A Multicentered, Single-group Phase 2, Exploratory, Open-label Study to Investigate Safety and Effect of Sparsentan in Combination With SGLT2 Inhibition in the Treatment of Adult Participants With Immunoglobulin A Nephropathy (IgAN)
Phase: PHASE2
Conditions: Immunoglobulin A Nephropathy
Sponsor: Travere Therapeutics, Inc.

 
 
 
 
 
 
 
 
 
Protocol 
 
A Multicentered, Single-Group Phase 2, Exploratory, Open-Label, 
Study to Investigate Safety and Effect of Sparsentan in Combination 
with Sodium-Glucose Cotransporter-2 (SGLT2) Inhibition in the 
Treatment Adult Participants with Immunoglobulin A Nephropathy 
(IgAN) 
 
Date of Document: 21 February 2023 
 
NCT05856760 
 

CLINICAL STUDY PROTOCOL 
A MULTICENTERED, SINGLE-GROUP PHASE 2, EXPLORATORY, OPEN-LABEL 
STUDY TO INVESTIGATE SAFETY AND EFFECT OF SPARSENTAN IN 
COMBINATION WITH SODIUM GLUCOSE COTRANSPORTER-2 (SGLT2) 
INHIBITION IN THE TREATMENT OF ADULT PARTICIPANTS WITH 
IMMUNOGLOBULIN A NEPHROPATHY (IGAN) 
Protocol Number: 
Compound: 
Brief Title: 
Study Phase: 
Acronym: 
Sponsor Name and Legal 
Registered Address: 
TVTX-RE021-204 
sparsentan (RE-021) 
A study to investigate safety and effect of Sparsentan 
in combination with SGLT2 inhibition in adult 
participants with IgAN 
2 
SPARTACUS 
Travere Therapeutics, Inc. 
3611 Valley Centre Drive, Suite 300 
San Diego, CA 92130 
USA 
Regulatory Agency Identifier 
Number(s): 
Registry 
ID 
IND 
137918 
Version: 
Original 
Approval Date: 
13 February 2023 
CONFIDENTIAL 
The information contained herein is the property of Travere Therapeutics, Inc. (Travere) and 
may not be reproduced, published, or disclosed to others without written authorization of 
Travere Therapeutics, Inc. 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
1.1. 
Synopsis ......................................................................................................................10 
1.2. 
Schema ........................................................................................................................15 
1.3. 
Schedule of Activities (SoA) ......................................................................................16 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Study Rationale ...........................................................................................................19 
2.2. 
Background .................................................................................................................19 
2.3. 
Benefit/Risk Assessment ............................................................................................19 
2.3.1. 
Risk Assessment .........................................................................................................19 
2.3.2. 
Benefit Assessment .....................................................................................................21 
2.3.3. 
Overall Benefit/Risk Conclusion ................................................................................22 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ..................................................22 
3.1. 
Primary Estimand .......................................................................................................22 
3.2. 
Secondary Estimand(s) ...............................................................................................22 
4. 
STUDY DESIGN .......................................................................................................23 
4.1. 
Overall Design ............................................................................................................23 
4.2. 
Scientific Rationale for Study Design ........................................................................23 
4.2.1. 
Rationale for Endpoints ..............................................................................................23 
4.2.1.1. 
Safety Endpoints .........................................................................................................23 
4.2.1.2. 
Efficacy Endpoints ......................................................................................................23 
4.2.2. 
Rationale for Study Population ...................................................................................24 
4.3. 
Justification for Dose ..................................................................................................24 
4.4. 
End of Study (EOS) Definition ...................................................................................25 
4.5. 
End of Treatment (EOT) Definition ...........................................................................25 
5. 
STUDY POPULATION .............................................................................................25 
5.1. 
Inclusion Criteria ........................................................................................................25 
5.2. 
Exclusion Criteria .......................................................................................................26 
5.3. 
Lifestyle Considerations .............................................................................................28 
5.4. 
Screen Failures ............................................................................................................28 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................29 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
3 
6.1. 
Study Intervention(s) Administered ...........................................................................29 
6.2. 
Preparation, Handling, Storage, and Accountability ..................................................30 
6.2.1. 
Dose Preparation .........................................................................................................30 
6.2.2. 
Handling, Storage, and Accountability .......................................................................30 
6.3. 
Assignment to Study Intervention ..............................................................................30 
6.4. 
Blinding and Masking .................................................................................................30 
6.5. 
Study Intervention Compliance ..................................................................................30 
6.6. 
Dose Modification ......................................................................................................31 
6.7. 
Treatment of Overdose ...............................................................................................31 
6.8. 
Prior and Concomitant Therapy ..................................................................................31 
6.8.1. 
Prohibited ....................................................................................................................32 
6.8.2. 
Rescue Medication ......................................................................................................32 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................32 
7.1. 
Discontinuation of Study Intervention ........................................................................32 
7.1.1. 
Liver Chemistry Stopping Criteria .............................................................................33 
7.1.2. 
Temporary Discontinuation ........................................................................................33 
7.1.3. 
Study Intervention Restart ..........................................................................................34 
7.1.3.1. 
Study Intervention Restart or Rechallenge After Liver Chemistry Stopping 
Criteria Are Met ..........................................................................................................34 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................34 
7.3. 
Lost to Follow-up .......................................................................................................35 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................36 
8.1. 
Administrative and General Procedures .....................................................................36 
8.1.1. 
Informed Consent .......................................................................................................36 
8.1.2. 
Inclusion/Exclusion Criteria .......................................................................................36 
8.2. 
Screening and Baseline Procedures ............................................................................36 
8.2.1. 
Screening Assessments ...............................................................................................36 
8.2.2. 
Demographics .............................................................................................................36 
8.2.3. 
Medical History ..........................................................................................................37 
8.3. 
Efficacy Assessments .................................................................................................37 
8.3.1. 
Quantitative Urinalysis ...............................................................................................37 
8.3.2. 
eGFR Calculation .......................................................................................................37 
8.4. 
Safety Assessments .....................................................................................................37 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
4 
8.4.1. 
Physical Examinations ................................................................................................37 
8.4.2. 
Peripheral Edema ........................................................................................................37 
8.4.3. 
Vital Signs ..................................................................................................................37 
8.4.4. 
Clinical Safety Laboratory Tests ................................................................................38 
8.4.5. 
Pregnancy Testing ......................................................................................................38 
8.4.6. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................39 
8.5. 
AEs SAEs, and Other Safety Reporting .....................................................................39 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................39 
8.5.2. 
Method of Detecting AEs and SAEs ..........................................................................40 
8.5.3. 
Follow-up of AEs and SAEs .......................................................................................40 
8.5.4. 
Regulatory Reporting Requirements for SAEs ...........................................................40 
8.5.5. 
Pregnancy ...................................................................................................................40 
8.5.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ...............................................................................................................41 
8.5.7. 
Adverse Events of Special Interest .............................................................................42 
8.6. 
Pharmacokinetics ........................................................................................................42 
8.7. 
Pharmacodynamics .....................................................................................................42 
8.8. 
Genetics ......................................................................................................................42 
8.9. 
Biomarkers ..................................................................................................................42 
8.10. 
Health Economics .......................................................................................................42 
9. 
STATISTICAL CONSIDERATIONS .......................................................................43 
9.1. 
Statistical Hypothesis ..................................................................................................43 
9.1.1. 
Multiplicity Adjustment ..............................................................................................43 
9.2. 
Analysis Sets ...............................................................................................................43 
9.3. 
Statistical Analyses .....................................................................................................43 
9.3.1. 
Procedures for Handling Missing Data .......................................................................43 
9.3.2. 
Definition of Endpoint(s) ............................................................................................43 
9.3.3. 
Main Analytical Approach .........................................................................................44 
9.4. 
Interim Analysis ..........................................................................................................44 
9.5. 
Sample Size Determination ........................................................................................44 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................45 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................45 
10.1.1. 
Study Contact Information .........................................................................................45 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
5 
10.1.2. 
Regulatory and Ethical Considerations ......................................................................45 
10.1.3. 
Financial Disclosure ...................................................................................................46 
10.1.4. 
Informed Consent Process ..........................................................................................46 
10.1.5. 
Recruitment Strategy ..................................................................................................47 
10.1.6. 
Data Protection ...........................................................................................................47 
10.1.7. 
Dissemination of Clinical Study Data ........................................................................47 
10.1.8. 
Data Quality Assurance ..............................................................................................48 
10.1.9. 
Source Documents ......................................................................................................49 
10.1.10. 
Study and Site Start and Closure ................................................................................49 
10.1.11. 
Publication Policy .......................................................................................................50 
10.2. 
Appendix 2: Minimum ACEI/ARB Daily Dose Requirements at Screening .............51 
10.3. 
Appendix 3: Clinical Laboratory Tests .......................................................................52 
10.4. 
Appendix 4: Peripheral Edema Assessment Guidance ...............................................53 
10.5. 
Appendix 5: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................54 
10.5.1. 
Definition of AE .........................................................................................................54 
10.5.2. 
Definition of SAE .......................................................................................................55 
10.5.3. 
Recording and Follow-Up of AE and/or SAE ............................................................56 
10.5.4. 
Reporting of SAEs ......................................................................................................58 
10.6. 
Appendix 6: Concomitant Medication Considerations ...............................................60 
10.7. 
Appendix 7: Contraceptive and Barrier Guidance ......................................................63 
10.7.1. 
Definitions ..................................................................................................................63 
10.7.2. 
Contraception Guidance .............................................................................................64 
10.8. 
Appendix 8: Recommendations for Management of Hyperkalemia ..........................65 
10.9. 
Appendix 9: Liver Safety: Suggested Actions and Follow-up Assessments 
and Study Intervention Rechallenge Guidelines .........................................................66 
11. 
REFERENCES ...........................................................................................................68 
 
