofetil and other immunosuppressive agents, RAAS inhibitors (ie, ACE inhibitors, ARBs, 
aldosterone blockers, and aliskiren) prior to the 2-week washout, diuretics, additional 
antihypertensive treatments, and statins. 
Likewise, demographic data and baseline characteristics for the OLEFAS will be summarized 
overall using descriptive statistics. 
12.5. 
Patient Accountability 
For the double-blind period, frequencies and percentages will be displayed for the number of 
patients who: screened, failed screening, enrolled, were randomized, were treated, completed 
treatment, completed the study, discontinued treatment early, and withdrew from the study. Data 
will be presented overall and by treatment group. Similarly, the number and percentage of 
patients in each analysis set (FAS, PP, and Safety) will be summarized. 
For the open-label extension, frequencies and percentages will be displayed for the number of 
patients who: entered the open-label extension, discontinued open-label treatment, and 
completed the open-label extension. Data will be presented overall using the OLEFAS. 
12.6. 
Study Treatment Usage and Compliance 
For the double-blind period, compliance rates during the treatment period will be derived with 
the following formula: 
100 × ((Total number of capsules/tablets dispensed – Total number of capsules/tablets 
returned) / (Expected number of capsules/tablets to be taken based on the patient’s titration 
schedule)). 
If a patient is lost to follow-up and did not return all unused capsules/tablets, it will be assumed 
that the patient did not take any capsules/tablets since the last visit date. 
Compliance rates will be presented for the Safety Analysis Set using summary statistics and 
percentage for the frequency distributions (<40%, 40-<80%, 80-<120%, ≥120%) by treatment 
group and overall. Duration of treatment in weeks, defined as: 
(date of last dose of study medication - date of first dose of study medication + 1)/7 
will also be summarized by treatment group for the Safety Analysis Set. 
For the open-label extension, compliance will be calculated using an analogous approach as 
above but using dosage strength instead of number of capsules/tablets. Compliance will be 
summarized overall for the OLEFAS. 

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12.7. 
Efficacy Analysis 
All efficacy analyses during the double-blind period will be performed based on the FAS. The 
primary endpoint analysis will also be conducted using the PP Analysis Set. 
The eGFR during the screening period will be determined using the CKD-EPI equation for adults 
(Levey 2009) and the Modified Schwartz formula (Schwartz 2009a; Schwartz 2009b) for 
children <18 years of age. 
The eGFR for each timepoint (visit) during the double-blind period will be determined using the 
CKD-EPI equation for adults (Levey 2009) and children ≥16 years of age at screening for the 
double-blind period, and the Modified Schwartz formula for children <16 years of age at 
screening for the double-blind period (Schwartz 2009a; Schwartz 2009b). The eGFR for each 
timepoint (visit) during the open-label extension will be determined using the CKD-EPI equation 
for adults (Levey 2009) and children ≥16 years of age at Week 108, and the Modified Schwartz 
formula for children <16 years of age at Week 108 (Schwartz 2009a; Schwartz 2009b). 
For the double-blind period, UP/C will be determined using first morning void urine samples and 
will be calculated as the average of 3 first morning void urine samples collected within 5 days 
prior to each visit at which UP/C is assessed. For the open-label extension, UP/C will be 
determined using 1 first morning void urine sample collected within 5 days prior to each visit at 
which UP/C is assessed. As UP/C is a highly skewed variable, analyses will be performed on 
log-transformed data; however, for ease of interpretation, results will be presented in the original 
units. 
12.7.1. 
Primary Efficacy Analysis 
12.7.1.1. Primary Efficacy Endpoint: Slope of eGFR at the Final Analysis 
For the primary endpoint of slope of eGFR evaluated following the initial acute effect of 
randomized treatment (ie, from Week 6 to Week 108; chronic slope over 2 years), a 
mixed-effects model with linear spline (knot or change point at Week 6) will be fitted to the 
available eGFR data. The response variable is the eGFR measured at post-baseline assessments 
for each patient during the double-blind period. The model will include fixed effects for 
treatment, both stratification factors for randomization, baseline eGFR (continuous), time (in 
weeks) from baseline (continuous), and time (in weeks) from the change point (ie, 
timek = max (time – 6, 0)), time-by-treatment, and timek-by-treatment interactions. The model 
will also include a random intercept and random slopes (time and timek) for each patient. The 
mixed model will utilize restricted maximum likelihood (REML) estimation with 
Kenward-Roger method used to compute the denominator degrees of freedom for tests of fixed 
effects. The model will assume an unstructured covariance matrix. If the model does not 
converge under the unstructured covariance matrix, the autoregressive-1 covariance structure 
will be used. 
The primary efficacy hypothesis of interest is whether eGFR slopes over the blinded treatment 
period (after adjusting for early hemodynamic effects) are different between the 2 treatment 
groups, ie: 
H0: (βtime*treatment + βtimek*treatment) = 0 versus: 
H1: (βtime*treatment + βtimek*treatment) ≠ 0. 

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This hypothesis will be tested using the mixed model by testing whether the time-by-treatment 
interaction parameters least-squares (LS) mean estimate is equal to 0. 
For the primary endpoint of slope of eGFR evaluated following initiation of randomized 
treatment (ie, from Day 1 to Week 108; total slope over 2 years), a mixed-effects model will be 
fitted to the available eGFR data. The response variable is the eGFR measured at post-baseline 
assessments for each patient during the double-blind period. The model will include fixed effects 
for treatment, both stratification factors for randomization, baseline eGFR (continuous), time (in 
weeks) from baseline (continuous), and time-by-treatment interaction. The model will also 
include a random intercept and a random slope for each patient. The mixed model will utilize 
restricted maximum likelihood estimation with Kenward-Roger method used to compute the 
denominator degrees of freedom for tests of fixed effects. The model will assume an 
unstructured covariance matrix. If the model does not converge under the unstructured 
covariance matrix, the autoregressive-1 covariance structure will be used. 
The primary efficacy hypothesis of interest is whether eGFR slopes over the blinded treatment 
period (after adjusting for early hemodynamic effects) are different between the 2 treatment 
groups, ie: 
H0: βtime*treatment = 0 versus 
H1: βtime*treatment ≠ 0. 
This hypothesis will be tested using the mixed model by testing whether the time-by-treatment 
interaction parameter LS mean estimate is equal to zero. 
Sensitivity analyses are planned to assess the potential impact of major protocol deviations, 
premature treatment discontinuations, changes in immunosuppressive medications, and the 
choice of the change point. 
12.7.1.2. Surrogate Efficacy Endpoint: Proportion of Patients Achieving a UP/C ≤1.5 g/g 
(170 mg/mmol) and a >40% Reduction from Baseline at Week 36 
Analyses of the proportion of patients achieving a UP/C ≤1.5 g/g (170 mg/mmol) and a > 40% 
reduction from baseline at each visit (including the surrogate efficacy endpoint at Week 36) will 
be performed using a generalized linear model with logit link function to model the probability 
of achieving UP/C ≤1.5 g/g (170 mg/mmol) and a >40% reduction from baseline and to compare 
sparsentan with irbesartan. The response variable will be a binary indicator of achievement of 
UP/C ≤1.5 g/g (170 mg/mmol) and a >40% reduction from baseline at each post-baseline visit. 
Missing response variables will be imputed using the multiple imputation (MI) procedure before 
analysis. Fixed effects in the model will include baseline UP/C, treatment, time (categorical, in 
weeks), and treatment-by-time interaction. Analysis will be stratified by randomization 
stratification variables (4 levels based on Screening eGFR and UP/C). An unstructured 
covariance matrix within patient will be assumed. If convergence issues arise, the autoregressive-
1 covariance structure will be used. 
At each post-baseline visit included in the model, the probability of achieving UP/C ≤1.5 g/g 
(170 mg/mmol) and a >40% reduction from baseline (risk) for each treatment group, treatment 
effect (risk difference), standard errors of risk and risk difference, 95% CIs of risks and risk 
difference, and p-values will be extracted from the model. Relative risk ratios and odds ratios, 

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along with standard errors and 95% CIs, will also be presented. This analysis will be performed 
at the interim analysis (ie, surrogate efficacy endpoint). 
Sensitivity analyses will be performed using a Cochran-Mantel-Haenszel (CMH) test at 
Week 36, tipping point analysis, and analysis using observed cases (ie, no MI). 
12.7.2. 
Secondary Efficacy Analyses 
The percent change from Week 6 in eGFR at Week 108 will be analyzed at the final analysis 
using a Mixed Model Repeated Measures (MMRM) described in Section 12.7.3. Specifically, for 
this endpoint, the statistical significance of the treatment difference at Week 108 will be assessed 
by testing: 
H0: (βWK108*treatment – βWK6*treatment) = 0 vs H1: (βWK108*treatment – βWK6*treatment) ≠ 0 
where βWK108*treatment is the treatment effect at Week 108 and βWK6*treatment is the treatment effect 
at Week 6. The LS mean estimate from the MMRM model will be used to perform treatment 
group comparisons. 
The percent change from baseline to 4 weeks post-cessation of randomized treatment at 
Week 112 in eGFR will be analyzed via analysis of covariance (ANCOVA). The dependent 
variable will be the natural log(eGFR) of analysis visit Week 112, with treatment and baseline 
eGFR in log scale included as fixed effects. The analysis will be stratified by the randomization 
strata. The treatment effect will be the contrast between sparsentan and irbesartan LS means. The 
LS means, treatment effect estimate, 95% CI, and p-value will be presented. Estimates and CIs 
will be converted to percentage. 
The change from baseline to 4 weeks post-cessation of randomized treatment at Week 112 in 
eGFR will be analyzed via analysis of covariance (ANCOVA). The dependent variable will be 
the eGFR at analysis visit Week 112 with treatment and baseline eGFR included as fixed effects. 
The analysis will be stratified by the randomization strata. The treatment effect will be the 
contrast between sparsentan and irbesartan LS means. The LS means, treatment effect estimate, 
95% CI, and p-value will be presented. 
12.7.3. 
Additional Efficacy Analyses 
For the analysis of eGFR absolute change from baseline by visit, a MMRM model will be fitted 
to the available eGFR data, incorporating all post-baseline visits at which eGFR was measured 
for each patient during the double-blind period. The model will include treatment, both 
stratification factors for randomization, baseline eGFR, visit (categorical), and visit-by-treatment 
interaction as fixed effects. In addition, patient will be included as a random effect. 
The model will utilize REML estimation with Kenward-Roger method used to compute the 
denominator degrees of freedom for tests of fixed effects. An unstructured within-patient 
covariance structure will be assumed. If the model does not converge under the unstructured 
covariance matrix, the autoregressive-1 covariance structure will be used. The LS mean estimate 
for βWKj*treatment (ie, the treatment effect at the visit j of interest) from the MMRM model will be 
used to perform treatment group comparisons by visit. 
For the analysis of eGFR percent change from baseline by visit, a MMRM approach analogous 
to the model described for the absolute change from baseline will be used, except that the 