LIST OF TABLES 
Table 1: 
Risk Assessment .........................................................................................................20 
Table 2: 
Study Intervention(s) Administered ...........................................................................29 
Table 3: 
Study Arm ...................................................................................................................30 
Table 4: 
Clinical Safety Laboratory Tests and Quantitative Urinalysis ...................................52 
 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
6 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................15 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACEI 
Angiotensin converting enzyme inhibitor 
AE 
Adverse event 
AEOI 
Adverse event of interest 
AESI 
Adverse event of special interest 
AKI 
Acute kidney injury 
ALP 
Alkaline phosphatase 
ALT 
Alanine transferase 
AngII 
Angiotensin II 
ARB 
Angiotensin receptor blocker 
AST 
Aspartate aminotransferase 
AT1R 
Angiotensin II type 1 receptor 
BP 
Blood pressure 
 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology  
CONSORT 
Consolidated Standards of Reporting Trials 
CRFs 
Case report forms 
CTFG 
Clinical Trial Facilitation Group 
CYP3A 
Cytochrome P450 3A 
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 Participants with Focal Segmental Glomerulosclerosis 
(FSGS):  A Randomized, Double-blind, Active-control, Dose-escalation Study 
DUPLEX 
Study 021FSGS16010, NCT03493685, EudraCT 2016-00514123: 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 Participants with Primary Focal Segmental 
Glomerulosclerosis (FSGS) 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
8 
Abbreviation 
Definition 
EOS 
End of Study 
EOT 
End of Treatment 
ERA 
Endothelin receptor antagonist 
ETAR 
Endothelin type A receptor 
ET1 
Endothelin-1 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FMV 
First morning void 
FSGS 
Focal segmental glomerulosclerosis 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GMR 
Geometric mean ratio 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDFU 
Investigational Directions for Use 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgAN 
Immunoglobulin A nephropathy 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology system 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
KDIGO 
Kidney Disease Improving Global Outcomes 
KF 
Kidney failure 
LAM 
Lactational amenorrhea method 
MLD 
Maximum labeled dose 
MMRM 
Mixed Model Repeated Measures  
MRA 
Mineralocorticoid receptor antagonist 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
9 
Abbreviation 
Definition 
MTD 
Maximum tolerated dose 
NSAID 
Non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PP 
Per Protocol (analysis set) 
QD 
Once daily 
RAAS 
Renin-angiotensin-aldosterone system 
RAASi 
Renin-angiotensin-aldosterone system inhibitor 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SGLT2 
Sodium glucose cotransporter-2 
SGLT2i 
Sodium glucose cotransporter-2 inhibitor 
SoA 
Schedule of activities 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
UA/C 
Urine albumin-to-creatinine ratio 
UP/C 
Urine protein-to-creatinine ratio 
US 
United States 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
10 
1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A multicentered, single-group Phase 2, exploratory, open-label study to investigate safety and effect 
of sparsentan in combination with sodium glucose cotransporter-2 (SGLT2) inhibition in the 
treatment of adult participants with Immunoglobulin A nephropathy (IgAN) 
Brief Title: 
A study to investigate safety and effect of sparsentan in combination with SGLT2 inhibition in adult 
participants with IgAN  
Regulatory Agency Identifier Number(s): 
Registry 
ID 
IND 
137918 
Protocol Number:  
TVTX-RE021-204 
Compound: 
Sparsentan (RE-021) 
Type of Study: 
Phase 2 
Total Number of Study Site(s) Projected:  
Approximately 30 multinational sites. 
Name of Sponsor/Company:  
Travere Therapeutics, Inc. 
3611 Valley Centre Drive, Suite 300 
San Diego, CA 92130 
USA 
Study Rationale 
Due to their antiproteinuric and long-term nephroprotective effects, SGLT2 inhibitors are being 
increasingly used in the treatment of patients with both diabetic and non-diabetic chronic kidney 
diseases including IgAN. Sparsentan, a non-immunosuppressive single molecule with dual 
antagonism of the endothelin type A receptor (ETAR) and the angiotensin II type 1 receptor (AT1R), 
is being developed for the treatment of IgAN. 
An interim analysis of data from the randomized, controlled, Phase 3 PROTECT (021IGAN17001) 
study in participants with IgAN at risk of progression to kidney failure (KF) despite optimized 
renin-angiotensin-aldosterone system inhibitor (RAASi) demonstrated a significantly greater 
antiproteinuric effect of sparsentan as compared to the angiotensin receptor blocker (ARB), 
irbesartan, used as an active control. This observation suggests long-term nephroprotective potential 
of sparsentan in IgAN, a hypothesis which will be tested by analysis of long-term estimated 
glomerular filtration rate (eGFR) based confirmatory endpoints of the PROTECT trial.  
With more widespread use of sodium glucose cotransporter-2 inhibitor (SGLT2i) and the possibility 
of concomitant use of SGLT2i and sparsentan in patients with IgAN, there is an increasing need to 
study the safety and effect of a combination of these 2 therapeutic approaches. The current study, 
SPARTACUS, has been designed to determine the safety and effect of such a combination of 
therapies. 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
11 
Objectives and Endpoints   
Objectives 
Endpoints 
Safety: 
To assess the safety and tolerability of 
sparsentan in participants with IgAN on 
chronic stable treatment with an SGLT2 
inhibitor. 
The incidence of treatment-emergent AEs (TEAEs), 
serious adverse events (SAEs), adverse events 
(AEs) leading to treatment discontinuation, and 
adverse event of interest (AEOIs).  
Changes from baseline in body weight, vital signs, 
physical examinations, peripheral edema, and 
clinical laboratory parameters. 
Primary (Efficacy): 
To evaluate the effect of sparsentan on 
albuminuria in participants with IgAN on 
SGLT2 inhibitor medication. 
The change from baseline (Day 1) in urine 
albumin-to-creatinine ratio (UA/C) at Week 24. 
Secondary (Efficacy): 
To evaluate the effect of sparsentan on 
proteinuria variables, eGFR and blood 
pressure (BP), in participants with IgAN on 
SGLT2 inhibitor medication over the duration 
of the study. 
Achievement of UA/C of <0.2 g/g at Week 24. 
Achievement of 30% and 50% reduction from 
baseline in UA/C at Week 24. 
The change from baseline in UA/C, urine protein-
to-creatinine ratio (UP/C), eGFR, and BP at each 
visit. 
Overall Design: 
This is a 28-week, open-label, multicenter, single-group Phase 2 exploratory study to determine the 
safety and effect of sparsentan in participants with IgAN who are at risk of disease progression to KF 
despite being on both stable RAASi and SGLT2 inhibitor treatment for at least 12 weeks prior to 
study entry.  
Participants who provide written informed consent will be assessed for eligibility and will undergo 
baseline evaluations including clinical laboratory tests. Per the eligibility criteria, all participants are 
required to be on a stable dose(s) of angiotensin converting enzyme inhibitor (ACEI) and/or ARB and 
on a stable dose of a SGLT2 inhibitor at screening and will continue their stable treatments through 
the screening period. Eligible participants entering the study will remain on the stable dose of the 
SGLT2 inhibitor for the duration of the study, however, they will discontinue ACEI and/or ARB 
therapy before the Day 1 visit. The final dose of an ACEI and/or ARB should be taken on the day 
before the Day 1 visit. Baseline evaluations will be taken on Day 1 prior to administration of the first 
dose of the study intervention (sparsentan) according to Section 6.1.  
Study intervention will be administered daily for a treatment period of 24 weeks with study visits 
conducted at weeks 2-, 4-, 12-, and 24- following Day 1. Following the 24-week treatment period, 
study intervention will be discontinued for 4 weeks. At this time, the Investigator should resume 
standard of care treatment, including RAASi treatment. Participants will return to the site for a visit at 
Week 28 for the safety follow-up visit. 
UA/C and UP/C will be determined using first morning void (FMV) samples and will be calculated as 
the average of 2 FMV samples collected within 3 days prior to each visit. If one of the samples is 
missing, UA/C and UP/C from the single sample will be used. 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
12 
The overall study design is summarized in Figure 1. For individual participants, the total duration of 
participation from the screening visit to the safety follow-up visit (Week 28) will be a maximum 34 
weeks.  
Specific procedures to be performed during the study, as well as their prescribed times and associated 
visit windows are outlined in the Schedule of Activities (SoA) in Section 1.3. Details of each 
procedure are provided in Section 8.  
Brief Summary: This is a 28-week, open-label, multicenter, single-group Phase 2 exploratory study 
to determine the safety and effect of sparsentan in participants with IgAN who are at risk of disease 
progression to KF despite being on both stable RAASi and SGLT2 inhibitor treatment for at least 
12 weeks prior to study entry.  
Health Measurement/Outcome: The purpose of this study is to evaluate safety and effect of 
sparsentan in combination with SGLT2 inhibitors in adult participants with IgAN. 
Study Intervention and Intervention Form: Sparsentan tablets 
Condition/Disease: IgAN 
Study Duration: The duration of the study for a participant will be up to 34 weeks. 
Treatment Duration: The study design included a screening period of up to 6 weeks, treatment 
period of 24 weeks, and a follow-up period of 4 weeks. 
Visit Frequency: Site visits will be conducted for screening, at Day 1 (baseline), and at weeks 2, 4, 
12, and 24 following Day 1. Following the 24-week treatment period, study intervention will be 
discontinued for 4 weeks. At this time, the Investigator should resume standard of care treatment, 
including RAAS inhibitor treatment. Participants will return to the site for a visit at Week 28 for the 
safety follow-up visit. 
Number of Participants:  
Approximately 60 participants aged >18 years will be enrolled into this study. 
Note: Enrolled means participants’, or their legally acceptable representatives’, agreement to 
participate in a clinical study following completion of the informed consent. Potential participants 
who are screened for the purpose of determining eligibility for the study, but do not participate in the 
study, are not considered enrolled, unless otherwise specified by the protocol.  
Study Arms and Duration: 
This study includes 3 periods: a screening period (up to 42 days), a treatment period (24 weeks) and a 
follow-up period (4 weeks).  
All participants will be on stable doses of standard of care ACEI and/or ARB and an SGLT2 inhibitor 
at study entry, with prohibited concomitant medications discontinued before the baseline (Day 1) 
visit. The full daily dose of study intervention (sparsentan) is preferred to be taken prior to the 
morning meal, with the exception of the day of a study visit. Allowed doses of sparsentan during the 
treatment period are 200 mg and 400 mg. The goal is to titrate from the initial dose of 200 mg (Day 1) 
to the target dose of 400 mg at Week 2. 
Planned maximum duration for each participant in this study is 34 weeks.  
• 
Screening period of up to 6 weeks. 
• 
Treatment period of 24 weeks. 
• 
Safety follow-up visit 4 weeks after the final dose. 
Key Eligibility Criteria 
For a full list of eligibility criteria, please refer to Section 5.  

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
13 
 
Inclusion Criteria 
• 
Participant aged ≥18 years at the time of signing the informed consent.  
• 
Participant has biopsy-proven IgAN. The biopsy may have been performed at any time in 
the past.  
• 
Participant has a UA/C ≥0.3 g/g at screening.  
• 
Participant has an eGFR value of ≥25 mL/min/1.73m2 at screening.  
• 
The participant has been on a stable dose of an SGLT2 inhibitor for at least 12 weeks 
prior to screening. 
• 
Participant has been on a stable dose of ACEI and/or ARB therapy for at least 12 weeks 
prior to screening that is: 
− 
The participant’s maximum tolerated dose (MTD), and  
− 
at least one half of the maximum labeled dose (MLD)  
Exclusion Criteria 
• 
Participant has IgAN secondary to another condition or immunoglobulin A (IgA) 
vasculitis. 
• 
Participant has undergone any organ transplant, with the exception of corneal transplants. 
• 
Participant has a documented history of heart failure, clinically significant cardiovascular 
or liver disease.  
• 
Participant has been taking high dose (defined as >10 mg/day prednisone) or other any 
systemic immunosuppressive medications within 12 weeks of prior to screening.  
Statistical Considerations: 
Sample Size Justification 
To investigate the safety and effect of sparsentan in participants with IgAN on chronic stable 
treatment with an SGLT2 inhibitor, approximately 60 participants will be enrolled in the study. The 
sample size of the study is determined empirically without formal statistical assumptions. A sample 
size of 60 is sufficient to detect at least one adverse event with probability 95%, assuming an 
expected adverse event incidence of 5% using the binomial distribution. 
Analysis Sets 
Full Analysis Set (FAS):  All participants who take at least 1 dose of sparsentan will be included in the 
FAS. All efficacy analyses will be based on the FAS. 
Per Protocol (PP) Analysis Set:  The PP analysis set is a subset of the FAS containing participants 
who meet study eligibility requirements and have no protocol deviations that might impact the 
assessment of efficacy measurements. The PP analysis set will be used for sensitivity analyses 
relating to efficacy. The type of protocol deviations governing exclusion from the PP analysis set will 
be determined prior to database lock and will be detailed in the statistical analysis plan (SAP). 
Efficacy Analyses 
All efficacy analyses will be done descriptively on the FAS as well as PP analysis set in observed 
case. Change from baseline will be summarized with mean and 95% confidence interval (CI) as 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
14 
appropriate. For categorical efficacy endpoints, the proportion of participants in the category will be 
presented along with corresponding 95% CI. 
Safety Analyses 
All safety analyses will be based on the FAS. Descriptive statistics will be presented. TEAE will be 
summarized by system organ class and preferred terms, by severity, and by relationship to study 
intervention. Changes from baseline in body weight, vital signs, physical examinations, peripheral 
edema, and clinical laboratory parameters will be summarized and/or listed. In addition, shifts in 
laboratory parameters and peripheral edema will be summarized. 
Data Monitoring/Other Committee:  No 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
15 
1.2. 
Schema 
A study schema is provided in Figure 1.  
Figure 1: 
Study Design 
 
Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; 
mg = milligrams; SGLT2i = sodium glucose cotransporter-2 inhibitor; SOC = standard of care.  

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
16 
1.3. 
Schedule of Activities (SoA) 
 
Screening 
Baseline 
Study Treatment Period 
Safety 
Follow-up 
Visit 
Week 
-- 
Day 1 
Week 2 
Week 4 
Week 12 
Week 24/ 
EOT 
Week 
28/4-week 
Safety Visit 
Visit 
1 
2 
3 
4 
5 
6 
7 
Visit Window 
Day –42 to 
Day –1 
-- 
± 5 days 
± 7 days 
± 7 days 
± 7 days 
 
± 7 days 
 
Informed 
Consent 
X 
 
 
 
 
 
 
Inclusion/Exclu
sion 
X 
 
 
 
 
 
 
Screening 
Testsa 
X 
 
 
 
 
 
 
IRT 
X 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Peripheral 
Edema 
Assessmentb 
X 
X 
X 
X 
X 
X 
X 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Laboratory 
Assessmentsd 
X 
X 
X 
X 
X 
X 
X 
Lipid Panele 
X 
X 
 
 
X 
X 
 
Physical 
Examinationf 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
--------------------------------------------------Continuous Monitoring ---------------------------- 
Concomitant 
Medications/Th
erapies 
------------------3 Months prior to screening followed by Continuous Monitoring----------- 
RAAS Inhibitor 
Treatmentg 
X 
 
 
 
 
X 
 
SGLT2 
Inhibitor 
Treatment 
--------------------------------------------------Continuous Treatment ---------------------------- 
Quantitative 
urinalysis 
X 
X 
 
X 
X 
X 
X 
Calculate 
eGFRh 
X 
X 
X 
X 
X 
X 
X 
Study 
Intervention 
Dispensing 
 
X 
X 
X 
X 
 
 
Study 
Intervention 
Accountability 
 
 
X 
X 
X 
X 
 
Pregnancy Testi 
X 
X 
X 
X 
X 
X 
X 
Dispense Urine 
Pregnancy Testj 
 
 
 
X 
X 
 
 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; BP = 
blood pressure; BUN = blood urea nitrogen; eGFR = estimated glomerular filtration rate; EOT = end of treatment; 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
17 
HDL = high-density lipoprotein; IRT = interactive response technology system; LDL = low-density lipoprotein; 
MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean 
corpuscular volume; pH = potential for hydrogen; RAAS = renin-angiotensin-aldosterone system; SOC = standard 
of care; SGLT2 = sodium glucose cotransporter-2; WBC = white blood cell.  
a 
Includes plasma follicle stimulating hormone level (to confirm menopausal status only). 
b 
Peripheral edema assessment guidance provided in Section 10.4. 
c 
Vital signs should be measured prior to having blood drawn for laboratory evaluations. BP will be measured 
after participants 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. Weight, heart 
rate, temperature, respiration rate, and height (height measured only at screening) will also be recorded.  
d 
Includes clinical chemistry (serum 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); 
hematology (red blood cells, hemoglobin, hematocrit, MCV, MCH, MCHC, platelets, WBC, and WBC 
differential [percentage and absolute] neutrophils, eosinophils, basophils, lymphocytes, and monocytes); and 
routine urinalysis (color, appearance, and dipstick [pH, specific gravity, protein, glucose, ketones, bilirubin, 
blood, urobilinogen, and leukocyte esterase]). All chemistry and hematology analytes are shown in 
Section 10.3.  
e 
Includes total cholesterol, LDL (direct), HDL (direct), and triglycerides (direct). All lipid analytes are shown 
in Section 10.3. 
f 
Full physical examination will be performed at screening. A symptom directed targeted physical 
examination will be performed for all other visits.  
g 
After Week 24/EOT, participants are expected to restart SOC treatment. The restart of RAAS inhibitor is at 
the discretion of the Investigator. 
h 
The day before visit, participants should avoid strenuous exercise and a high protein meal, and participants 
should maintain a stable water intake. 
i 
At screening, serum pregnancy tests will be performed on participants who can become pregnant. Urine 
pregnancy tests will be performed at all other visits and monthly between visits. A positive urine pregnancy 
test will be confirmed by a serum test.  
j 
Sites will provide participants who can become pregnant with 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. 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
18 
2. 
INTRODUCTION 
Immunoglobulin A nephropathy (IgAN), also known as Berger’s disease, is a form of 
glomerulonephritis originally described in 1968. Although the pathogenesis of IgAN has not 
been elucidated, several lines of evidence indicate that it is an autoimmune disease with an 
extrarenal etiology (Knoppova 2016). IgAN is a serious, progressive disease in which 20% to 
40% of patients progress to kidney failure (KF) within 10 to 20 years of diagnosis (Manno 2007; 
Berthoux 2011; Moriyama 2014). As most patients are diagnosed in their 20s or 30s, they face 
the prospect of dialysis or the need for kidney transplantation in the prime of their lives. Geddes 
et al (Geddes 2003) conducted a retrospective analysis of patients with IgAN across 4 countries 
on 3 continents (Europe, North America, and Australia) to assess long-term outcome of the 
disease. From first clinical presentation, the overall 10-, 15-, and 20- year actuarial renal survival 
rates were 77.8%, 69.8%, and 55.3%, respectively. Due to the extrarenal etiology of IgAN in 
which the kidney is the end organ damaged by a systemic immunological condition, the 
incidence of IgAN recurrence following kidney transplantation is high; when posttransplant 
biopsies were routinely collected (regardless of symptomology), the recurrence of IgAN has 
been reported in 50% to 60% of patients, with an estimated 10-year incidence of graft loss due to 
recurrence of approximately 10% (Choy 2006). 
Patients with IgAN typically present in 1 of 3 ways (Donadio 2002b; Galla 1995). 
Approximately 40% to 50% of patients present with 1 or recurrent episodes of visible hematuria, 
usually following an upper respiratory tract infection; these patients are not considered to be at 
risk for progression to KF. Less than 10% of patients present with nephrotic syndrome or acute, 
rapidly progressing glomerulonephritis and, in rare cases, may present with malignant 
hypertension. The remaining 30% to 40% of patients have persistent proteinuria that may be 
accompanied by microscopic hematuria, which is detected incidentally upon routine examination 
(Hall 2004; Topham 1994); this group is the target patient population for treatment with 
sparsentan and is addressed by the Kidney Disease Improving Global Outcomes (KDIGO) 
Clinical Practice Guideline for Glomerulonephritis (KDIGO 2021). 
While there are currently no approved medicinal products specifically indicated for the treatment 
of IgAN, the cornerstone of treatment is rigorous blood pressure (BP) control using 
renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, (angiotensin converting 
enzyme inhibitors [ACEIs], or angiotensin receptor blockers [ARBs]) to target BP values 
<130/80 mmHg in order to reduce hemodynamic stress and proteinuria and, thereby, slow the 
progression of renal disease (Floege 2011; Locatelli 2006; Aucella 2009). Randomized, 
placebo-controlled trials have shown long-term benefit of RAASi treatment (Ruggenenti 2000; 
Praga 2003; Coppo 2007), which is universally considered to be first line standard of care, as 
outlined in the KDIGO Clinical Practice Guideline (KDIGO 2021). However, despite optimized 
RAASi therapy, persistent overt proteinuria remains in many patients, concurrent with loss of 
renal function and progression to KF.  
Recently conducted large randomized controlled trials in patients with diabetic and non-diabetic 
chronic kidney disease (CKD) on stable RAASi treatment, have shown the sodium glucose 
cotransporter-2 (SGLT2) inhibitors, dapagliflozin and empagliflozin, to reduce proteinuria, slow 
progression of kidney function loss and reduce risk of KF (Heerspink 2020; Herrington 2022; 
Baigent 2022). Pre-specified sub-group analyses, show the benefit for IgAN patients to be 
consistent with the overall CKD population (Wheeler 2021; Herrington 2022; Baigent 2022).  