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response variable will be natural log(eGFR) and corresponding baseline value natural 
log(baseline eGFR). The LS mean estimate for βWKj*treatment (ie, the treatment effect at the visit j 
of interest) from the MMRM model will be used to perform treatment group comparisons by 
visit. Estimates and CIs will be converted to percentages via the following transformation: 
[exp (LS mean change from baseline in natural log(eGFR)) – 1] × 100 
For the analysis of eGFR percent change from Week 6 by visit, the estimates from the MMRM 
model used in the analysis of eGFR relative percent change from baseline by visit described 
above will be utilized. However, for this analysis, the statistical significance of the treatment 
difference at visit j (eg, Week 108 for the secondary endpoint) will be assessed by testing the 
following hypothesis: 
H0: (βWKj*treatment – βWK6*treatment) = 0, versus: 
H1: (βWKj*treatment – βWK6*treatment) ≠ 0, 
where βWKj*treatment is the treatment effect at the visit j of interest and βWK6*treatment is the effect 
estimate at Week 6. The LS mean estimate from the MMRM model will be used to perform 
treatment group comparisons by visit. Estimates and CIs will be converted to percentages via the 
following transformation: 
[exp(least-squares mean change from Week 6 in natural log(eGFR)) – 1] × 100. 
Change from baseline to all post-baseline visits during the double-blind period in natural 
log(UP/C) will be analyzed using a MMRM model analogous to the one described for percent 
change from baseline in eGFR. The LS mean estimate for βWKj*treatment (ie, the treatment effect at 
the visit j of interest) from the MMRM model will be used to perform treatment group 
comparisons by visit. Estimates and CIs will be converted to percentages via the following 
transformation: 
[exp (LS mean change from baseline in natural log(UP/C)) – 1] × 100. 
The time to achieve the target reduction in UP/C during the double-blind period will be analyzed 
using a Cox proportional hazards model, stratified by randomized stratification variables, with a 
comparison between treatment groups. Patients who discontinue from treatment during the 
double-blind period prior to achieving the target reduction will be censored at the time of 
treatment discontinuation. Patients who never meet the target during the double-blind period will 
be censored at the time of analysis. 
The following endpoints will be summarized descriptively for the double-blind period and 
compared between treatment groups using a CMH test controlling for the randomization 
stratification variables: 
• the proportion of patients reaching a confirmed 40% reduction in eGFR, ESRD, or 
death. (ESRD is defined as initiation of RRT or sustained eGFR <15 mL/min/1.73 m2 
during the study); 
• the proportion of patients requiring initiation of or intensification in 
immunosuppressive medication during the study; 
• the proportion of patients with reduction in immunosuppressive medication during the 
study. 

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Changes from baseline to all post-baseline visits during the double-blind period with respect to 
QoL scores and blood pressure (systolic and diastolic) values will be analyzed using a MMRM 
model analogous to the one described for changes from baseline in eGFR. 
The number of hospitalization days during the double-blind period will be analyzed 
descriptively, and the incidence of patient hospitalizations analyzed using Fisher’s exact test. 
Separate analyses will be presented for hospitalizations due to any reason and due to reasons 
related to the kidney (list to be determined prior to unblinding). 
12.8. 
Safety Analyses 
All safety analyses for the double-blind period will be conducted based on the Safety Analysis 
Set. 
Safety data will include AEs, physical examination results, vital signs, ECG results, and clinical 
laboratory measurements. Observed data will be listed by patient and summarized using 
descriptive statistics by treatment group for the double-blind period. 
12.8.1. 
Physical Examination and Vital Signs 
The number and percentage of patients with physical examination abnormalities at each visit will 
be summarized and presented for each body system. A listing of abnormalities will also be 
provided. 
The presence and staging of edema will be summarized by frequency counts and percentages 
based on semi-quantitative (0, 1+, 2+, 3+, 4+) evaluation of physical examination findings. A 
shift table indicating changes in edema from baseline to each post-baseline visit will be provided. 
Vital signs data will be summarized as changes from baseline and will be classified as low, 
normal, or high based on reference ranges prespecified in the SAP. Vital sign abnormalities for 
each treatment will be summarized using shift tables. 
12.8.2. 
Clinical Laboratory Tests 
Clinical and laboratory parameters will be measured at baseline and post-baseline visits. Each 
continuous laboratory variable will be summarized as changes from baseline by treatment group. 
Laboratory data will also be classified as low, normal, or high relative to the parameter’s 
reference range. Laboratory abnormalities for each treatment will also be summarized using shift 
tables. 
12.8.3. 
Adverse Events 
Adverse events will be mapped to preferred term and body system using MedDRA. Adverse 
events that begin after the first administration of study medication, or existing AEs that worsen 
after the first dose of study medication are considered TEAEs. The number and percentage of 
patients reporting TEAEs will be summarized for each treatment group by MedDRA system 
organ class and preferred term, then by severity, and by relationship to study medication. 
Drug-related TEAEs will be considered those to be at least possibly related to study medication 
based on the Investigator’s assessment. The number and percentage of patients reporting serious 
AEs or AEOIs, and the number and percentage of patients reporting AEs leading to treatment 

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discontinuation will also be summarized for each treatment group by MedDRA system organ 
class and preferred term. 
12.8.4. 
Other Safety Assessments 
Electrocardiogram results will be presented descriptively by treatment group and visit and will 
also be listed. 
12.9. 
Other Analyses 
12.9.1. 
Prior Medications, Concomitant Medications, and Concomitant Medical 
Procedures 
Concomitant medications will be coded using the WHO-DD, and concomitant medical 
procedures will be coded using MedDRA. The incidence of prior medications, concomitant 
medications, and concomitant medical procedures will be summarized using frequency and 
percentage for the double-blind period and separately for the open-label extension. 
The use of diuretics required for controlling urine volume, edema, and blood pressure will be 
summarized separately. Specifically, the number of patients requiring an increase, decrease, or 
no change in the number of diuretics used from baseline will be analyzed. Prior to analysis, a 
defined list of medications based on coded terms will be developed to identify appropriate 
diuretics for this analysis. For the double-blind period, this review and identification of diuretics 
will be conducted prior to unblinding. 
All concomitant medications and medical procedures will be listed for individual patients by 
treatment group; this listing will include the indication for use, start/stop date, dose/units, 
frequency, and route of administration. 
12.9.2. 
Pharmacokinetics 
Trough plasma study medication levels will be summarized using descriptive statistics. 
12.10. 
Other Statistical Issues 
12.10.1. 
Significance Levels 
Unless otherwise specified, all tests will be 2-tailed, using a 0.05 level of significance. All CIs 
will be 2-sided 95% CIs. 
12.10.2. 
Multiple Comparisons/Multiplicity 
To control the overall type I error for this study when conducting significance tests for the 
primary and secondary efficacy endpoints, a hierarchical (gate-keeping) testing procedure will be 
used. 
The surrogate efficacy endpoint (UP/C response at Week 36) will first be tested at the interim 
analysis at 2-sided α = 0.05. If the test is not significant, hypothesis testing stops. If the test is 
significant, then the following country-specific hierarchical testing will be performed. 
For non-US countries, the hierarchy for the hypothesis testing will be as follows, if the test of the 
surrogate efficacy endpoint (UP/C response at Week 36) is significant: 

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1. test the primary efficacy endpoint (eGFR chronic slope over 2 years) at the final analysis 
at 2-sided α = 0.05. If the test is not significant, hypothesis testing stops. If the test is 
significant, 
2. test the 3 secondary endpoints using a Bonferroni-Holm procedure to control for 
family-wise error rate at 2-sided α = 0.05. 
For the US, the hierarchy for the hypothesis testing will be as follows, if the test of the surrogate 
efficacy endpoint (UP/C response at Week 36) is significant: 
1. test the primary efficacy endpoint (eGFR total slope over 2 years) at the final analysis at 
2-sided α = 0.05. If the test is not significant, hypothesis testing stops. If the test is 
significant, 
2. test the efficacy endpoint of eGFR chronic slope over 2 years at the final analysis at 
2-sided α = 0.05. If the test is not significant, hypothesis testing stops. If the test is 
significant, 
3. test the efficacy endpoint of change in eGFR from baseline of the double-blind period to 
4 weeks post-cessation of randomized treatment at Week 112 at the final analysis at 
2-sided α = 0.05. 
12.10.3. 
Missing Data 
Patients who discontinue will not be replaced. To the extent possible, attempts will be made to 
minimize the amount of missing data through measures planned in the study conduct. However, 
if missing data are present, they will be handled as follows: 
• Continuous endpoints analyzed via mixed-effects models (including the primary 
efficacy endpoint): Only available data will be analyzed, using the mixed-effects 
model with random slope and intercepts and the MMRM approaches described 
throughout Section 12.7.1. These models implicitly adjust for missing data through a 
variance covariance structure. 
• UP/C response: Missing data at specific visits will be imputed using an MI procedure. 
Sensitivity analyses will also be performed on observed cases (ie, no imputation) and 
at Week 36 only imputing missing data as non-responders. 
12.11. 
Interim Analysis 
An unblinded interim analysis will be performed after 36 weeks following randomization of at 
least 190 patients (approximately 95 patients per treatment group) to determine whether the 
surrogate endpoint (the proportion of patients achieving a UP/C ≤1.5 g/g [170 mg/mmol] and a 
>40% reduction from baseline in UP/C) is statistically significant. The statistical evaluation will 
be performed on the subset of patients in the FAS who are scheduled to have completed their 
Week 36 visit, using a generalized linear model with logit link function, at a significance level of 
α = 0.05. The interim analysis will be conducted by an independent statistical team, and the study 
team will remain blinded to the interim data (see Section 8.6). No unblinded individual patient 
data will be published. Processes to ensure that the blind is appropriately preserved will be 
detailed and documented prior to unblinding for the interim analysis. 

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12.12. 
Analyses for the Open-Label Extension 
Analysis of endpoints for the open-label extension will be performed using the methods 
described in the sections above as appropriate. 
Efficacy and safety endpoints for the open-label extension will be summarized using descriptive 
statistics and presented overall and by original randomized treatment based on the OLEFAS. 
Analyses using baselines other than Week 112 (eg, prior to first dose of study medication in the 
double-blind period) may be explored; details will be provided in the SAP. 