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
19 
As a consequence of these findings, there is increasing use of SGLT2 inhibitors for the treatment 
of IgAN in addition to standard of care renin-angiotensin-aldosterone system (RAAS) inhibition. 
2.1. 
Study Rationale 
Due to their antiproteinuric and long-term nephroprotective effects, SGLT2 inhibitors are being 
increasingly used in the treatment of patients with both diabetic and non-diabetic chronic kidney 
diseases including IgAN. Sparsentan, a non-immunosuppressive single molecule with dual 
antagonism of the endothelin type A receptor (ETAR) and the angiotensin II type 1 receptor 
(AT1R), is being developed for the treatment of IgAN. 
An interim analysis of data from the randomized, controlled, Phase 3 PROTECT 
(021IGAN17001) study in participants with IgAN at risk of progression to KF despite optimized 
RAASi demonstrated a significantly greater antiproteinuric effect of sparsentan as compared to 
the ARB, irbesartan, used as an active control. This observation suggests long-term 
nephroprotective potential of sparsentan in IgAN, a hypothesis which will be tested by analysis 
of long-term estimated glomerular filtration rate (eGFR) based confirmatory endpoints of the 
PROTECT trial.  
With more widespread use of sodium glucose cotransporter-2 inhibitor (SGLT2i) and the 
possibility of concomitant use of SGLT2i and sparsentan in patients with IgAN, there is a need 
to study the safety and effect of a combination of these 2 therapeutic approaches. The current 
study, SPARTACUS, has been designed to determine the safety and effect of such a combination 
of therapies. 
2.2. 
Background 
Sparsentan is a non-immunosuppressive single molecule with dual antagonism of ETAR and 
AT1R. Given the well-known role of angiotensin II (AngII) and endothelin-1 (ET1) in 
glomerulonephropathies, it is anticipated that sparsentan, as a dual antagonist, will have a 
positive effect on the pathophysiological changes in the glomeruli and tubulointerstitial 
compartment that occurs in IgAN. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
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. 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 
endothelin receptor antagonists (ERAs) is associated with increased rates of edema and 
congestive heart failure (CHF) in patients with diabetic nephropathy (Mann 2010). 
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 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
20 
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. 
Selective and non-selective endothelin type A/endothelin receptor subtype B 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 participants and their female 
partners indicates that, similar to marketed ERAs and ARBs, the requirement for contraception 
in male study participants is not warranted. 
Table 1: 
Risk Assessment 
Identified/Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Study Intervention (s): Sparsentan 
Transaminase elevations. 
Elevations of aspartate 
aminotransferase (AST) or alanine 
aminotransferase (ALT) greater 
than 3x upper limit of normal 
(ULN) have been observed in 
studies of sparsentan, though 
concurrent elevation of bilirubin 
has not been observed. 
Sparsentan can be discontinued in 
participants with clinically relevant 
aminotransferase elevations or if 
aminotransferase elevation is 
accompanied by a greater than 2x 
ULN increase in bilirubin or by 
clinical symptoms of 
hepatotoxicity.  
Hyperkalemia. 
Participants with advanced kidney 
disease or taking concomitant 
potassium-increasing drugs are at 
increased risk for hyperkalemia. 
Potassium will be monitored at 
each visit for clinical evidence of 
electrolyte imbalance, with the 
course of action dependent on the 
potassium level and likely cause of 
increase. Management includes 
modifications in diet, diuretics, or 
potassium lowering medications. 
Sparsentan can be held or 
discontinued in participants who 
develop clinically significant 
hyperkalemia. 
AKI. 
Changes in kidney function and 
impaired kidney function can be 
caused by drugs that inhibit the 
RAAS system. Participants with 
renal artery stenosis, CKD, severe 
CHF, or volume depletion may be 
at particular risk of developing 
clinically significant AKI. The 
combination of sparsentan and 
SGLT2 inhibitors may enhance the 
risk of AKI. 
Kidney function will be monitored 
periodically in this clinical 
study.Sparsentan can be held or 
discontinued in participants who 
develop clinically significant 
disease. 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
21 
Table 1: 
Risk Assessment (Continued) 
Identified/Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Hypotension. 
Hypotension has been observed in 
patients treated with ARBs and 
ERAs and has been observed in 
clinical studies of sparsentan. The 
combination of sparsentan and 
SGLT2 inhibitors may enhance the 
risk of hypotension.  
In patients at risk for hypotension, 
consider eliminating or adjusting 
other anti-hypertensive 
medications.If hypotension 
develops despite elimination or 
reduction of other anti-hypertensive 
medications, the dose of sparsentan 
can be reduced or interrupted. 
Fluid retention. 
Fluid retention is observed in 
patients with IgAN and may occur 
with drugs that antagonize ETAR. 
Fluid retention has been observed 
in clinical studies of sparsentan. 
Treatment with ERAs is associated 
with increased rates of edema and 
CHF in patients with diabetic 
nephropathy.  
If clinically significant fluid 
retention develops, diuretics may 
need to be initiated or modified. 
The dose of sparsentan can also be 
reduced.Sparsentan should be used 
with caution in patients with Stage 
3/4 CKD and with extreme caution 
in patients with Stage 5 CKD. 
Sparsentan should be avoided in 
patients with Stage 2-4 CHF. 
Fetal harm. 
Selective and non-selective 
endothelin type A/endothelin 
receptor type B antagonists are 
expected to cause fetal harm. ARBs 
reduce fetal renal function and 
increase fetal and neonatal 
morbidity and death during the 
second and third trimesters of 
pregnancy.  
Participants will be advised of the 
risks and pregnancy testing will be 
conducted monthly.  
Study Procedures 
Venipuncture will be performed 
during the study.  
There is risk of bleeding, bruising, 
hematoma formation, and infection 
at the venipuncture site. 
Only appropriately qualified 
personnel will obtain the blood 
draw. 
Abbreviations: AKI = acute kidney injury; ARBs = angiotensin receptor blockers; CHF = congestive heart failure; 
CKD = chronic kidney disease; ERAs = endothelin receptor antagonists; ETAR = Endothelin type A receptor; 
IgAN = Immunoglobin A nephropathy; SGLT2 = sodium glucose cotransporter-2.  
2.3.2. 
Benefit Assessment 
In an interim analysis of data from PROTECT, sparsentan had an early and sustained effect on 
reducing proteinuria compared to participants in the irbesartan arm. Consistent reduction of 
proteinuria in PROTECT was observed across pre-specified baseline subgroups. Additionally, 
preliminary eGFR analyses suggest the rate of eGFR decline is attenuated in participants taking 
sparsentan may further reduce residual proteinuria in patients treated with a combination of 
RAASi and SGLT2i. 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
22 
2.3.3. 
Overall Benefit/Risk Conclusion 
It cannot be guaranteed that participants in clinical studies will directly benefit from treatment 
during participation, as clinical studies are designed to provide information about the safety and 
effectiveness of an investigational medicine.  
However, sparsentan has demonstrated a clinically meaningful benefit in reducing proteinuria in 
an interim analysis of data from PROTECT. In PROTECT, no new safety signals were 
identified; the nature, severity, and frequency of adverse events (AEs) were generally consistent 
with the safety profile of sparsentan in participants with focal segmental glomerulosclerosis 
(FSGS) (DUET, DUPLEX studies). Thus, the potential risks and benefits identified in 
association with sparsentan and participation in this study support a favorable benefit-risk 
analysis for sparsentan in this study population. 
Additional details regarding specific benefits and risks for participants of this clinical study may 
be found in the accompanying Investigator’s Brochure (IB) and informed consent form (ICF).  
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Objectives 
Endpoints 
Safety 
To assess the safety and tolerability of sparsentan 
in participants with IgAN on chronic stable 
treatment with an SGLT2 inhibitor. 
The incidence of treatment-emergent AEs 
(TEAEs), serious adverse events (SAEs), AEs 
leading to treatment discontinuation, and adverse 
event of interest (AEOIs).  
Changes from baseline in body weight, vital signs, 
physical examinations, peripheral edema, and 
clinical laboratory parameters. 
Primary (Efficacy) 
To evaluate the effect of sparsentan on 
albuminuria in participants with IgAN on SGLT2 
inhibitor medication. 
The change from baseline in urine albumin-to-
creatinine ratio (UA/C) at Week 24. 
Secondary (Efficacy) 
To evaluate the effect of sparsentan on proteinuria 
variables, eGFR and BP, in participants with 
IgAN on SGLT2 inhibitor medication over the 
duration of the study. 
Achievement of UA/C of <0.2 g/g at Week 24. 
Achievement of 30% and 50% reduction from 
baseline in UA/C at Week 24.  
The change from baseline in UA/C, urine protein-
to-creatinine ratio (UP/C), eGFR, and BP at each 
visit. 
3.1. 
Primary Estimand  
Not applicable. No estimands are developed for this study.  
3.2. 
Secondary Estimand(s) 
Not applicable. No estimand(s) are developed for this study.  

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
23 
4.
STUDY DESIGN
4.1. 
Overall Design
This is a 28-week, open-label, multicenter, single-group Phase 2 exploratory study to determine 
the safety and effect of sparsentan in participants with IgAN who are at risk of disease 
progression despite being on both stable RAASi and SGLT2 inhibitor treatment for at least 
12 weeks prior to study entry.  
Participants who provide written informed consent will be assessed for eligibility and will 
undergo baseline evaluations including clinical laboratory tests. Per the eligibility criteria, all 
participants are required to be on a stable dose(s) of ACEI and/or ARB therapy and on a stable 
dose of a SGLT2 inhibitor at screening and will continue their stable treatments through the 
screening period. Eligible participants entering the study will remain on the stable dose of the 
SGLT2 inhibitor for the duration of the study, however, they will discontinue ACEI and/or ARB 
therapy before the Day 1 visit. The final dose of an ACEI and/or ARB therapy should be taken 
on the day before the Day 1 visit. Baseline evaluations will be taken on Day 1 prior to 
administration of the first dose of the study intervention (sparsentan) according to Section 6.1.  
Study visits will be conducted at weeks 2-, 4-, 12-, and 24- following Day 1. Following the 
24-week treatment period, study intervention will be discontinued for 4 weeks. At this time, the
Investigator should resume standard of care treatment, including RAAS inhibitor treatment.
Participants will return to the site for a visit at Week 28 for the safety follow-up visit.
UA/C and UP/C will be determined using first morning void (FMV) samples and will be 
calculated as the average of 2 FMV samples collected within 3 days prior to each visit. If 1 of the 
samples is missing, UA/C and UP/C from the single sample will be used. 
The overall study design is summarized in Figure 1. For individual participants, the total duration 
of participation from the screening visit to the safety follow-up visit (Week 28) will be a 
maximum of 34 weeks. 
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows are outlined in the SoA in Section 1.3. Details of each procedure are 
provided in Section 8.  
4.2. 
Scientific Rationale for Study Design 
4.2.1. 
Rationale for Endpoints 
4.2.1.1. 
Safety Endpoints 
Safety parameters commonly used for evaluating investigational CKD treatments are included as 
safety endpoints, but not limited to, the incidence of causality and outcomes of AEs/SAEs, and 
changes in vital signs and laboratory values. AEs will be assessed and defined according to 
severity. Severity of AEs are defined in Section 10.5. 
4.2.1.2. 
Efficacy Endpoints 
The primary and secondary endpoints evaluate change from baseline in albuminuria and 
achievement of remission of albuminuria at 24 weeks. Albuminuria is not only a major symptom 
of IgAN but also an established risk factor for disease progression and KF in IgAN (Reich 2007; 

Travere Therapeutics, Inc.  
 
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
 
Confidential and Proprietary 
24 
Le 2011). Meta-analyses of randomized controlled trials in IgAN have established mean 
percentage change in albuminuria from baseline as a surrogate endpoint for rate of loss of eGFR 
and risk of KF (Inker 2016; Thompson 2019; Inker 2021) and the change in albuminuria from 
baseline is therefore applied as the primary efficacy endpoint.  
A secondary endpoint analysis will determine additional measures of antialbuminuric and 
antiproteinuric effects of sparsentan, such as the proportion of participants achieving 30% and 
50% reductions in albuminuria, which, based on the meta-analyses, reflect thresholds for 
clinically meaningful benefit (Inker 2016; Inker 2021; Thompson 2019). Additionally, 
achievement of remission of albuminuria, is associated with low risk of KF (Reich 2007). 
Changes in eGFR, as a measure of renal function, and BP, the major determinant of the risk of 
CKD progression, from baseline will be evaluated over the duration of the study as secondary 
endpoints.  
4.2.2. 
Rationale for Study Population 
The study enrolls an adult population of biopsy-proven participants with IgAN, remaining 
proteinuric despite combination treatment with RAASi and SGLT2 inhibitor, who might benefit 
from further reduction or normalization of proteinuria by sparsentan.  
4.3. 
Justification for Dose 
As of August 2021, Sparsentan has been studied in approximately 1320 healthy volunteers, and 
in approximately 550 patients with Stage 1 hypertension, Stage 2 hypertension, FSGS or IgAN. 
In these studies, sparsentan has exhibited a favorable safety profile.  
In this study, sparsentan treatment is planned to be initiated at a dose of 200 mg once daily (QD) 
by mouth for 14 days, and then increased to the recommended target dose of 400 mg QD, as 
tolerated. 
This same dosing scheme is applied in PROTECT, PROTECT is an ongoing randomized, 
controlled Phase 3 study investigating the safety and efficacy of sparsentan, as compared to 
irbesartan, in 404 participants with IgAN at high risk of progression to KF. Participants are 
randomized 1:1 to receive either sparsentan or irbesartan with target doses of 400 mg and 
300 mg, respectively, for a treatment period of 110 weeks. The target dose of 400 mg sparsentan 
was chosen for this study as an appropriate target dose for treatment of IgAN, based upon the 
knowledge of sparsentan pharmacokinetics (PK) characteristics and the perceived benefit/risk 
profile in this progressive disease. 
At a pre-specified interim analysis, triggered 36 weeks after the Randomization of 
280 participants, the primary efficacy endpoint of change from baseline in UP/C at Week 36 was 
met. Subjects receiving sparsentan achieved a mean reduction in proteinuria from baseline of 
50%, compared with a mean reduction in proteinuria from baseline of 15% for irbesartan-treated 
subjects. This observed reduction in proteinuria corresponds to a clinically meaningful and 
significantly higher relative reduction from baseline of 41% in favor of sparsentan compared 
with irbesartan (geometric mean ratio [GMR] = 0.59, p<0.0001). Key secondary endpoints will 
evaluate the rate of change in eGFR after 1 and 2 years of treatment once all participants 
complete the double-blind phase of the study. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
25 
4.4. 
End of Study (EOS) Definition 
The EOS is defined as the date of the last visit of the last participant in the study. 
4.5. 
End of Treatment (EOT) Definition 
The EOT is defined as the end of the study intervention treatment period. EOT may be at Week 
24 (participant completes the study intervention treatment period as planned) or at the timepoint 
when a participant discontinues the study intervention permanently. In both circumstances, the 
EOT electronic case report form (eCRF) will be completed at the associated visit 
(see Section 7.1). 
5. 
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Informed Consent 
Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
Age 
1. Participant must be ≥18 years of age inclusive, at the time of signing the informed
consent.
Type of Participant and Disease Characteristics 
2. Participant has biopsy-proven IgAN. The biopsy may have been performed at any time in
the past.
3. Participant has a UA/C ≥0.3 g/g at screening.
4. Participant has an eGFR value of ≥25 mL/min/1.73 m2 at screening
Contraceptive/Barrier Requirements 
5. Participants who can become pregnant, 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 intervention until 30 days after the last dose of study intervention.
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 a duration defined as effective in product labeling.
If hormonal contraception is used, one additional barrier method must also be used during
sexual activity, such as a diaphragm or diaphragm with spermicide (preferred), or male
condom or male condom with spermicide (preferred), from Day 1/Randomization until
30 days after the last dose of study intervention. Hormonal implants do not require an