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13. 
SPECIAL REQUIREMENTS AND PROCEDURES 
This protocol was designed and will be conducted, recorded, and reported in compliance with the 
ICH Harmonised Tripartite Guidelines for Good Clinical Practice, 1996; ICH Guidelines for 
Safety Data Management, 1994; the US Code of Federal Regulations (CFR 21 Parts 50, 56, and 
312); and the EU Clinical Trials Directive, 2001/20/EC. The protocol meets legal and regulatory 
requirements according to the country of conduct. 
13.1. 
Institutional and Ethics Review 
This protocol and associated ICF, patient information sheet, any information provided to the 
patient, the Investigator’s Brochure, and any proposed advertising material will be submitted to 
an appropriate IRB/IEC, applicable regulatory authorities, and host institution(s) for written 
approval (where applicable). These documents will also be submitted to, and approved by, the 
above parties for all amendments to the original approved documents (where applicable) prior to 
implementation. Documentation of any applicable approval(s) and the approved ICF and assent 
form (if applicable) will be received by the Sponsor or its designee prior to enrollment of patients 
and release of study medication. 
13.2. 
Data Monitoring Committee 
During the double-blind period, the study will employ an independent DMC that may include 
nephrology, internal medicine, statistician(s), and/or pharmacovigilance physicians. The DMC 
members will not be involved in the study as Investigators or consultants. The DMC will have 
study conduct oversight as defined by the DMC charter. All members will have considerable 
experience with clinical study conduct and DMCs. Any candidate found to have a financial, 
intellectual, or personal conflict of interest, or whose name is listed on the FDA debarment list, 
will not be offered membership. Conflicts of interest will be assessed regularly, and if members 
are found to have a new conflict of interest they will be replaced. 
The DMC will meet approximately biannually at scheduled meetings but may agree to adjust 
meeting frequency based upon actual and projected data availability. In addition, ad hoc 
meetings may be convened, as appropriate, to review safety data. Based on review of available 
data, the DMC will advise the Sponsor on the validity and scientific merit of continuing the 
study. Adjustments to or stopping of the protocol defined doses may be considered based on 
DMC evaluation of safety and tolerability data. 
Written minutes of both open and closed DMC sessions will be prepared. The minutes of closed 
sessions will be made available to the appointed Sponsor representatives only after the database 
is locked and all data are unblinded. 
The DMC may request unblinded individual patient data as appropriate. Data reviewed during 
the meetings will include, at a minimum, disposition, demographics, exposure, clinical 
laboratory results, MedDRA-coded AEs, and AEs leading to early withdrawal of study 
medication. At each meeting, detailed narratives of interval SAEs (including events resulting in 
death) are reviewed by the DMC in addition to a cumulative list of all SAEs. 
All Investigators and responsible IRBs/IECs will be informed of any decisions made by the 
Sponsor based on recommendations from the DMC relating to patient safety that alter the 

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conduct of this study. The Investigators will inform patients of such actions, and the protocol and 
ICF will be revised, as appropriate. 
13.3. 
Changes to the Conduct of the Study or Protocol 
Any changes to the study protocol, such as changes in the study design, objectives or endpoints, 
inclusion and exclusion criteria, and/or procedures (except to eliminate an immediate hazard) 
will be implemented only after approval by the Sponsor or its designee. All protocol changes will 
be documented in protocol amendment(s). Protocol amendment(s) (excluding urgent safety 
amendments) will be signed by the Investigator and approved by the IRB/IEC and regulatory 
agencies (where required) prior to implementation. Any changes in study conduct that result 
from a pending amendment will be considered protocol deviations and should be reported to the 
IRB/IEC. Documentation of IRB/IEC approval will be returned to the Sponsor or its designee. 
13.4. 
Investigator's Responsibilities 
The Investigator agrees to: 
• Conduct the study in accordance with the protocol and make changes only after 
receiving written approval from the Sponsor or its designee, except to protect the 
safety, rights, or welfare of patients. 
• Personally conduct or supervise the study. 
• Ensure that requirements related to obtaining informed consent and IRB/IEC review 
and approval comply with ICH E6, CFR 21 Parts 50 and 56, and local laws. 
• Report to the Sponsor or its designee any AEs that occur during the study in 
accordance with ICH E6, CFR 21 Part 312.64 and local laws. 
• Read and understand the Investigator’s Brochure, including potential risks and side 
effects of the investigational product (study medication). 
• Ensure that all associates, colleagues, and employees assisting in the conduct of the 
study are informed of their obligations in meeting the above commitments. 
• Maintain adequate records in accordance with ICH E6, 21 CFR Part 312.62, and local 
laws, and have records available for inspection by the Sponsor, FDA, or other 
authorized agency. 
• Ensure that the IRB/IEC complies with requirements of ICH E6, 21 CFR Part 56, and 
local laws and will be responsible for initial and continuing review and approval of 
the clinical study. 
• Promptly report to the IRB/IEC and the Sponsor or its designee all changes in 
research activity and unanticipated problems involving risks to patients or others 
(including amendments and expedited safety reports). 
• Comply with all other requirements regarding obligations of Investigators and all 
other pertinent requirements listed in ICH E6, 21 CFR Part 312 and local laws. 
• Provide progress reports and notifications of SAEs to the IRB/IEC according to local 
regulations and guidelines. 

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13.4.1. 
Patient Informed Consent 
Investigators agree to adhere to GCP, which includes ethical principles that have their origin in 
the Declaration of Helsinki, when developing the patient ICF and Assent Form (where 
applicable) and when obtaining consent/assent from the patient, parent, or legal guardian. 
Written informed consent is required prior to enrollment in the study. It is the responsibility of 
the Investigator to document the consent process within the source documents and obtain 
consent/assent using an IRB/IEC-approved consent/assent form. 
The Investigator will ensure that each patient/parent/legal guardian is given full and adequate 
oral and written information about the nature, purpose, possible risks, and benefits of the study as 
well as potential treatment alternatives. Patients/parents/legal guardians will be notified that they 
are free to discontinue participation in the study at any time and will be given the opportunity to 
ask questions and allowed time to consider the information provided. A copy of the signed ICF 
will be provided to the patient. A separate ICF will be obtained for patients who participate in the 
open-label extension. 
If necessary, due to challenges related to the COVID-19 pandemic or other unexpected 
circumstances, each patient or parent/legal guardian may provide informed consent/assent 
remotely (ie, via telephone, email, etc.), as dictated by local public health authority requirements. 
It is the responsibility of the Investigator to document this consent/assent process within the 
source documents. Each patient or parent/legal guardian must also provide a manually signed 
copy of the ICF as soon as reasonably possible, either by mail or at the next site visit. 
13.4.2. 
Case Report Forms 
Copies of pertinent records in connection with the study, including all source documents, will be 
made available to the Sponsor or its designee upon request with due precaution toward protecting 
the privacy of the patient. 
Data will be entered by the site onto the eCRFs in the Electronic Data Capture system or 
downloaded from a device, in the case of PROs. Unless explicitly directed, blank data fields are 
not acceptable. Any erroneous entries made on the eCRFs will be corrected by the site. Changes 
made to the data after initial entry into the eCRF will be captured via an electronic audit trail and 
will include the reason for change. Incomplete entries or entries needing additional explanation 
will be queried to the site for clarification. 
13.4.3. 
Record Retention 
The Investigator is responsible for oversight and maintenance of the study records and patient 
source documents. These records will be readily available for audit or inspection. 
The Investigator will retain study records for at least 2 years after the last marketing approval has 
been granted and there are no pending marketing applications in an ICH region, or until at least 
2 years have elapsed since the formal discontinuation of the clinical program. However, these 
documents should be retained for a longer period, if required by other applicable requirements 
(eg, applicable local regulatory requirement) or by an agreement with the Sponsor or its 
designee. The Investigator will contact the Sponsor or its designee prior to any record 
destruction. 

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Patient records or other source data will be kept for the maximum period of time mandated by 
the hospital, institution, or private practice, but not less than 15 years. 
If off-site archiving is used, all records will be retrieved and made available for review at the 
time of an audit or regulatory authority inspection. 
13.4.4. 
Monitoring 
A representative of the Sponsor or its designee will visit the Investigator periodically for the 
purpose of monitoring the progress of this study in accordance with the protocol, GCP, and local 
regulations. Noncompliance with the protocol, GCP, and local regulations will be documented 
and corrective actions implemented, if necessary. It is the responsibility of the Investigator to be 
present or available for consultation during monitoring visits. During these routine visits, all data 
pertaining to a patient’s participation in this clinical investigation will be made available to the 
Study Monitor. The Investigator will comply with applicable privacy and security laws for use 
and disclosure of information. Study Monitors will perform source document verification 
according to the clinical monitoring plan to ensure consistency between the eCRFs and source 
documents. Discrepancies will be resolved in accordance with the principles of GCP. 
If necessary, due to challenges related to the COVID-19 pandemic or other unexpected 
circumstances, monitoring activities may be performed remotely as dictated by local public 
health authority requirements. An emergency remote data verification (rDV) process is being 
implemented in countries where this is allowed, according to local laws and regulations. 
Alternative ways of monitoring the data, where allowed, will be implemented. It is intended that 
this process will facilitate adequate ongoing oversight of the conduct of clinical studies in order 
to identify and eliminate any immediate risk to study patients while on-site monitoring activities 
cannot be performed due to COVID-19 restrictions or other unexpected circumstances. 
At any time prior to, during, or after completion of the clinical study, an audit may be performed 
on a study site by the Sponsor or its designee, an IRB/IEC, or a representative of a national 
regulatory agency. Investigators will notify the Sponsor or its designee upon notification of 
inspection by a representative of a national regulatory agency. A Sponsor or designee 
representative will be available to assist in the preparation for study site inspections. All 
pertinent study data will be made available for verification, audit, or inspection purposes. 
13.4.5. 
Study or Site Termination 
If the Sponsor or its designee, the Investigator, or regulatory authorities discover any conditions 
during the study that indicate that the study or study site should be terminated, this action may be 
taken after appropriate consultation between the Sponsor, its designee, and the Investigator. The 
Sponsor has the right to terminate the participation of either an individual site or the study at any 
time, for any reason which may include the following: 
• The incidence and severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
• Patient enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 

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• Investigator(s) do(es) not adhere to the protocol or applicable regulatory guidelines in 
conducting this study. 
• Knowingly false information from the study site is submitted to the Sponsor, its 
designee, or regulatory authorities. 
• The site does not randomize any patients into the double-blind period of the study, the 
site has no patients who participate in the open-label extension, or patients 
participating in the open-label extension discontinue from the study. 
In the event that the study is terminated early, the Sponsor or its designee will provide specific 
guidance to investigational sites regarding the End of Study procedures. 
13.4.6. 
Study Medication Control 
The Investigator will acknowledge that study medication supplies are investigational, and as 
such must be used strictly in accordance with the protocol and only under the supervision of the 
Investigator or Sub-Investigator(s) listed on Form FDA 1572 (or regional equivalent). Study 
medication must be stored in a safe and secure place with limited access and according to 
Sponsor instructions. 
The Investigator must maintain adequate records documenting the receipt and disposition of all 
study medication supplies. The Sponsor or its designee will supply forms on which to record the 
date study medication was received and a dispensing record in which to record each patient’s 
use. It is the Investigator's responsibility to ensure that patients return their unused study 
medication. 
13.4.6.1. Receipt of Study Medication 
A proof of receipt, which details the quantity and description of the study medication, will 
accompany the shipment from the Sponsor or its designee to the Investigator. The Investigator 
will provide the Sponsor or its designee with a signed and dated copy of this receipt (or an 
electronic equivalent) within 48 hours after receipt of study medication, while retaining the 
original within the site pharmacy files. The Investigator is responsible for ensuring that the study 
medication is maintained in a controlled location, with limited access, and under adequate 
storage conditions. 
13.4.6.2. Disposition of Unused Study Medication 
All unused study medication will be maintained under adequate storage conditions in a limited 
access area. If any unused material is remaining upon completion of the study, the material will 
be returned to the Sponsor or its designee or destroyed only after the following has been 
completed: 
• Accountability has been performed by a representative of the Sponsor or its designee. 
• Appropriate study medication return/destruction documentation has been completed 
by the clinical site pharmacist or their designee. 

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13.4.6.3. Product Handling and Complaints Reporting 
If any issues arise during the course of the study-related to the quality of the study medication, 
the clinical site pharmacist or pharmacy designee will contact the product handling/complaints 
group listed on the Study Contact Information page of this protocol. 
13.4.7. 
Insurance 
The Sponsor will maintain a liability insurance policy covering all clinical studies under its 
sponsorship, and that policy will comply with local laws and requirements. The Sponsor or its 
designee will provide a certificate of insurance to any IRB/IEC, National Competent Authority, 
or regional health authority that may require such a document. Note that this Sponsor insurance 
coverage does not relieve the Investigator, the institution, and their collaborators from each 
maintaining their own liability insurance policy for their clinical research activity. 
13.4.8. 
Data Confidentiality 
All patient information obtained during the conduct of the study will be regarded as confidential. 
Study Monitors, auditors, and inspectors who require access to a patient’s medical notes for 
source document verification will maintain patient confidentiality at all times. An agreement for 
disclosure of any such information will be obtained in writing and is included in the ICF. No 
study data will be disclosed to a third party (with the exception of auditors and/or regulatory 
authorities) without the written consent of the Sponsor. All data shall be secured against 
unauthorized access. 
13.4.9. 
Clinical Study Report 
The Sponsor or its designee is responsible for preparing a clinical study report. Study results will 
be provided to the Investigator. 

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14. 
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accommodate all assessments. Patients who are taking an RAAS inhibitor will be informed that they will be contacted once screening results confirm 
eligibility so these medications can be discontinued and the washout period can begin (see footnote b). Patients who fail screening may be re-screened up to 
2 additional times. Patients who are re-screened will undergo all screening procedures and will be assigned a new patient number. Patients will also repeat the 
informed consent procedure at this time. 
c Patients taking RAAS inhibitors at screening (Visit 1) will complete a 2-week (14-day) washout from these medications prior to Day 1/Randomization. The 
washout period should begin no later than 4 weeks (28 days) after Visit 1. Appropriate blood pressure control must be achieved during the washout period 
using antihypertensive agents, with the exception of those that inhibit the RAAS and endothelin systems. Patients undergoing washout will return to the clinic 
for a follow-up visit to assess safety and blood pressure control approximately 1 week after the start of the washout period. 
d A review and confirmation of inclusion and exclusion will be completed at Visit 3. Patients who require RAAS inhibitor washout will remain eligible for the 
study based on their screening results, unless at Visit 3 they have a positive pregnancy test (positive urine pregnancy tests will be confirmed by a serum test) 
or have experienced the occurrence of any medical condition or circumstance that, in the opinion of the Investigator, exposes them to substantial risk and/or 
does not allow them to adhere to the requirements of the protocol. Patients who turn 18 years of age after the Screening visit do not need to undergo the 
screening autoimmune panel. 
e Physical examinations will include assessment of the following body systems: abdomen; cardiovascular; ear, nose, and throat; eyes; hair and skin; lymph 
nodes; mental status; musculoskeletal; neurological; peripheral edema; and respiratory. Peripheral edema will be assessed using the semi-quantitative scale 
shown in Appendix B (Section 15.2.3). 
f Vital signs will always be measured prior to having blood drawn for laboratory evaluations. Blood pressure will be measured after patients have been sitting 
comfortably in a chair for at least 5 minutes prior to obtaining 3 readings using the same arm for each reading; the mean of the last 2 readings will then be 
recorded. At the Day 1/Randomization visit, vital signs will be obtained prior to dosing and at 1, 2, 3, and 4 hours after the first dose of study medication. 
Measurements of blood pressure intended to detect possible orthostatic hypotension will also be performed at each visit (see Section 9.6). For these 
measurements, blood pressure will be measured 3 times: 1 time after the patient has been in a supine position for 5 minutes, 1 time after the patient has been 
standing for 1 minute, and 1 time after the patient has been standing for 3 minutes. Weight, heart rate, temperature, respiration rate, and height (only at 
screening for patients ≥18 years of age) will also be recorded. For patients <18 years of age, height will be measured every 6 months after screening until the 
patient turns 18. 
g Includes clinical chemistry (sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, phosphate, glucose, cystatin, uric acid, BUN, creatinine 
[including calculation of eGFR], bilirubin [total, direct, and indirect], ALT, AST, ALP, gamma glutamyl transferase, creatine kinase, amylase, lipase, and bile 
acids [bile acids only on Day 1 and Weeks 4 and 12]); lipid panel (total cholesterol, LDL [direct], HDL [direct], triglycerides [direct], and VLDL [indirect]); 
and hematology (red blood cells, hemoglobin, hematocrit, MCV, MCH, MCHC, platelets, WBC, and WBC differential [neutrophils, eosinophils, basophils, 
lymphocytes, and monocytes; % and absolute]). All chemistry, hematology, and lipid analytes are shown in Section 15.2.4. 
h NT-proBNP in patients ≥18 years of age only. 
i Includes HBsAg, HBeAg, hepatitis B DNA (performed if HBsAg and HBeAg are positive), immunoglobulin M hepatitis B core antibody, anti-hepatitis C 
antibody, hepatitis C ribonucleic acid (performed if anti- hepatitis C antibody is positive), and HIV antibody. Abnormal hepatitis C results will require an 
additional sample drawn for confirmation. 
j For patients ≥18 years of age; however, at the Investigator’s discretion these tests may be performed in patients <18 years of age under clinically relevant 
circumstances. Includes serum antinuclear antibody, anti-double stranded DNA, anti-neutrophil cytoplasmic antibodies, anti-glomerular basement membrane, 
kappa and lambda light chains, clinically significant abnormalities identified by serum and urine protein electrophoresis, complement components C3 and C4, 
and rheumatoid factor. 
k Urine total protein, albumin, creatinine, urea, and sodium. The patient will collect the first morning void on 3 mornings within 5 days prior to the visit and 
bring them to the site visit. 

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l A blood sample for plasma PK will be drawn within 1 hour prior to study medication administration. In particular, on visit days at which dose adjustments are 
made, the PK sample will be drawn prior to the dose adjustment. 
m Patients ≥18 years of age will complete the KDQOL instrument, and patients <18 years of age will complete the PedsQL QoL questionnaire. All patients will 
also complete the EQ-5D. If the questionnaires were NOT completed at baseline for the double-blind period (Day 1), the patient should not complete them for 
the rest of the double-blind period. Patients participating in the open-label extension who did not complete the questionnaires at Day 1 should complete them 
at Week 112 as baseline assessments for the open-label extension. 
n Urine pregnancy tests will be dispensed to WOCBP to conduct pregnancy testing at home between study visits. Site will provide the patient enough tests to 
conduct pregnancy testing once per month until the next scheduled study visit and will contact these patients monthly to confirm that the pregnancy test has 
been performed and the results are negative. A positive urine pregnancy test at any visit, including Screening, will be confirmed by a serum test. 
o Dispense study medication. Note: at Visit 3, patients will be randomized via IWRS and the first dose will be administered in the clinic. Patients will be 
instructed to take their study medication at the clinic on the day of office visits. All other days, study medication should be taken at approximately the same 
time each day, preferably prior to the morning meal. Patients will be instructed to swallow the capsules whole, and not to open, break, chew, crush, or split the 
capsule prior to taking. Patients will also be instructed to avoid drinking or eating anything that contains grapefruit, Seville oranges (bitter oranges often used 
as marmalade), or starfruit (carambola) throughout the study. The patient will be instructed to bring all study medication and their original containers to the 
next clinic visit. 

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ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; eGFR = estimated glomerular 
filtration rate; EOT = end of treatment; EQ-5D = EuroQol, 5-dimension QoL instrument; ET = early termination; HDL = high-density lipoprotein; 
KDQOL = Kidney Disease Quality of Life instrument; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular 
hemoglobin concentration; MCV = mean corpuscular volume; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; OLE = open-label 
extension; PedsQL = Pediatrics Quality of Life Inventory; PK = pharmacokinetics; QoL = quality of life; RAAS = renin-aldosterone-angiotensin; 
WBC = white blood cell; WOCBP=women of childbearing potential 
a Physical examinations will include assessment of the following body systems: abdomen; cardiovascular; ear, nose, and throat; eyes; hair and skin; lymph 
nodes; mental status; musculoskeletal; neurological; peripheral edema; and respiratory. Peripheral edema will be assessed using the semi-quantitative scale 
shown in Appendix B (Section 15.2.3). 
b Vital signs will always be measured prior to having blood drawn for laboratory evaluations. Blood pressure will be measured after patients have been sitting 
comfortably in a chair for at least 5 minutes prior to obtaining 3 readings using the same arm for each reading; the mean of the last 2 readings will then be 
recorded. Measurements of blood pressure intended to detect possible orthostatic hypotension will also be performed at each visit (see Section 9.6). For these 
measurements, blood pressure will be measured 3 times: 1 time after the patient has been in a supine position for 5 minutes, 1 time after the patient has been 
standing for 1 minute, and 1 time after the patient has been standing for 3 minutes. Weight, heart rate, temperature, and respiration rate will also be recorded. 
For patients <18 years of age, height will be measured every 6 months. 
c Includes clinical chemistry (sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, phosphate, glucose, cystatin, uric acid, BUN, creatinine 
[including calculation of eGFR], bilirubin [total, direct, and indirect], ALT, AST, ALP, gamma glutamyl transferase, creatine kinase, amylase, and lipase); 
lipid panel (total cholesterol, LDL [direct], HDL [direct], triglycerides [direct], and VLDL [indirect]); hematology (red blood cells, hemoglobin, hematocrit, 
MCV, MCH, MCHC, platelets, WBC, and WBC differential [neutrophils, eosinophils, basophils, lymphocytes, and monocytes, % and absolute]). All 
chemistry, hematology, and lipid analytes are shown in Section 15.2.4. 
d NT-proBNP in patients ≥18 years of age only. 
e Urine total protein, albumin, creatinine, and sodium. The patient will collect the first morning void on 3 mornings within 5 days prior to the visit and bring 
them to the site visit. 
f A blood sample for plasma PK will be drawn within 1 hour prior to study medication administration. In particular, on visit days at which dose adjustments are 
made, the PK sample will be drawn prior to the dose adjustment. 
g Patients ≥18 years of age will complete the KDQOL instrument, and patients <18 years of age will complete the PedsQL QoL questionnaire. All patients will 
also complete the EQ-5D. If the questionnaires were NOT completed at baseline for the double-blind period (Day 1), the patient should not complete them for 
the rest of the double-blind period. Patients participating in the open-label extension who did not complete the questionnaires at Day 1 should complete them 
at Week 112 as baseline assessments for the open-label extension. 
h Urine pregnancy tests will be dispensed to WOCBP to conduct pregnancy testing at home between study visits. Site will provide the patient enough tests to 
conduct pregnancy testing once per month until the next scheduled study visit and will contact these patients monthly to confirm that the pregnancy test has 
been performed and the results are negative. A positive urine pregnancy test will be confirmed by a serum test. At every visit and monthly, sites will verify 
that WOCBP are continuing to use highly reliable contraception methods. 
i Dispense study medication. Patients will be instructed to take their study medication at the clinic on the day of office visits. All other days, study medication 
should be taken at approximately the same time each day, preferably prior to the morning meal. Patients will be instructed to swallow the capsules whole, and 
not to open, break, chew, crush, or split the capsule prior to taking. Patients will also be instructed to avoid drinking or eating anything that contains 
grapefruit, Seville oranges (bitter oranges often used as marmalade), or starfruit (carambola) throughout the study. The patient will be instructed to bring all 
study medication and their original containers to the next clinic visit. 