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
26 
additional barrier method to be used. Participants who can become pregnant 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 12 consecutive months without an alternative medical cause; 
participants on hormone replacement therapy must have a documented plasma follicle 
stimulating hormone level >40 mIU/mL. All participants who can become pregnant 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 
baseline (Visit 2) and after. See Section 10.7 for additional details on contraceptive and 
barrier guidance.   
Other Inclusion Criteria 
6. Participant has been on a stable dose of ACEI and/or ARB therapy for at least 12 weeks
prior to screening that is:
a.
The participant's maximum tolerated dose (MTD), and
b. at least one half of the maximum labeled dose (MLD) (See Section 10.2 for minimum
ACEI/ARB daily dose requirements at screening).
7. The participant has been on a stable dose of an SGLT2 inhibitor for at least 12 weeks
prior to screening.
8. Participant systolic BP must be ≤160 mmHg, and diastolic BP must be ≤110 mmHg at
screening.
9. For participants receiving chronic low dose systemic corticosteroids (defined as ≤10
mg/day prednisone or equivalent), or an enteric formulation of budesonide and/or a
mineralocorticoid receptor antagonist (MRA), the dosage must be stable for ≥12 weeks
prior to screening.
10. The participant is willing to undergo a change in ACEI and/or ARB and anti hypertensive
medications.
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participant has IgAN secondary to another condition (eg, systemic lupus erythematosus
and liver cirrhosis) or immunoglobulin A (IgA) vasculitis.
2. Participant has undergone any organ transplantation, with the exception of corneal
transplants.
3. Participant has a documented history of heart failure [New York Heart Association
(NYHA) Class II-IV] and/or previous hospitalization for heart failure or unexplained
dyspnea, orthopnea, paroxysmal nocturnal dyspnea, ascites, and/or peripheral edema (see
Section 10.4 for assessment of peripheral edema).