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j Following the 108-week blinded treatment period, treatment with study medication will be discontinued. Assessments at this visit will be used to determine 
eligibility to continue in the open-label extension. At this time, the Investigator should resume standard-of-care treatment, including treatment with RAAS 
inhibitors provided there are no contraindications for their use. If the patient was treated with irbesartan at study entry, an alternative ARB at an equivalent 
dose is required from Week 108 to Week 112. The Investigator may make additional adjustments in antihypertensive medications as necessary to adequately 
control the patient’s blood pressure. Standard-of-care treatment (ACEI and/or ARB therapy) will be discontinued before the Week 112 visit. The final dose of 
an ACEI and/or ARB should be taken on the day before the Week 112 visit. If an EOT visit is completed, study medication cannot be resumed. 
k Assessments at this visit will be used as baseline for patients entering the open-label extension. All Week 112 evaluations must be completed prior to the first 
dose of open-label sparsentan. 
l Patients entering the open-label extension only. Patients who may be eligible for the OLE should be given the OLE informed consent document at Week 108 
if at all possible. 

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standing for 1 minute, and 1 time after the patient has been standing for 3 minutes. Weight, heart rate, temperature, and respiration rate will also be recorded. 
For patients <18 years of age, height will be measured every 6 months until the patient turns 18. 
d Except for Week 114 (see footnote e), Includes clinical chemistry (sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, phosphate, 
glucose, cystatin, uric acid, BUN, creatinine [including calculation of eGFR], bilirubin [total, direct, and indirect], ALT, AST, ALP, gamma glutamyl 
transferase, creatine kinase, and amylase); lipid panel (total cholesterol, LDL [direct], HDL [direct], and triglycerides [direct]); hematology (red blood cells, 
hemoglobin, hematocrit, MCV, MCH, MCHC, platelets, WBC and WBC differential [neutrophils, eosinophils, basophils, lymphocytes, and monocytes, % 
and absolute]). All chemistry, hematology, and lipid analytes are shown in Section 15.2.4. 
e Includes only serum creatinine and serum potassium. 
f NT-proBNP in patients ≥18 years of age only. 
g Urine total protein, creatinine, and microalbumin. The patient will collect the first morning void within 5 days prior to the visit and bring the sample to the site 
visit. 
h Patients ≥18 years of age will complete the KDQOL instrument, and patients <18 years of age will complete the PedsQL QoL questionnaire. All patients will 
also complete the EQ-5D. If the questionnaires were NOT completed at Week 112 (ie, Visit 17), the patient should not complete them for the rest of the 
open-label extension. 
i Urine pregnancy tests will be dispensed to WOCBP to conduct pregnancy testing at home between study visits. Site will provide the patient enough tests to 
conduct pregnancy testing once per month until the next scheduled study visit and will contact these patients monthly to confirm that the pregnancy test has 
been performed and the results are negative. A positive urine pregnancy test will be confirmed by a serum test. At every visit and monthly, sites will verify 
that WOCBP are continuing to use highly reliable contraception methods. 
j Dispense investigational product. Patients will be instructed to take their investigational product at the clinic on the day of office visits. All other days, 
investigational product should be taken at approximately the same time each day, preferably prior to the morning meal. Patients will be instructed to swallow 
the tablets whole, and not to open, break, chew, crush, or split the tablet prior to taking. Patients will also be instructed to avoid drinking or eating anything 
that contains grapefruit, Seville oranges (bitter oranges often used as marmalade), or starfruit (carambola) throughout the study. The patient will be instructed 
to bring all investigational product and their original containers to the next clinic visit. 

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c Includes clinical chemistry (sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, phosphate, glucose, cystatin, uric acid, BUN, creatinine 
[including calculation of eGFR], bilirubin [total, direct, and indirect], ALT, AST, ALP, gamma glutamyl transferase, creatine kinase, and amylase); lipid 
panel (total cholesterol, LDL [direct], HDL [direct], and triglycerides [direct]); hematology (red blood cells, hemoglobin, hematocrit, MCV, MCH, MCHC, 
platelets, WBC and WBC differential [neutrophils, eosinophils, basophils, lymphocytes, and monocytes, % and absolute]). All chemistry, hematology, and 
lipid analytes are shown in Section 15.2.4. 
d NT-proBNP in patients ≥18 years of age only. 
e Urine total protein, creatinine, and microalbumin. The patient will collect the first morning void within 5 days prior to the visit and bring the sample to the site 
visit. 
f Patients ≥18 years of age will complete the KDQOL instrument, and patients <18 years of age will complete the PedsQL QoL questionnaire. All patients will 
also complete the EQ-5D. If the questionnaires were NOT completed at Week 112 (ie, Visit 17), the patient should not complete them for the rest of the 
open-label extension. 
g Urine pregnancy tests will be dispensed to WOCBP to conduct pregnancy testing at home between study visits. Site will provide the patient enough tests to 
conduct pregnancy testing once per month until the next scheduled study visit and will contact these patients monthly to confirm that the pregnancy test has 
been performed and the results are negative. A positive urine pregnancy test will be confirmed by a serum test. At every visit and monthly, sites will verify 
that WOCBP are continuing to use highly reliable contraception methods. 
h Dispense investigational product. Patients will be instructed to take their investigational product at the clinic on the day of office visits. All other days, 
investigational product should be taken at approximately the same time each day, preferably prior to the morning meal. Patients will be instructed to swallow 
the tablets whole, and not to open, break, chew, crush, or split the tablet prior to taking. Patients will also be instructed to avoid drinking or eating anything 
that contains grapefruit, Seville oranges (bitter oranges often used as marmalade), or starfruit (carambola) throughout the study. The patient will be instructed 
to bring all investigational product and their original containers to the next clinic visit.  
 

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15.2. 
Appendix B: Supplemental Study Information 
15.2.1. 
Concomitant Medication Considerations 
A. While Taking Study Medication (ie, Day 1 Through Week 108) 
1. Prohibited Medications While Taking Study Medication (ie, Day 1 Through 
Week 108) 
Inhibitors of RAAS and the endothelin system: 
− Patients who are taking any dose of these agents will undergo a 2-week washout 
period prior to randomization. 
− Examples of RAAS inhibitors include (not all inclusive): ACE inhibitors, 
aldosterone blockers, ARBs, spironolactone, eplerenone, and aliskiren. 
− Examples of the endothelin system include: bosentan, macitentan, and 
ambrisentan. 
• Potassium-sparing diuretics (eg, amiloride, triamterene). 
• Selected anti-diabetic drugs (thiazolidinediones and sodium-glucose cotransporter-2 
inhibitors) should be avoided completely. Other anti-diabetic drugs (eg, metformin, 
glyburide) should be used in accordance with their guidelines for use in patients with 
impaired kidney function. 
• Digoxin, amiodarone, or any other antiarrhythmic medications that may put the 
patient at higher risk due to the underlying disease. 
• Amphetamines, amphetamine derivative agents, and prescribed weight loss 
medications including orlistat (eg, Alli®, Xenical®). 
• St. John’s Wort or other hypericum-derived products. 
• Strong CYP3A inhibitors. For a detailed list of these medications, see the P450 Drug 
Interaction Table at: http://medicine.iupui.edu/clinpharm/ddis/main-table.  
NOTE: The Sponsor recognizes that in some cases concomitant use of these 
medications may be medically necessary (for example, azole antifungals for severe 
mycotic infections) and alternatives are either unavailable or inappropriate from a 
medical and safety perspective. In these cases, limited systemic exposure may be 
warranted; however, systemic use of strong CYP3A4 inhibitors should be avoided. In 
addition, a reduction in dose or temporary cessation of study medication and more 
intensive patient monitoring is recommended. 
• The following medications are prohibited for 7 days prior to study visits and should 
be used with caution at other times during the study. Investigators must review each 
patient case individually and use clinical judgment. 
− Sulfamethoxazole/trimethoprim (eg, Bactrim™, Septra®), cimetidine, 
pyrimethamine, cetirizine, cobicistat, probenecid, vandetinib, dolutegravir, 
ranolazine, dronedarone, ritonavir, and telaprevir cannot be used within at least 
7 days prior to any visit at which eGFR is assessed. 

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− Fibrates. 
See Bullet B for prohibited medications following discontinuation of study medication. 
2. 
Medications to Be Used with Caution While Taking Study Medication (ie, Day 1 
Through Week 108) 
For any of the medications in this category, the dosage of study medication may need to be 
adjusted. 
• Strong P-gp inhibitors: 
− In a clinical drug-drug interaction study, administration of cyclosporine increased 
sparsentan overall exposure by approximately 1.7-fold. Adjustment of study 
medication dosage may be needed during concomitant administration of a strong 
P-gp inhibitor. 
− The Investigator should actively look for potential AEs such as hypotension, 
hyperkalemia, or decline in eGFR, during the concomitant use of a strong P-gp 
inhibitor. See sparsentan dose reduction guidance in (Section 8.3.2). 
− Examples relevant to the study population include (not all inclusive): cyclosporine 
A, verapamil, quinidine. 
• CYP2B6 substrates: 
− In a clinical drug-drug interaction study, administration of sparsentan for several 
days decreased exposure of bupropion, a CYP2B6 substrate, to approximately 
66% to 68%. 
− Dosage adjustment of CYP2B6 substrate medications may be required during 
study medication treatment. 
− Examples relevant to the study population include (not all inclusive): bupropion, 
cyclophosphamide, ketamine, meperidine, methadone. 
• Statins: 
− As CKD and proteinuria are associated with high cardiovascular risk, the use of 
statins may be warranted to reduce this risk. 
− Treatment should be initiated at the discretion of the Investigator (after consulting 
with the Medical Monitor, if needed), based on current guidelines for 
cardiovascular risk reduction. The lowest possible effective dose should be used. 
• Non-steroidal anti-inflammatory drugs (NSAIDs): 
− NSAID use is discouraged during the study. Short-term (<1 week) or intermittent 
NSAID use is allowed, provided no doses are taken within 48 hours immediately 
preceding a study visit. 
− Aspirin at doses >325 mg/day is not allowed during the study. 
• Steroids, calcineurin inhibitors, mycophenolate mofetil, and azathioprine doses must 
be stable for at least 30 days prior to screening and during the screening period. 