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
27 
4. Participant 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 3 months prior to
screening.
5. Participant has jaundice, hepatitis, or known hepatobiliary disease (excluding
asymptomatic cholelithiasis), or ALT and/or AST >2 times the ULN range at screening.
6. Participant has a history of malignancy other than adequately treated basal cell or
squamous cell skin cancer or cervical carcinoma within the past 2 years.
7. Participant has a history of serious side effect or allergic response to any AngII
antagonist, ERA or sparsentan, or has a hypersensitivity to any of the excipients in the
study intervention.
Prior/Concomitant Therapy 
8. Participant requires any of the prohibited concomitant medications (Section 10.6).
9. Participant has been taking high dose systemic corticosteroids (defined as >10 mg/day 
prednisone or equivalent) or other any systemic immunosuppressive medications or 
enteric budesonide greater than the MLD and/or a MRA greater than the MLD within 12 
week prior to screening.
Prior/Concurrent Clinical Study Experience 
10. Treatment with sparsentan within 12 weeks prior to screening
11. Participant 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.
Diagnostic Assessments 
12. Participant has a screening hematocrit value <27% (0.27 Volume/Volume) or
hemoglobin value <9 g/dL (90 g/L).
13. Participant has a screening potassium value of >5.5 mEq/L (5.5 mmol/L).
Other Exclusion Criteria 
14. The participant is pregnant, plans to become pregnant during the course of the study, or is
breastfeeding.
15. The participant, in the opinion of the Investigator, is unable to adhere to the requirements
of the study, including the ability to swallow the study intervention capsules whole.
Participants 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 participant for enrollment. If, 
in the Investigator’s opinion, a laboratory value at screening is deemed unlikely to be 
representative of the participant’s true status, the Investigator may have 1 additional 
measurement on that variable through the Central Laboratory to assess participant eligibility. 
Participants who fail screening may be rescreened according to Section 5.4. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
28 
5.3. 
Lifestyle Considerations 
The full daily dose of study intervention is preferred to be taken prior to the morning meal, with 
the exception of the day of a study visit.  
5.4. 
Screen Failures 
A screen failure occurs when a participant who has consented to participate in the clinical study 
is not subsequently entered in the study. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE. 
Participants who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 additional times. Rescreened participants should be assigned a new participant 
number for every screening/rescreening event and will need to repeat all screening tests. 
Participants will also repeat the informed consent procedure each time they are rescreened. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
29 
6.
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all pre-specified, investigational, and non-investigational medicinal 
products, medical devices, and other interventions (e.g., surgical, and behavioral) intended to be 
administered to the study participants during the study conduct.  
6.1. 
Study Intervention(s) Administered 
The study intervention to be used in this study is outlined in Table 2. 
Table 2: 
Study Intervention(s) Administered 
Intervention Label 
Sparsentan 
Intervention Name 
Sparsentan 
Intervention Description 
Week 1: Starting dose will be 1 tablet 
(1 x 200 mg) taken prior to the morning meal. 
Starting Week 3: Dose will be titrated to 1 tablet 
(1 × 400 mg) taken prior to the morning meal, if 
tolerated and determined safe by the 
Investigator. 
Type 
Drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
200 mg or 400 mg 
Dosage Level(s) 
Week 1: Starting dose will be 1 tablet (1 x 200 
mg) taken prior to the morning meal.  
Starting Week 3: Dose will be titrated to 1 tablet 
(1 × 400 mg) taken prior to the morning meal, if 
tolerated and determined safe by the 
Investigator. 
Route of Administration 
Oral 
Use 
Experimental 
Investigational Medicinal Product 
(IMP)/Non-Investigational Medicinal Product 
(NIMP) 
IMP 
Sourcing 
Provided centrally by the Sponsor. 
Packaging and Labeling 
Study intervention will be provided in container. 
Each container will be labeled as required per 
country requirement. Additional details about 
packaging and labeling can be found in the 
Pharmacy Manual.  
Definition of IMP and NIMP is based on guidance issued by the European Commission. Regional and/or Country 
differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
30 
Table 3: 
Study Arm 
6.2. 
Preparation, Handling, Storage, and Accountability 
6.2.1. 
Dose Preparation 
Details about administration of sparsentan are provided in the Pharmacy Manual. 
6.2.2. 
Handling, Storage, and Accountability 
The Investigator or designee must confirm appropriate conditions (eg, temperature) have been 
maintained during transit for all study intervention received, and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply, prepare, or administer study intervention.  
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the Investigator and authorized site staff. 
The Investigator is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided by the Sponsor in a Pharmacy Manual.  
6.3. 
Assignment to Study Intervention 
This is an open-label study. All participants will be centrally assigned to study intervention using 
an interactive response technology system (IRT). Before the study is initiated, the log-in 
information and directions for the IRT will be provided to each site. 
6.4. 
Blinding and Masking 
This is an open-label study. 
6.5. 
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
Arm Title 
Sparsentan 
Arm Type 
Experimental 
Arm Description 
At Week 1, the starting dose will be 1 tablet (1 x 200 mg) for all participants. 
At Week 3, the sparsentan dose will be titrated to 1 tablet (1 × 400 mg), if 
tolerated and determined safe by the Investigator. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
31 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by counting returned 
tablets during the site visits and documented in the source documents and relevant form. 
Deviation(s) from the prescribed dosage regimen should be recorded. 
A record of the quantity of sparsentan dispensed to and administered by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded. 
6.6. 
Dose Modification 
The Investigator may titrate up the participant’s dose to the target dose based on BP and lack of 
AEs at Week 2. Participants who tolerate the initial dose after 2 weeks but display asymptomatic 
systolic BP values ≤100 mmHg, or diastolic BP values ≤60 mmHg will continue the initial dose 
after the Week 2 visit without titrating up to the target dose. Participants who do not titrate up to 
the target dose at Week 2 for any reason, may titrate up to target dose at any time thereafter 
based on evaluation of the Investigator and if allowed by BP and lack of AEs in consultation 
with the Medical Monitor as needed. Participants who do not tolerate the initial dose for any 
reason at the Week 2 visit may discontinue study intervention. 
Throughout the study, participants will be maintained on the maximum allowed dose of study 
intervention they can tolerate while secondarily maintaining BP as close as possible to the target 
of 125/75 mmHg. To maintain BP, the Investigator will be encouraged to either treat participants 
with additional anti-hypertensive agents [with the exception of ACEIs, aliskiren, ARBs, or 
ERAs (see Section 10.6)] or withdraw anti-hypertensive agents. In the case of intolerable 
hypotension, withdrawal of additional anti-hypertensive agents should be accomplished before 
considering withdrawal or dose reduction of study intervention.  
Doses may be modified (titrate up or down) at any time throughout the study for safety or 
tolerability reasons at the Investigator’s discretion, and if appropriate, additional safety testing 
may be performed.  
6.7. 
Treatment of Overdose 
There is limited clinical experience with sparsentan overdose in participants. Sparsentan has 
been administered in doses of up to 1600 mg/day in healthy subjects without evidence of dose 
limiting toxicities.  
In the event of an overdose, the Investigator should: 
•
Evaluate the participant to determine, in consultation with the Medical Monitor, if
possible, whether the study intervention should be interrupted or whether the dose
should be reduced.
•
Closely monitor the participant for any AE/SAE and laboratory abnormalities as
medically appropriate and at least until the next scheduled follow-up.
6.8. 
Prior and Concomitant Therapy
For enrolled patients, prior and concomitant medications and therapies will be collected from the 
3 months prior to screening through the participant's final study visit. In addition, a 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
32 
comprehensive history of medications previously used for treatment of IgAN, including systemic 
corticosteroids or other systemic immunotherapeutic agents, will be collected.  
Any medication or vaccine (including over the counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest that the 
participant is receiving at the time of enrollment or receives during the study must be recorded 
along with: 
•
Reason for use.
•
Dates of administration including start and end dates.
•
Dosage information including dose and frequency.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1. 
Prohibited 
Medications specifically prohibited in the exclusion criteria are not allowed during time periods 
specified by this protocol for that medication or vaccination. If there is a clinical indication for 
any medication or vaccination specifically prohibited, discontinuation from study intervention 
may be required. The final decision on any supportive therapy or vaccination rests with the 
Investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the Investigator, the Sponsor, 
and the participant.  
Prohibited concomitant medications and other concomitant medication considerations during 
study participation are outlined in Section 10.6. 
For details regarding all non-clinical and clinical data on sparsentan, as well as warnings, 
precautions, and contraindications, the Investigator should refer to the IB. 
6.8.2. 
Rescue Medication 
No rescue or supportive medications are specified for use in this study. 
7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Discontinuation of specific sites or of the study as a whole are detailed in Section 10.1. 
7.1. 
Discontinuation of Study Intervention 
During the course of the study, it may be necessary for a participant to permanently discontinue 
study intervention prematurely. If study intervention is permanently discontinued prematurely, 
the participants should return to the site for a visit as close as possible to the participant’s last 
dose of study intervention. This visit may be a regularly scheduled visit or an unscheduled visit, 
and all assessments for this visit are to be completed per the regular scheduled visit or the 
Week 24 visit/EOT for an unscheduled visit, respectively, as listed in the SoA (Section 1.3). At 
this visit, the primary reason for premature discontinuation from study intervention, will be 
recorded on the EOT eCRF. Following this visit, participants are to complete the safety 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
33 
follow-up visit as listed in the SoA (Section 1.3) within approximately 4 weeks after the last 
dose of study intervention.  
The discontinuation of the SGLT2 inhibitor at any point during the study is not a reason for 
participant removal from protocol-required investigational product(s) or procedural assessments. 
Reasons for removal from protocol-required investigational product(s) or procedural assessments 
include any of the following: 
•
Decision by Sponsor.
•
Lost to follow-up.
•
Death.
•
Ineligibility determined.
•
Protocol deviation.
•
Noncompliance.
•
Adverse event.
•
Participant request.
•
Pregnancy.
•
Receipt of a kidney transplant or initiation of chronic dialysis.
•
Diagnosis of NYHA Class II-IV CHF.
•
Hyperkalemia that is resistant to treatment (see Section 10.8).
The need for additional intervention for the treatment of IgAN or the occurrence of safety 
endpoints are not, by themselves, criteria for discontinuation of study intervention.  
The primary reason for discontinuation of study intervention, will be recorded on the EOT eCRF. 
Subsequent study visit data will be recorded on the visit specific eCRF (either a regular 
scheduled visit or unscheduled visit). Once the EOT eCRF is completed, study intervention 
cannot be resumed. 
Additional details regarding temporary interruption or permanent discontinuation of the study 
intervention are outlined in Section 7.1.2 and Section 7.2. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study intervention for abnormal liver tests is required by the Investigator 
when a participant meets one of the conditions outlined in Section 10.9 or in the presence of 
abnormal liver chemistries not meeting protocol-specified stopping rules if the Investigator 
believes that it is in the best interest of the participant.  
Additional details regarding suggested actions and follow-up assessments for liver safety 
are outlined in Section 10.9.  
7.1.2. 
Temporary Discontinuation 
Participants who temporarily interrupt study intervention will be encouraged to restart study 
intervention at the Investigator’s discretion and should continue in the study. Participants who 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
34 
temporarily interrupt study intervention prior to completion of the study will continue with study 
visits and assessments according to the SoA (Section 1.3). Unless contraindicated, treatment 
should be resumed (titrated at the Investigator’s discretion) whenever possible (including 
between visits) as long as the EOT eCRF has not completed.  
7.1.3. 
Study Intervention Restart 
Study intervention restart after temporary interruption or after liver chemistry stopping criteria 
are met is allowed in this study. Refer to Section 7.1.2 for details on temporary discontinuation. 
Refer to Section 7.1.3.1 and Section 10.9 for details on study intervention restart after liver 
chemistry stopping criteria are met.  
7.1.3.1. 
Study Intervention Restart or Rechallenge After Liver Chemistry Stopping 
Criteria Are Met 
Study intervention restart after liver chemistry stopping criteria is met is allowed in this study. If 
the participant meets liver chemistry stopping criteria, do not restart the participant with study 
intervention unless: 
Monitoring indicates abnormalities have resolved or stabilized. 
Refer to Section 10.9 Liver Safety: Suggested Actions and Follow-up Assessments and Study 
Intervention Rechallenge Guidelines for details on the restart process.  
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw consent and/or discontinue participation in the study at any time 
without prejudice to subsequent standard of care treatment. A participant’s participation in the 
study may also be discontinued at any time at the discretion of the Investigator or Sponsor. 
Participants will also be discontinued from the study if the study is terminated 
(see Section 10.1.10 ). The Investigator is to discuss with the participant appropriate procedures 
for withdrawal from the study and must document the participant’s decision to withdraw in the 
participant’s medical records. 
•
A participant may withdraw from the study at any time at the participant’s own
request for any reason (or without providing any reason).
•
A participant may be withdrawn at any time at the discretion of the Investigator for
safety, behavioral, or compliance reasons.
•
At the time of discontinuing from the study, if possible, the visit data, including the
primary reason for premature discontinuation from study intervention, will be
recorded on the EOT eCRF. See SoA (Section 1.3) for data to be collected at the time
of study discontinuation.
•
The participant will be permanently discontinued from the study intervention and the
study at that time.
•
If the participant withdraws consent for disclosure of future information, the Sponsor
may retain and continue to use any data collected before such a withdrawal of
consent.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
35 
•
If a participant withdraws from the study, the participant may request destruction of
any samples taken and not tested, and the Investigator must document this in the site
study records.
Participants will be permanently discontinued from the study for any of the following reasons: 
•
Death.
•
Voluntary withdrawal of participant consent (complete withdrawal of consent
requires a participant’s documented refusal of all methods of follow-up noted in the
ICF).
•
Termination of the study by the Sponsor, FDA, or other regulatory authorities.
•
Lost to follow-up.
7.3. 
Lost to Follow-up
A participant will be considered lost to follow-up if the participant repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible, counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain whether the participant wishes to and/or should
continue in the study.
•
Before a participant is deemed lost to follow-up, the Investigator or designee must
make every effort to regain contact with the participant (where possible, telephone
calls, and if necessary, a certified letter to the participant’s last known mailing
address or local equivalent methods). These contact attempts should be documented
in the participant’s medical record.
•
Should the participant continue to be unreachable, the participant will be considered
to have withdrawn from the study.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
36 
8.
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
In the event of a significant study-continuity issue (eg, caused by a pandemic),
alternate strategies for participant visits, assessments, medication distribution and
monitoring may be implemented by the Sponsor or the Investigator, as per local
health authority/ethics requirements.
8.1. 
Administrative and General Procedures
8.1.1. 
Informed Consent
All participants or their legally authorized representative must sign (wet-ink or electronically, if 
permitted) and date the Institutional Review Board (IRB)/independent ethics committee (IEC) 
approved informed consent before any study specific procedures are performed. 
8.1.2. 
Inclusion/Exclusion Criteria 
For a full list of eligibility criteria, please refer to Section 5. 
8.2. 
Screening and Baseline Procedures 
8.2.1. 
Screening Assessments 
Screening visit assessments must be performed within 6 weeks prior to Day 1; the screening 
window begins on the day of the patient’s first in-clinic study procedure. Each participant will be 
registered in the IRT as screening and assigned a unique identification number which will stay 
the same throughout the study. If, in the Investigator’s opinion, a laboratory value at screening is 
deemed unlikely to be representative of the participant’s true status, the Investigator may have 1 
additional measurement on that variable through the Central Laboratory to assess participant 
eligibility. Participants who fail screening may be rescreened according to Section 5.4.  
Participants who do not meet the criteria for participation in this study (screen failure) may be 
rescreened up to 2 additional times. Rescreened participants should be assigned a new participant 
number for every screening/rescreening event and will need to repeat all screening tests. 
Participants will also repeat the informed consent procedure each time they are rescreened. 
8.2.2. 
Demographics 
Demographic data collection including sex, age, race, and ethnicity (as allowed by local 
regulations) will be collected. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
37 
8.2.3. 
Medical History 
A complete medical history will be obtained detailing other comorbid conditions and history of 
complications of IgAN, including the following: 
•
All prior treatments for IgAN, including systemic corticosteroids, other systemic
immunotherapeutic agents, and SGLT2 inhibitors.
•
Current ongoing concomitant medications, including over the counter and other
non-IgAN medications. See Section 6.8 for additional details on prior and
concomitant medications.
8.3. 
Efficacy Assessments
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3). 
8.3.1. 
Quantitative Urinalysis 
UA/C and UP/C will be determined using FMV samples and will be calculated as the average of 
2 FMV samples collected within 3 days prior to each visit. If 1 of the samples is missing, UA/C 
and UP/C from the single sample will be used. 
Participants 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.  
8.3.2. 
eGFR Calculation 
The list of clinical laboratory analysis to be tested is presented in Section 10.3 and includes 
serum creatinine for the estimation of GFR. The eGFR for each time point (visit) will be 
determined using the Chronic Kidney Disease Epidemiology (CKD-EPI) race free equation 
(Inker 2021).
8.4. 
Safety Assessments 
The safety and tolerability of sparsentan will be evaluated by AEs, body weight, vital signs, 
peripheral edema, physical examinations, and clinical laboratory parameters.  
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.4.1. 
Physical Examinations 
Physical examinations will be performed according to the SoA in Section 1.3. Full physical 
examinations will be performed at screening; a symptom directed targeted physical examination 
will be performed at all other visits. 
8.4.2. 
Peripheral Edema 
Peripheral edema will be assessed at all visits using the semi-quantitative scale in Section 10.4. 
8.4.3. 
Vital Signs 
Vital signs should be measured prior to having blood drawn for laboratory evaluations. BP will 
be measured after participants 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 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
38 
then be recorded. Weight, heart rate, temperature, respiration rate, and height (height measured 
only at screening) will also be recorded.  
8.4.4. 
Clinical Safety Laboratory Tests 
Routine blood and urine samples for laboratory assessments will be collected at the visits 
specified in the SoA in Section 1.3. 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 patients with clinically significant abnormal test results will be followed 
regularly until the values return to normal ranges, until a valid reason other than study 
intervention related AE is identified, 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. 
8.4.5. 
•
See Section 10.3 for the list of clinical laboratory tests to be performed and the SoA
(Section 1.3) for the timing and frequency.
•
The Investigator must review the laboratory results, document this review, and record
any clinically significant changes occurring during the study as an AE. The laboratory
results must be retained with source documents.
•
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or until EOS should be repeated until the values return to
normal or baseline or are no longer considered clinically significant by the
Investigator or Medical Monitor.
•
If clinically significant values do not return to normal/baseline within a period of time
judged reasonable by the Investigator, the etiology should be identified, and the
Sponsor notified.
•
All protocol-required laboratory tests, as defined in Section 10.3, must be conducted
in accordance with the laboratory manual and the SoA (Section 1.3).
•
If laboratory values from non-protocol-specified laboratory tests performed at the
institution’s local laboratory require a change in participant management or are
considered clinically significant by the Investigator (eg, SAE or AE or dose
modification), then the results must be recorded.
Pregnancy Testing
Participants who can become pregnant, as defined in Section 10.7 , must not become pregnant. 
Acceptable forms of contraception are also defined in Section 10.7 .  
At screening, serum pregnancy tests will be be performed on participants who can become 
pregnant. Urine pregnancy tests will be performed at all other visits and monthly between visits. 
Urine pregnancy tests will be dispensed to participants who can become pregnant to conduct 
pregnancy testing at home once per month until the next scheduled study visit. If the urine 
pregnancy test is positive, study intervention will be immediately discontinued, and a serum 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
39 
pregnancy test will be performed to confirm the result. If the serum pregnancy test is positive, 
the Sponsor will be notified, and the participant will be followed to pregnancy outcome as 
outlined in Section 8.5.5. 
•
Refer to Section 5.1 Inclusion Criteria for pregnancy testing entry criteria.
•
Pregnancy testing (urine or serum as required by local regulations) is to be conducted
every 4 weeks during intervention.
•
Pregnancy testing (urine or serum as required by local regulations) should be
conducted at the end of relevant systemic exposure and correspond with the time
frame for contraception in Section 5.1 Inclusion Criteria.
•
Additional serum or urine pregnancy tests may be performed, as determined
necessary by the Investigator or required by local regulation, to establish the absence
of pregnancy at any time during the participant’s participation in the study.
8.4.6. 
Suicidal Ideation and Behavior Risk Monitoring
No known risk of suicidal ideation associated with the use of sparsentan. If suicidal ideation 
and/or behavior risk monitoring is to occur, participant should refer to mental health services. 
8.5. 
AEs SAEs, and Other Safety Reporting 
The participant will be evaluated for new AEs and the status of existing AEs per the SoA 
(Section 1.3) and any time contact is made with the participant outside of a scheduled visit. 
The definitions of AEs and SAEs can be found in Section 10.5. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7). This 
includes events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.5. 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the ICF until the follow-up visit at the timepoints 
specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.5. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and the Investigator considers the 
event to be reasonably related to the study intervention or study participation, the Investigator 
must promptly notify the Sponsor. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
40 
8.5.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.5.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AEs of special interest (as defined in 
Section 8.5.7) will be followed until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-
up procedures is provided in Section 10.5. 
8.5.4. 
Regulatory Reporting Requirements for SAEs 
•
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that
legal obligations and ethical responsibilities towards the safety of participants and the
safety of a study intervention under clinical investigation are met.
•
The Sponsor has a legal responsibility to notify both the local regulatory authority
and other regulatory agencies about the safety of a study intervention under clinical
investigation. The Sponsor will comply with country-specific regulatory requirements
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
•
An Investigator who receives an Investigator safety report describing an SAE or other
specific safety information (eg, summary or listing of SAEs) from the Sponsor will
review and then file it along with the Investigator’s Brochure/Investigational
Directions for Use (IDFU)/package insert and will notify the IRB/IEC, if appropriate
according to local requirements.
•
Investigator safety reports must be prepared for suspected unexpected serious adverse
reactions (SUSARs) according to local regulatory requirements and Sponsor policy
and forwarded to investigators as necessary.
8.5.5. 
Pregnancy
•
Details of all pregnancies in participants will be collected after the start of study
intervention and until 90 days following the final dose of study intervention.
•
If a pregnancy is reported, the Investigator will record pregnancy information on the
appropriate form and submit it to the Sponsor within 24 hours of learning of the
participant's pregnancy.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy for medical reasons will be
reported as an AE or SAE.
•
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth,
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported
as such.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
41 
•
The participant will be followed to determine the outcome of the pregnancy. The
Investigator will collect follow-up information on the participant and the neonate, and
the information will be forwarded to the Sponsor.
•
Any poststudy pregnancy-related SAE considered reasonably related to the study
intervention by the Investigator will be reported to the Sponsor as described in
Section 8.5. While the Investigator is not obligated to actively seek this information
in former study participants, he or she may learn of an SAE through spontaneous
reporting.
•
Any participant who becomes pregnant while participating in the study will
discontinue study intervention.
Participants will be instructed to discontinue study intervention and 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 (Section 10.1.1) of this protocol 
or by fax to the number in the Investigator Site File. 
All pregnancies in participants 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 the AE using the pregnancy follow-
up form. The Investigator will inform the participant that the Sponsor or its designee is required 
to gather information regarding the course and outcome of the pregnancy after exposure to the 
study intervention. 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 participant). 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 (Section 10.1.1) 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 participant and the participant decides to continue in the study after 
permanently discontinuing study intervention, the event will be processed per routine study 
guidelines. However, if the participant 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 (Section 10.1.1) 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. 
8.5.6. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
All events, whether typically associated with the disease under study or not, will be reported 
according to the standard process for expedited reporting of AEs/SAEs. Disease-related events 
reporting is not applicable to this study.  