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Stable doses are defined as unchanged for the prior 30 days, with the exception of 
routine minor changes in calcineurin inhibitors. NOTE: It is recommended that 
systemic corticosteroid and/or immunosuppressive therapy for the treatment of FSGS 
be avoided for the duration of participation in the study. If, in the Investigator’s 
opinion, systemic corticosteroid and/or immunosuppressive therapy is warranted, 
such intervention may be provided in addition to study medication at the discretion of 
the Investigator. Consultation with the Medical Monitor is recommended before 
starting interventional therapy, when possible. The medications in the categories 
above should be avoided or used with caution while taking study medication. 
• Lithium: 
− Caution is required when combining lithium with inhibitors of RAAS, as it may 
enhance the actions of ACE inhibitors or ARBs. 
• Warfarin: 
− Although no specific drug-drug interaction clinical studies have been performed, 
a theoretical potential exists for a drug-drug interaction between sparsentan and 
warfarin via protein binding displacement. 
− INR monitoring is recommended if warfarin is used concomitantly with study 
medication. 
3. Additional Information 
Additional medications potentially interacting with sparsentan (CYP3A inhibitors, P-gp 
inhibitors, CYP 2B6 substrates) can be found at: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ 
B. Prohibited Medications Following Discontinuation of Study Medication 
1. Non-treatment Period from Week 108 Through Week 112 
• Irbesartan. 
• Selected anti-diabetic drugs (thiazolidinediones and sodium-glucose cotransporter-2 
inhibitors) should be avoided completely. Other anti-diabetic drugs (eg, metformin, 
glyburide) should be used in accordance with their guidelines for use in patients with 
impaired kidney function. 
• Digoxin, amiodarone, or any other antiarrhythmic medications that may put the 
patient at higher risk due to the underlying disease. 
• Amphetamines and amphetamine derivative agents. 
• The following medications are prohibited for 7 days prior to study visits and should 
be used with caution at other times during the study. Investigators must review each 
patient case individually and use clinical judgment. 
− Sulfamethoxazole/trimethoprim (eg, Bactrim™, Septra®), cimetidine, 
pyrimethamine, cetirizine, cobicistat, probenecid, vandetinib, dolutegravir, 
ranolazine, dronedarone, ritonavir, and telaprevir cannot be used within at least 
7 days prior to any visit at which eGFR is assessed. 

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− Fibrates. 
C. Patients Who Have Permanently Discontinued Study Medication Prior to Week 108 
• Irbesartan. 
• The following medications are prohibited for 7 days prior to study visits and should 
be used with caution at other times during the study. Investigators must review each 
patient case individually and use clinical judgment. 
− Sulfamethoxazole/trimethoprim (eg, Bactrim™, Septra®), cimetidine, 
pyrimethamine, cetirizine, cobicistat, probenecid, vandetinib, dolutegravir, 
ranolazine, dronedarone, ritonavir, and telaprevir cannot be used within at least 
7 days prior to any visit at which eGFR is assessed. 
− Fibrates. 
D. While Taking Study Medication During the Open-label Extension Period (Starting at 
Week 112) 
1. Prohibited Medications While Taking Study Medication (ie, During the Open-label 
Extension Period Starting at Week 112) 
• Inhibitors of the RAAS 
− Examples include (not all inclusive) the following: ACEIs, aldosterone blockers, 
ARBs, and aliskiren 
• Inhibitors of the endothelin system (bosentan, macitentan, and ambrisentan) 
• Potassium-sparing diuretics (eg, amiloride and triamterene) 
• Thiazolidinediones should be avoided completely. Other anti-diabetic drugs 
(eg, metformin and glyburide) should be used in accordance with their guidelines for 
use in patients with impaired kidney function. 
• Digoxin, amiodarone, or any other antiarrhythmic medications that may put the 
patient at higher risk due to the underlying disease 
• St. John’s Wort or other hypericum-derived products 
• Strong CYP3A inhibitors. For a detailed list of these medications, see the P450 Drug 
Interaction Table at: http://medicine.iupui.edu/clinpharm/ddis/main-table.  
NOTE: The Sponsor recognizes that, in some cases, concomitant use of these 
medications may be medically necessary (eg, azole antifungals for severe mycotic 
infections), and alternatives are either unavailable or inappropriate from a medical 
and safety perspective. In these cases, limited systemic exposure may be warranted; 
however, systemic use of strong CYP3A4 inhibitors should be avoided. In addition, a 
reduction in dose or temporary cessation of study medication and more intensive 
patient monitoring is recommended. 

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2. Medications to Be Used with Caution While Taking Study Medication During the 
Open-label Extension Period (Starting at Week 112) 
It is recommended that systemic corticosteroid and/or immunosuppressive therapy for the 
treatment of FSGS be avoided for the duration of participation in the study. If, in the 
Investigator’s opinion, systemic corticosteroid and/or immunosuppressive therapy is 
warranted, such intervention may be provided in addition to study medication at the 
discretion of the Investigator. Consultation with the Medical Monitor is recommended before 
starting interventional therapy, when possible. 
The medications in the categories below should be avoided or used with caution while taking 
study medication. 
• Mineralocorticoid receptor antagonists (spironolactone and eplerenone) could be used 
at the discretion of the Investigator with appropriate serum potassium monitoring. 
• Sodium-glucose cotransporter-2 inhibitors are allowed in the study at the discretion of 
the Investigator with appropriate monitoring of blood pressure and serum 
creatinine/eGFR. NOTE: When prescribing these medications, the Investigator should 
be aware of the fact that this class has not been tested and approved in pediatric 
patients and that the combination with immunosuppressive drugs is not 
recommended. 
• Strong P-gp inhibitors 
− In a clinical drug-drug interaction study, administration of cyclosporine increased 
sparsentan overall exposure by approximately 1.7-fold. Adjustment of study 
medication dosage may be needed during concomitant administration of a strong 
P-gp inhibitor. 
− The Investigator should actively look for potential AEs, such as hypotension, 
hyperkalemia, or decline in eGFR during the concomitant use of a strong P-gp 
inhibitor. See sparsentan dose reduction guidance in Section 8.3.2. 
− Examples relevant to the study population include (not all inclusive) the 
following: cyclosporine A, verapamil, and quinidine. 
• CYP2B6 substrates 
− In a clinical drug-drug interaction study, administration of sparsentan for several 
days decreased the exposure of bupropion, a CYP2B6 substrate, to approximately 
66% to 68%. 
− Effectiveness of drugs that are CYP2B6 substrates may be reduced, and 
monitoring of the effectiveness of CYP2B6 substrate medications, if possible, is 
recommended during treatment with study medication. 
− Examples relevant to the study population include (not all inclusive) the 
following: bupropion, cyclophosphamide, ketamine, meperidine, and methadone. 

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• NSAIDs 
− NSAID use is discouraged during the study. Short-term (<1 week) or intermittent 
NSAID, including aspirin use, is allowed. Chronic low-dose aspirin at doses 
≤100 mg/day for cardiovascular protection is allowed during the study. 
• Lithium 
− Caution is required when combining lithium with inhibitors of RAAS as it may 
enhance the actions of ACEIs or ARBs. 
• Warfarin 
− Although no specific drug-drug interaction clinical studies have been performed, 
a theoretical potential exists for a drug-drug interaction between sparsentan and 
warfarin via protein binding displacement. 
− INR monitoring is recommended if warfarin is used concomitantly with study 
medication. 
3. Additional Information 
Additional medications potentially interacting with sparsentan (CYP3A inhibitors, P-gp 
inhibitors, and CYP2B6 substrates) can be found at: 
http://medicine.iupui.edu/clinpharm/ddis/main-table/. 

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15.2.2. 
Recommendations for Management of Hyperkalemia 
Serum potassium checks should be completed at each visit for clinical evidence of electrolyte 
imbalance. If a patient has a serum potassium value >5.5 mmol/L (5.5 mEq/L) at any time during 
the study, the following steps are recommended: 
1. If the serum potassium value is ≥6.5 mmol/L, emergency management should be 
implemented based on the site policies and Investigator’s decision. 
2. If the serum potassium value is >5.5 and <6.5 mmol/L (6.5 mEq/L), rule out 
measurement errors or likely reasons for the increase (eg, sample hemolysis, metabolic 
acidosis, discontinuation of diuretic intake by the patient/lack of compliance, diet 
transgression). 
a. If the causes listed above are ruled out and the patient is not receiving a diuretic, it is 
recommended to start a diuretic (if the patient’s volume status and blood pressure 
permit). The choice of a thiazide or a loop diuretic is at the discretion of the 
Investigator. Assess the patient's tolerability and measure their blood pressure, eGFR, 
sodium, and potassium within 1 week after starting the diuretic. 
b. If the causes listed above are ruled out and the patient is already receiving a diuretic, 
increase the dose of the diuretic by 50% (if the patient’s volume status and blood 
pressure permit). Assess the patient's tolerability and measure their blood pressure, 
eGFR, sodium, and potassium within 1 week after increasing the dose. Consider 
correction of metabolic acidosis, if relevant. 
3. In both scenarios 2a and 2b, adjust the dose of diuretic accordingly after 1 week. If the 
patient’s serum potassium value is still >5.5 mmol/L, reinforce diet 
counseling/restrictions, rule out other potential causes of hyperkalemia, and consider 
increasing the diuretic dose. If, after an additional week, the serum potassium value is 
still >5.5 mmol/L, reduce the dose of study medication by 50%. For long-term prevention 
of hyperkalemia, consider treatment with patiromer or sodium zirconium cyclosilicate. 
4. If hyperkalemia persists or recurs, study medication must be discontinued permanently. 
 

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15.2.3. 
Peripheral Edema Assessment Guidance 
Assess for peripheral edema by pressing the area firmly with the thumb or index finger for 
5 seconds and then release. Determine depth of indentation to determine severity using the 
following grades/definitions: 
Grade 
Definition 
1+ 
2 mm depression, slight pitting, disappears immediately (Trace) 
2+ 
2- to 4-mm somewhat deeper pitting, disappears in 10 – 15 seconds (Mild)  
3+ 
4- to 6-mm noticeably deep pit, lasts 1 to 2 minutes (Moderate) 
4+ 
6- to 8-mm: very deep pit, lasts 2 to 5 minutes (Severe) 
Adapted from the Guelph General Hospital Congestive Heart Failure Pathway 
 
 

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15.2.4. 
Clinical Laboratory Assessments Performed During the Study 
Table 8: 
Clinical Laboratory Assessments During the Double-Blind Period 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
Cystatin 
Uric Acid 
Blood urea nitrogen 
Creatinine, including eGFR 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
 
ALT 
AST 
ALP 
GGT 
Creatine kinase 
Amylase 
Lipase 
Bile acids 
Screening Tests 
Hepatitis B surface antigen 
Hepatitis B “e” antigen 
Hepatitis B DNA 
Immunoglobulin M hepatitis B core 
antibody 
Anti-hepatitis C antibody 
Hepatitis C RNA 
HIV antibody 
HbA1c 
Drug/Alcohol screen 
 
Screening Autoimmune Panel 
Antinuclear antibody 
Anti-neutrophil cytoplasmic 
antibodies 
Anti-glomerular basement 
membrane antibody 
Kappa and lambda light chains 
(plasma/urine) 
Serum/urine PEP 
Complement components 3 and 4 
Rheumatoid factor 
Anti-double stranded DNA 
 
Pregnancy Tests 
Urine pregnancy test 
Serum pregnancy test (at Screening 
and for confirmation of positive 
urine pregnancy test) 
Hematology 
Red blood cells 
Hemoglobin 
Hematocrit 
MCV, MCH, MCHC 
Platelets 
White blood cells 
WBC differential (% and 
absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Coagulation 
Prothrombin time, INR 
 
Other Tests 
Aldosterone 
Plasma renin activity 
NT-proBNP 
Endothelin 
 
Lipid Panel 
Total cholesterol 
LDL (direct) 
HDL (direct) 
Triglycerides (direct) 
VLDL-C (indirect) 
 
Pharmacokinetics 
Sparsentan 
Irbesartan 
 
Quantitative Urinalysis  
(first morning void samples) 
Total protein 
Albumin 
Creatinine 
Sodium 
Urea 
 
Routine Urinalysis 
Color 
Appearance 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Urobilinogen 
Leukocyte esterase 
Microscopic examination 
(performed if blood, protein, 
or leukocyte esterase is 
abnormal in urine) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DNA = 
deoxyribonucleic acid; eGFR = estimated glomerular filtration rate; GGT = gamma glutamyl transferase; HbA1c 
= hemoglobin A1c; HDL = high-density lipoprotein; HIV = human immunodeficiency virus; INR = international 
normalized ratio; LDL = low-density lipoprotein; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; NT-proBNP = N-terminal 
prohormone of brain natriuretic peptide; PEP = protein electrophoresis; RNA = ribonucleic acid; VLDL-C = 
very low-density lipoprotein cholesterol; WBC = white blood cells 

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Table 9: 
Clinical Laboratory Assessments During the Open-Label Extension 
Clinical Chemistry 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Phosphate 
Glucose 
Cystatin 
Uric acid 
Blood urea nitrogen 
Creatinine, including eGFR 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
 
ALT 
AST 
ALP 
GGT 
Creatine kinase 
Amylase 
 
Pregnancy Tests 
Urine pregnancy test 
Serum pregnancy test (at 
Screening and for confirmation of 
positive urine pregnancy test) 
 
 
Other Tests 
NT-proBNP 
 
Lipid Panel 
Total cholesterol 
LDL (direct) 
HDL (direct) 
Triglycerides (direct) 
 
Hematology 
Red blood cells 
Hemoglobin 
Hematocrit 
MCV, MCH, MCHC 
Platelets 
White blood cells 
WBC differential (% and 
absolute) 
• Neutrophils 
• Eosinophils 
• Basophils 
• Lymphocytes 
• Monocytes 
 
 
Quantitative Urinalysis  
(first morning void 
samples) 
Total protein 
Creatinine 
Microalbumin 
Microalbumin/Creatinine 
Ratio 
Urine Protein/Creatinine 
Ratio 
 
Routine Urinalysis 
Color 
Appearance 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Urobilinogen 
Leukocyte esterase 
Microscopic examination 
(performed if blood, 
protein, or leukocyte 
esterase is abnormal in 
urine) 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
eGFR = estimated glomerular filtration rate; GGT = gamma glutamyl transferase; HDL = high-density 
lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; MCH = mean corpuscular 
hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; 
NT-proBNP = N-terminal prohormone of brain natriuretic peptide; WBC = white blood cells 

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15.3. 
Appendix C: Germany-Specific Requirements 
This appendix provides language for Germany-specific regulatory requirements and other 
procedures to follow in the execution of the global study. 
The summary of changes outlined in the table below: 
• provides Germany-specific protocol language (in bold text) that replaces the 
corresponding language in the body of the global protocol and applies only for 
Germany. 
• specifies requirements for sites and patients participating in Germany. 

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Table 10: 
Germany Summary of Changes 
Protocol Section  
Germany Text (revised text in bold) 
Synopsis 
Supportive Measures for 
Coronavirus 
Disease 2019/Unexpected 
Circumstances 
Supportive Measures for Coronavirus Disease 2019 
Study sites will be permitted to send study medication to patients’ homes via a traceable courier and/or shipping 
provider to ensure continuing medication. Prior to shipping, study sites will be instructed to acquire and document 
verbal consent from the patient as well as verify the patient’s correct shipping address and their availability to 
receive the shipment. Additionally, a second physically signed consent from the patient to send study medication to 
the patient’s home will also be obtained at the next site visit. The study site will call the patient to confirm receipt 
of the study medication. The patient will be instructed to return all unused study medication at their next site visit. 
Details are included in the protocol. 
Section 8.2.3 
Preparation and 
Administration of the 
Study Medication 
Paragraph 3 
Shipment of Study Medication from Study Sites Directly to Patients 
Study sites will be permitted to send study medication to patients’ homes via a traceable courier and/or shipping 
provider to ensure continuing medication. Prior to shipping, study sites will be instructed to acquire and document 
verbal consent from the patient as well as verify the patient’s correct shipping address and their availability to receive 
the shipment. Additionally, a second physically signed consent from the patient to send study medication to the 
patient’s home will also be obtained at the next site visit. Study medication will be shipped and stored between 20° 
and 25°C (68° to 77°F); excursions between 15°and 30°C (59° to 86°F) are allowed. Further guidance is provided in 
the Pharmacy Manual. The study site will call the patient to confirm receipt of the study medication. Confirmation 
of receipt will be obtained over the phone by the study site and documented in the source documentation. The patient 
will also sign the Study Patient Acknowledgement of Receipt of Study Drug form. The patient’s identity and personal 
information will continue to be kept confidential and will not be shared with the Sponsor. The patient will be instructed 
to return all unused study medication at their next site visit.  
Section 9.1 
Schedule of Study Events 
The Sponsor is taking all necessary measures to ensure data integrity while implementing the home care visit by 
requiring that a licensed and qualified home care nurse (Service Provider) is trained to perform specific study 
assessments per GCP and Good Documentation Practice standards. Study procedure instructions for the Service 
Provider will be provided in the home care visit training manual, which has been developed by the Sponsor in 
collaboration with the home care agency to follow protocol-mandated study procedures. 

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Protocol Section  
Germany Text (revised text in bold) 
Given the importance of ongoing laboratory and clinical tests for safety evaluations, and to reduce the risk of 
COVID-19 infection during the pandemic, the Sponsor is contracting with a home care agency to assist with study 
visits as permitted during the COVID-19 pandemic. 
The Principal Investigator (PI) will confirm that the Service Provider assigned to perform study procedures 
during the home care visit is qualified and has the appropriate education, training, and experience to perform the 
specified tasks. This will be documented by a current signed and dated curriculum vitae or resume and license 
and/or certificates of qualification, documentation of completion of study-specific training, and documentation of 
compliance with study-specific requirements, GCP/ICH guidelines, Patient Privacy Laws, General Data Protection 
Regulation, Health Insurance Portability and Accountability Act, International Air Transport Association 
Dangerous Goods local and national regulations, and the home care agency’s SOPs relating to services, as 
applicable. 
The PI may request to speak to or meet with the Service Provider prior to the home care visit and request to 
review and approve the adequate qualification of the Service Provider as well as review their practical 
performance according to local legal requirements. The PI will be responsible for ensuring that the Service 
Provider is properly trained on study-related procedures and the protocol and training will be documented in the 
site-specific training log, but the Service Provider will be trained on study-related procedures and the protocol by 
the Country Coordinator from the Training Manual. 
The PI and the patient will assess if it is necessary to implement the home care visit in the event the patient is 
unable to visit the site for the conduct of the study visit due to the COVID-19 pandemic. The PI may decline 
implementation of the home care visit at their site at any time. If the PI agrees with the patient to utilize the home 
care services, the PI will send the study-specific Service Request Form (Physician Orders) to the home care agency 
to initiate the request. The PI will delegate study-specific procedures to the Service Provider and document the 
delegated procedures in the site-specific delegation log for the study. 
In order to conduct the home care visit, the Country Coordinator (home care agent responsible for managing and 
coordinating ambulant care services within their country), and the Service Provider (responsible for conducting 
the study-specific services ordered by the PI and in compliance with the protocol and the Ambulant Care Training 
Manual) will have access to the patient’s personal data including their individually identifiable protected health 
information, such as the patient’s name, address, or phone number. This type of information will only be used by 

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Protocol Section  
Germany Text (revised text in bold) 
the Service Provider or home care Country Coordinator as necessary to contact the patient to schedule their home 
care visit and will not be provided to the Sponsor. The Service Provider will communicate the date and time of the 
home care visit to the study site. The site must be available during the conduct of the home care visit; furthermore, 
the site will provide the Service Provider with an emergency phone number where the PI can be reached during 
the home care visit should there be the need to speak to the PI. 
Home care visits may be implemented at Week 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, and 108 during the 
double-blind treatment period of the study. Home care visits are not allowed to be utilized for screening, Day 1 
(randomization), and Week 112 (end of double-blind treatment visit/first open-label extension visit). Study 
procedures conducted at these visits may not be delegated to the Service Provider and are required to be 
conducted at the site. 
Home care visits may be implemented at Week 114, 124, 136, 148, 160, 172, 184, 196, 208, 220, 232, 244, 256, and 
268 during the open-label extension treatment period of the study. 
The PI may delegate and supervise the following study procedures to the Service Provider to be conducted during 
the home care visit: 
• Measure vital signs (blood pressure, heart rate, respiratory rate, body weight, and body temperature) 
• Measure orthostatic vitals (heart rate and blood pressure), as applicable. If any signs of orthostatic hypotension 
are observed, the Service Provider must promptly communicate this to the Investigator at site by telephone call 
during the visit 
• Collect biologic specimens (including processing, packaging, and shipment to the designated laboratory) to 
include the following: hematology, chemistry, chemistry with N-terminal prohormone of brain natriuretic peptide; 
serum pregnancy test; aldosterone, plasma renin; endothelin; pre-dose PK; quantitative urinalysis; urinalysis; 
urine pregnancy test; and collection of biomarker samples (serum, plasma, and urine samples). 
• Perform body system assessment per local regulations (only peripheral assessment allowed in European Union 
countries) 
• Perform 12-lead ECG, as applicable 

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Protocol Section  
Germany Text (revised text in bold) 
• Confirm receipt of site package (study medication, home pregnancy kit, and urine collection cups) 
• Assess changes in signs and/or symptoms and promptly communicate these changes to the Investigator site by 
telephone call during the visit 
• Assess changes in concomitant medications 
• Perform documentation, communication, and records retention 
The Service Provider will complete the services ordered by the PI, including collection of laboratory samples, and 
document the services provided during the home care visit in the Ambulant Care Source Documents (source 
documents). Following the home care visit, source documents will be reviewed for quality and completeness by the 
home care Country Coordinator. The electronic copy of the source documents will be sent to the site within 
48 hours of the visit, followed by the original hard copy sent to the study site via courier, and the study site will 
review the source documents. The PI will contact the patient over the phone to assess the patient’s health and 
safety. The home care agency, Country Coordinator, or Service Provider will not share patient data with the 
Sponsor. Study data will be source verified by the Study Monitor as per study monitoring plan, and any missed 
study procedures will be documented as a protocol deviation and reported accordingly. Although the home care 
services are delegated to the Service Provider, the PI holds responsibility for ensuring the quality of the data and 
the well-being of the patient for the procedures performed as per legal requirements. 
The urgent safety measures will be temporary and revert to on-site procedures as soon as the situation allows. 
However, these urgent safety measures may be implemented again if the need arises (ie, an additional wave of 
COVID-19) as dictated by local public health authority requirements. The Sponsor acknowledges that German 
regulations do not permit the use of the urgent safety measures outside of the COVID-19 pandemic. Therefore, 
these urgent safety measures will only be in effect during the COVID-19 pandemic. 
Phone and Video Contact with Patients 
Investigators may interface with patients via telephone or live video conferencing using a secured system chosen by 
the study site. Telephone or video conferences will not be recorded or screenshot. These contacts will be allowed at 
all protocol-required visits and at any time during the conduct of the study. The sites will discuss the patient’s current 
health status, AEs, concomitant medications, and medication compliance during the phone and video contacts. Patients 

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Protocol Section  
Germany Text (revised text in bold) 
will be instructed to contact the site personnel with any health concerns. Results of these patient contacts will be fully 
documented in the patient source documents. Patients will return for an on-site visit as soon as the PI and patient 
determine it is appropriate and safe. 
Subject to prior agreement by the study sites/Investigators, these urgent safety measures will only be implemented 
in cases where on-site patient visits are not possible due to COVID-19-related challenges, without awaiting 
approval of this submission by German Regulatory Authorities and Ethics Committees.  
Section 9.6 
Vital Signs 
Paragraph 2 
The Sponsor may implement home blood pressure monitoring to allow for further safety assessment. If requested 
by the PI, the Sponsor will supply blood pressure cuffs to the study site to be provided to the patients for 
monitoring of blood pressure at home. The PI will be responsible for providing the patient with instructions on 
how to monitor and record blood pressure at home. 
At all protocol-specified time points, blood pressure will be measured after the patient has been sitting comfortably in a 
chair for at least 5 minutes prior to obtaining 3 readings, using the same arm for each reading, and the mean of the last 2 
readings will be recorded. At the Day 1/Randomization visit, vital signs will be obtained prior to dosing and at 1, 2, 3, and 
4 hours after the first dose of study medication. 
Section 9.8 
Clinical Laboratory 
Assessments 
Paragraph 5 
Patients will be provided kits for the home collection of quantitative urinalysis samples. They will also receive full 
instructions regarding the proper collection of those samples. If necessary, due to challenges related to the COVID-19 
pandemic, a patient or parent/legal guardian may transport the first morning void samples to the site via courier service 
for processing and shipment to the central laboratory. If a patient cannot come to the site, safety labs may be tested at a 
local laboratory. It is the responsibility of the Investigator to document this process in the patient’s source documents. 
Section 9.8 
Clinical Laboratory 
Assessments 
Paragraph 9 
If the patient is unable to visit the site, the patient may use a courier to transport the first 3 morning urine void samples to 
the site. The PI will be responsible for providing the patient with instructions and making the transport arrangements with 
the courier. The list of clinical laboratory analytes to be tested is presented in Section 15.2.4.  

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Protocol Section  
Germany Text (revised text in bold) 
Section 13.4.1 
Patient Informed Consent 
Paragraph 3 
The following should apply to Germany regarding patient informed consent for pandemic-related measures. 
Pandemic-related measures will be explained to the patient in the supplementary patient information and ICFs. If 
due to current COVID-19 circumstances the patient is not scheduled to come to the site for a visit soon, the study 
site staff will provide them the supplementary patient information and ICF via post mail and will discuss the 
details of these documents with the patient via phone or video conference. Verbal consent will be taken over the 
phone and recorded within the patient’s medical records. In addition, the patient’s written consent will be 
obtained remotely. If the patient agrees with this approach, the Investigator will ask the patient to send their 
signed and dated ICF by courier service (eg, DHL) or by registered mail (so that a signature is available as proof of 
delivery) to the study site. The pandemic-related procedures described below are carried out only after written 
consent has been obtained and if the signed and dated supplementary patient information and ICF have been 
received by the study site. 
Section 13.4.4 
Monitoring 
Paragraph 2 
If necessary, due to challenges related to the COVID-19 pandemic, monitoring activities may be performed remotely as 
dictated by local public health authority requirements. An emergency remote data verification (rDV) process is being 
implemented in countries where this is allowed, according to local laws and regulations. Please note that the rDV 
process will not be utilized in Germany. Alternative ways of monitoring the data, where allowed, will be implemented. 
It is intended that this process will facilitate adequate ongoing oversight of the conduct of clinical studies in order to 
identify and eliminate any immediate risk to study patients while on-site monitoring activities cannot be performed due to 
COVID-19 restrictions. 
Table 4 
Double-Blind Period: 
Schedule of Events from 
Screening Through 
Week 12 
Footnote a 
If an on-site visit is not feasible due to challenges related to the COVID-19 pandemic, Investigators/appropriately 
designated study staff will be allowed to perform study visits as remote study visits (eg, conducted via telephone or video 
conference). These contacts will be allowed at all protocol-required visits and at any time during the conduct of the study. 
However, Screening, Washout, and Day 1 visits must be conducted at the study site. 

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15.4. 
Appendix D: Protocol History 
Protocol Version 
Date Issued 
Rationale for Update 
Amendment 9 
18 January 2024 
Removed the extension of the open-label extension 
period past Week 268 that was added in Protocol 
Amendment 8, as a result of a business decision to 
not extend the study.  
 
Amendment 8 
31 March 2023 
Added Table 8 to the Schedule of Activities to 
extend the open-label extension by 2 years, with 
visits every 6 months. 
Revised Section 8.2.1 to add that 30-count bottles 
are also available for the open-label extension. 
Revised Section 10.3.2 to change COVID SAE 
reporting procedure to follow normal SAE reporting 
procedure. 
Added Section 15.3 to allow for global 
consolidation of protocol. 
Minor edits were done for consistency as applicable 
Amendment 7-DE 
08 February 2022 
Updated Study Contact Information as per protocol 
administration letter dated 27 Jan 2021. 
Removed Global Safety officer contact details as per 
protocol administration letter dated 27 Jan 2021 
Revised Section 8.2.1 to add information regarding 
new presentation of 30-count bottles. 
Updated Section 8.2.3, Section 9.1, Section 9.6, 
Section 9.8, and Section 13.4.1 as per Germany 
Addendum. 
Removed “or other unexpected circumstances” from 
Synopsis, Section 8.2.3, Section 9.1, Section 9.8, 
Section 13.4.1, Section 13.4.4, and Section 15.1 due 
to restrictions in Germany on the implementation of 
these special measures for any reason other than the 
COVID-19 pandemic and any reference to other 
times when they could be used are being removed. 
Updated Section 10.7.2 to include information for 
recording of SAEs during the open-label extension. 
Due to recent positive results of large clinical 
studies with sodium-glucose cotransporter 2 
inhibitors (SGLT2i) in non-diabetic patients with 
proteinuric kidney diseases, these drugs are being 
used with increasing frequency. It has been 
concluded that there is no contraindication to the use 
of SGLT2i and sparsentan and with this amendment, 
SGLT2i use is being allowed in the open-label 

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Protocol Version 
Date Issued 
Rationale for Update 
portion of the study. Revised Section 15.2.1 to 
include information regarding SGLT2i. 
Minor edits were done for consistency as applicable. 
Amendment 7 
02 November 2021 
Updated Study Contact Information as per protocol 
administration letter dated 27 Jan 2021. 
Removed Global Safety officer contact details as per 
protocol administration letter dated 27 Jan 2021. 
Revised Section 8.2.1 to add information regarding 
new presentation of 30-count bottles. 
Updated Section 10.7.2 to include information for 
recording of SAEs during open-label extension. 
Due to recent positive results of large clinical 
studies with sodium-glucose cotransporter 2 
inhibitors (SGLT2i) in non-diabetic patients with 
proteinuric kidney diseases, these drugs are being 
used with increasing frequency. It has been 
concluded that there is no contraindication to the use 
of SGLT2i and sparsentan and with this amendment, 
SGLT2i use is being allowed in the open-label 
portion of the study. Revised Section 15.2.1 to 
include information regarding SGLT2i. 
Minor edits were done for consistency as applicable. 
Amendment 6 
01 December 2020 
Updated protocol to reflect Sponsor rebranding from 
“Retrophin” to “Travere Therapeutics”. 
Clarified the timing for discontinuing 
standard-of-care treatment. 
Added guidance for working with restrictions 
related to COVID-19. 
Added home care visit for patient retention in the 
double-blind and open-label extension periods. 
Updated with GBR Protocol Amendment 5 
specifications. 
Updated study endpoints per FDA recommendation. 
Amendment 5 
23 January 2020 
Added open-label extension period to protocol. 
Amendment 5-GBR 
08 April 2020 
Added open-label extension period to the United 
Kingdom version of the protocol. 
Amendment 4-GBR 
21 November 2019 
Allowed enrollment of pediatric patients in the 
United Kingdom. 
Amendment 3 
06 June 2019 
Removed mandate for contraception in male 
patients; see Amendment 3 Summary of Changes, 
Attachment 1. 
Added a minimum weight requirement to inclusion 
criteria. 

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Protocol Version 
Date Issued 
Rationale for Update 
Harmonized with PROTECT Protocol 
Amendment 2. 
Amendment 2 
07 January 2019 
Streamlined endpoints and statistical methods, 
added guidance and testing related to safety 
monitoring. 
Amendment 1 
26 June 2018 
Harmonized with PROTECT Protocol and 
addressed comments from regulatory agencies. 
Original Protocol 
19 January 2018 
N/A 
 

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