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
42 
8.5.7. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) (serious or nonserious) are listed below and are 
focused on liver safety. These events warrant further investigation and documentation in order to 
appropriately characterize the relationship of these events to study intervention treatment. 
•
Abnormal liver function test results that meet specific criteria (see Section 10.9) will
be considered AEOIs and must be reported to the Sponsor’s Medical Monitor within
24 hours of awareness.
If a reported AE/SAE falls under these AEOI criteria, additional information on the AE/SAE 
should be entered on the AESI form in the eCRF. 
8.6. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 
8.7. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.8. 
Genetics 
Genetics are not evaluated in this study.  
8.9. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.10. 
Health Economics 
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
43 
9.
STATISTICAL CONSIDERATIONS
The statistical analysis plan (SAP) will be finalized prior to first planned analysis, and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and secondary endpoints. 
9.1. 
Statistical Hypothesis 
There is not a pre-specified statistical hypothesis for efficacy for this study. 
9.1.1. 
Multiplicity Adjustment 
Not applicable. Multiplicity control is not relevant for the study. 
9.2. 
Analysis Sets 
Full Analysis Set (FAS):  All participants who take at least 1 dose of sparsentan will be included 
in the FAS All efficacy analyses will be based on the FAS. 
Per Protocol (PP) Analysis Set:  The PP analysis set is a subset of the FAS containing 
participants who meet study eligibility requirements and have no protocol deviations that might 
impact the assessment of efficacy measurements. The PP analysis set will be used for sensitivity 
analyses relating to efficacy. The type of protocol deviations governing exclusion from the PP 
analysis set will be determined prior to database lock and will be detailed in the SAP. 
9.3. 
Statistical Analyses 
9.3.1. 
Procedures for Handling Missing Data 
The study will have processes and procedures in place to minimize missing data and to collect 
information on participants even after discontinuing study intervention. Missing values will not 
be imputed.  
UA/C and UP/C will be determined using FMV samples and will be calculated as the average of 
2 FMV samples collected within 3 days prior to each visit. If 1 of the samples is missing, UA/C 
and UP/C from the single sample will be used. 
9.3.2. 
Definition of Endpoint(s) 
The safety endpoints include: 
•
Incidence of TEAEs, SAEs, AEs leading to treatment discontinuation, and AEOIs.
•
Changes from baseline in body weight, vital signs, physical examinations, peripheral
edema, and clinical laboratory parameters.
The primary efficacy endpoint is: 
•
The change from baseline in UA/C at Week 24.
The secondary efficacy endpoints are:  
•
Achievement of UA/C of <0.2 g/g at Week 24.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
44 
•
Achievement of 30% and 50% reduction from baseline in UA/C at Week 24.
•
Change from baseline in UA/C, UP/C, eGFR, and BP at each visit.
9.3.3. 
Main Analytical Approach
The general analytical approach for all endpoints will be descriptive in nature. Although no 
formal statistical hypothesis testing will be conducted, the change from baseline in UA/C may be 
analyzed using mixed model repeated measures (MMRM). Details description will be presented 
in the SAP as appropriate. 
For continuous variables, descriptive statistics will include means, standard deviations, medians, 
minimums, maximums, and the numbers of non-missing values. For categorical variables, 
descriptive statistics will include counts and percentages per category. Unless otherwise 
specified, endpoints will use the last non-missing observation prior to the first dose of study 
intervention as baseline. All data collected will be included in data listings. 
All efficacy analyses will be done descriptively on the FAS as well as PP analysis set in 
observed case. Change from baseline will be summarized with mean and 95% confidence 
interval (CI) as appropriate. For categorical efficacy endpoints, the proportion of participants in 
the category will be presented along with corresponding 95% CI. 
All safety analyses will be based on the FAS. Descriptive statistics will be presented. TEAE will 
be summarized by system organ class and preferred terms, by severity, and by relationship to 
study intervention. Changes from baseline in body weight, vital signs, physical examinations, 
peripheral edema, and clinical laboratory parameters will be summarized and/or listed. In 
addition, shifts in laboratory parameters and peripheral edema will be summarized. 
9.4. 
Interim Analysis 
An interim analysis will be performed 24 weeks after approximately 20 participants have been 
enrolled to evaluate the safety and efficacy endpoints. 
9.5. 
Sample Size Determination 
To investigate the safety and effect of sparsentan in participants with IgAN on chronic stable 
treatment with an SGLT2 inhibitor, approximately 60 participants will be enrolled in the study. 
The sample size of the study is determined empirically without formal statistical assumptions. A 
sample size of 60 is sufficient to detect at least one adverse event with probability 95%, 
assuming an expected adverse event incidence of 5% using the binomial distribution. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
45 
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Study Contact Information 
Medical Monitor 
(Travere Therapeutics): 
MD 
 Nephrology 
Clinical Development 
Travere Therapeutics, Inc. 
3611 Valley Centre Drive, Suite 300 
San Diego, CA, 92130, USA 
CRO Medical Monitor 
(George Clinical): 
George Clinical
Building 12, Suite 200 
10975 Benson Dr 
Overland Park, KS 66210 USA 
Phone: See Investigator Site File 
Email See Investigator Site File 
Serious Adverse Event 
Reporting: 
Qinecsa Solutions 
Email: clinicalsafety.travere@quinecsa.com 
Fax: 
See Investigator Site File 
Product Handling/Complaints: 
Travere Therapeutics, Inc. 
Tel:  +1-888-211-5014 
InvestigationalProductComplaints@travere.com 
10.1.2. 
Regulatory and Ethical Considerations 
•
This study will be conducted in accordance with the protocol and with the following:
−
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and Council for International Organizations of Medical
Sciences (CIOMS) international ethical guidelines.
−
Applicable International Council for Harmonisation (ICH) Good Clinical Practice
(GCP) guidelines.
−
Applicable laws and regulations.
•
The protocol, protocol amendments, ICF, IB, IDFU, and other relevant documents
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and
reviewed and approved by the IRB/IEC before the study is initiated.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
46 
•
Any amendments to the protocol will require IRB/IEC approval before
implementation of changes made to the study design, except for changes necessary to
eliminate an immediate hazard to study participants.
•
Protocols and any substantial amendments to the protocol will require health
authority approval prior to initiation except for changes necessary to eliminate an
immediate hazard to study participants.
•
The Investigator will be responsible for the following, as applicable:
−
Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC.
−
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures.
−
Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the
IRB/IEC, European regulation 536/2014 for clinical studies, European Medical
Device Regulation 2017/745 for clinical device research, and all other applicable
local regulations.
10.1.3. 
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.4. 
Informed Consent Process 
•
The Investigator or the Investigator’s representative will explain the nature of the
study, including the risks and benefits, to the potential participant and answer all
questions regarding the study.
•
Potential participants must be informed that their participation is voluntary. All
potential participants will be required to sign a statement of informed consent that
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and
data protection requirements, where applicable, and the IRB/IEC or study center.
•
The medical record must include a statement that written informed consent was
obtained before the participant was enrolled in the study and the date the written
consent was obtained. The authorized person obtaining the informed consent must
also sign the ICF.
•
Participants must be reconsented to the most current version of the ICF(s) during their
participation in the study.
•
A copy of the ICF(s) must be provided to the participant.
•
Participants who are rescreened are required to sign a new ICF.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
47 
10.1.5. 
Recruitment Strategy 
Potential patients will be identified using various methods which will include some or all of the 
following: site database and medical record review, site referral networks, patient advocacy 
groups and social media/traditional advertisements. Patient privacy will be always maintained, 
with no identifying information, such as the patient's name, used in communications with the 
Sponsor or Sponsor representative(s). Recruitment of patients will be from diverse backgrounds. 
10.1.6. 
Data Protection 
•
Participants will be assigned a unique identifier by the Sponsor. Any participant
records or datasets that are transferred to the Sponsor will contain the identifier only;
participant names or any information which would make the participant identifiable
will not be transferred.
•
The participant must be informed that their personal study-related data will be used
by the Sponsor in accordance with local data protection law. The level of disclosure
must also be explained to the participant who will be required to give consent for
their data to be used as described in the informed consent.
•
The participant must be informed that their medical records may be examined by
Clinical Quality Assurance auditors or other authorized personnel appointed by the
Sponsor, and by inspectors from regulatory authorities.
•
The contract between Sponsor and study sites specifies responsibilities of the parties
related data protection, including handling of data security breaches and respective
communication and cooperation of the parties.
•
Information technology systems used to collect, process, and store study-related data
are secured by technical and organizational security measures designed to protect
such data against accidental or unlawful loss, alteration, or unauthorized disclosure or
access.
10.1.7. 
Dissemination of Clinical Study Data 
Sponsor fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and other public 
registries in accordance with applicable local laws/regulations. In all cases, study results are 
reported by Sponsor in an objective, accurate, balanced, and complete manner and are reported 
regardless of the outcome of the study or the country in which the study was conducted. Clinical 
trial results are posted on www.clinicaltrials.gov for Sponsor-sponsored interventional studies 
(conducted in patients) that evaluate the safety and/or efficacy of a product, regardless of the 
geographical location in which the study is conducted. These results are submitted for posting in 
accordance with the format and timelines set forth by United States (US) law. Clinical trial 
results are posted on EudraCT for Sponsor-sponsored interventional studies with at least 1 site in 
the European Union (EU), in accordance with the format and timelines set forth by EU 
requirements. 
In addition, results from clinical trials may be submitted to peer-reviewed journals, scientific 
congresses, and corporate communications following internal company review for accuracy, fair 
balance and intellectual property. Travere is committed to data transparency and sharing data 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
48 
collected in completed and published clinical trials (Phase 3 and some Phase 2), observational 
trials, and post-marketing studies to further research while ensuring that patient privacy is 
protected. Pertinent individual patient-level data that underlie the results reported in a manuscript 
may be made available after deidentification. Relevant information may include redacted study 
protocol and redacted clinical study report. 
Requests for clinical trial data, including language stating its intended use, should be directed to 
datarequest@travere.com. If approved, the requested information will be provided to the 
requestor after signing a data access agreement. Requests can be made following completion of 
the study and full publication of the study data in a peer-reviewed journal for up to 36 months 
following its publication. Travere reserves the right to decline or recommend modifications to a 
request if it does not comply with the data sharing policy or if it is determined that the request is 
made by a biased source. 
10.1.8. 
Data Quality Assurance 
•
All participant data relating to the study will be recorded on printed or eCRFs unless
transmitted to the Sponsor or designee electronically (eg, laboratory data). The
Investigator is responsible for verifying that data entries are accurate and correct by
physically or electronically signing the case report form (CRF).
•
Guidance on completion of CRFs will be provided by the Sponsor.
•
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source documents.
•
Monitoring details describing strategy, including definition of study critical data
items and processes (eg, risk-based initiatives in operations and quality such as risk
management and mitigation strategies and analytical risk-based monitoring),
methods, responsibilities, and requirements, including handling of noncompliance
issues and monitoring techniques (central, remote, or on-site monitoring) are provided
by the Sponsor.
•
The Sponsor or designee is responsible for the data management of this study,
including quality checking of the data.
•
The Sponsor assumes accountability for actions delegated to other individuals (eg,
contract research organizations).
•
Records and documents, including signed ICFs, pertaining to the conduct of this
study must be retained by the Investigator for at least 2 years after study completion.
No records may be destroyed during the retention period without the written approval
of the Sponsor. No records may be transferred to another location or party without
written notification to the Sponsor.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
49 
10.1.9. 
Source Documents 
•
Source documents provide evidence for the existence of the participant and
substantiate the integrity of the data collected. Source documents are filed at the
Investigator’s site.
•
Data reported on the CRF or entered in the eCRF that are transcribed from source
documents must be consistent with the source documents or the discrepancies must be
explained. The Investigator may need to request previous medical records or transfer
records, depending on the study. Also, current medical records must be available.
•
The Investigator must maintain accurate documentation (source data) that supports
the information entered in the CRF.
•
The Sponsor or designee will perform monitoring to confirm that data entered into the
CRF by authorized site personnel are accurate, complete, and verifiable from source
documents; that the safety and rights of participants are being protected; and that the
study is being conducted in accordance with the currently approved protocol and any
other study agreements, ICH GCP, and all applicable regulatory requirements.
10.1.10. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 
•
Discontinuation of further study intervention development.
For site termination: 
•
Failure of the Investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines.
•
Inadequate or no recruitment (evaluated after a reasonable amount of time) of
participants by the Investigator.
•
Total number of participants included earlier than expected.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
50 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should 
assure appropriate participant therapy and/or follow-up. 
10.1.11. 
Publication Policy 
•
The Investigator agrees to the unrestricted use of results of the study for the purposes
of national and international registration, publication, and information for medical
and pharmaceutical professionals by the Sponsor. If required, the authorities will be
notified of the Investigator's name, address, qualifications, and extent of involvement.
•
Authorship will be determined by mutual agreement and in line with International
Committee of Medical Journal Editors authorship requirements.
•
For more details about the publication policy, the contract agreement between
Sponsor and Investigator should be consulted.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
51 
10.2. 
Appendix 2: Minimum ACEI/ARB Daily Dose Requirements at 
Screening 
Inclusion Criteria 6 requires that patients have been on a stable, MTD of ACEI and/or ARB 
therapy for at least 12 weeks prior to signing of the informed consent. The criterion also requires 
the MTD to be at least one half the MLD. The application of inclusion criterion 7 is intended to 
ensure that only patients with the potential to tolerate the minimum doses of study intervention, 
in terms of anti-hypertensive effect, are enrolled in the study. 
The table below shows the minimum daily doses for the most common ACEI or ARBs to guide 
eligibility screening. Values in the table represent 50% of the MLD of these drugs in most 
participating countries (in some countries [eg, the US], MLDs may be higher than in other 
countries). These values are considered approximately equivalent to the minimum daily dose of 
the active comparator for the treatment phase of the study (ie, irbesartan 150 mg/day). 
If a patient is on a combination of an ACEI and an ARB, the sum of the individual doses (as a 
percentage of the MLD on the table) should be at least 50% (eg, 2.5 mg/day Ramipril [25%] + 
25 mg losartan [25%] = 50% in total). 
For patients taking an ACEI and/or ARB not presented in the table, the Investigator is advised to 
contact the Medical Monitor to discuss patient eligibility. 
ACEI 
Minimum Daily Dose at 
Screening 
ARB 
Minimum Daily 
Dose at Screening 
Benazepril 
20 mg 
Candesartan 
16 mg 
Captopril 
75 mg 
Eprosartan 
300 mg 
Enalapril 
20 mg 
Irbesartan 
150 mg 
Fosinopril 
20 mg 
Losartan 
50 mg 
Moexipril 
15 mg 
Valsartan 
160 mg 
Perindopril 
4 mg 
Telmisartan 
40 mg 
Quinapril 
20 mg 
Olmesartan 
20 mg 
Ramipril 
5 mg 
Azilsartan 
40 mg 
Trandolapril 
2 mg 
Lisinopril 
20 mg 
Zofenopril 
30 mg 
Cilazapril 
5 mg 
Delapril 
60 mg 
Imidapril 
10 mg 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
52 
10.3. 
Appendix 3: Clinical Laboratory Tests 
Samples for the tests detailed below (Table 4) will be collected per the timelines provided in 
the SoA (Section 1.3). 
The tests detailed in Table 4 will be performed by a Central Laboratory. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Investigators must document their review of each laboratory safety report. 
Table 4: 
Clinical Safety Laboratory Tests and Quantitative Urinalysis 
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 (percentage 
and absolute) 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Screening Tests 
Plasma follicle stimulating 
hormone level (to confirm 
menopausal status) 
Quantitative 
Urinalysis 
(FMV samples) 
Albumin Excretion 
Protein Excretion 
Urea 
Creatinine 
Routine Urinalysis 
Color 
Appearance 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Urobilinogen 
Leukocyte esterase 
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
eGFR = estimated glomerular filtration rate; FMV = first morning void; GGT = gamma glutamyltransferase; 
HDL = high-density lipoprotein; 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. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
53 
10.4. 
Appendix 4: 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 – 4 mm somewhat deeper pitting, disappears in 10 – 15 seconds (Mild) 
3+ 
4 – 6 mm noticeably deep pit, lasts 1 to 2 minutes (Moderate) 
4+ 
6 – 8 mm:  very deep pit, lasts 2 to 5 minutes (Severe) 
Adapted from the Guelph General Hospital CHF Pathway 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
54 
10.5. 
Appendix 5: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.5.1. 
Definition of AE 
AE Definition 
•
An AE is any untoward medical occurrence in a clinical study participant, temporally
associated with the use of study intervention, whether or not considered related to the
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.
Definition of Unsolicited and Solicited AE 
•
An unsolicited AE is an AE that was not solicited using a participant diary and that is
communicated by a participant who has signed the informed consent. Unsolicited
AEs include serious and nonserious AEs.
•
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses
requiring a hospitalization, emergency room visit, or visit to/by a healthcare
provider). The participants will be instructed to contact the site as soon as possible to
report medically attended event(s), as well as any events that, though not medically
attended, are of participant concern. Detailed information about reported unsolicited
AEs will be collected by qualified site personnel and documented in the participant’s
records.
•
Unsolicited AEs that are not medically attended nor perceived as a concern by the
participant will be collected during an interview with the participants and by review
of available medical records at the next visit.
•
Solicited AEs are predefined local and systemic events for which the participant is
specifically questioned, and which are noted by the participant in their diary.
Events Meeting the AE Definition 
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or
other safety assessments (eg, electrocardiogram (ECG), radiological scans, vital signs
measurements), including those that worsen from baseline, considered clinically
significant in the medical and scientific judgment of the Investigator (ie, not related to
progression of underlying disease, or more severe than expected for the participant’s
condition).
•
Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.
•
New condition detected or diagnosed after study intervention administration even
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
55 
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as an
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming
intent. Such overdoses should be reported regardless of sequelae.
•
Lack of efficacy or failure of expected pharmacological action per se will not be
reported as an AE or SAE. Such instances will be captured in the efficacy
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE
or SAE.
Events not Meeting the AE Definition 
•
Any abnormal laboratory findings or other abnormal safety assessments that are
associated with the underlying disease, unless judged by the Investigator to be more
severe than expected for the participant’s condition.
•
The disease/disorder being studied or expected progression, signs, or symptoms of the
disease/disorder being studied, unless more severe than expected for the participant’s
condition.
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present
or detected at the start of the study that do not worsen.
10.5.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of 
the criteria listed: 
a.
Results in death
b. Is life threatening
The term life threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
In general, hospitalization signifies that the participant has been admitted (usually
involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the physician’s
office or outpatient setting. Complications that occur during hospitalization are AEs.
If a complication prolongs hospitalization or fulfills any other serious criteria, the
event is serious. When in doubt as to whether hospitalization occurred or was
necessary, the AE should be considered serious.
•
Hospitalization for elective treatment or a pre-existing condition that did not worsen
from baseline are not considered an SAE.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
56 
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) that may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
•
Medical or scientific judgment should be exercised by the Investigator in deciding
whether SAE reporting is appropriate in other situations such as important medical
events that that may not be immediately life threatening or result in death or
hospitalization but may jeopardize the participant or may require medical or surgical
intervention to prevent one of the other outcomes listed in the above definition. These
events should usually be considered serious.
−
Examples of such events include invasive or malignant cancers, intensive
treatment in an emergency room or at home for allergic bronchospasm, blood
dyscrasias, convulsions not resulting in hospitalization, or development of
intervention dependency or intervention abuse.
10.5.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
•
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics
reports) related to the event.
•
The Investigator will then record all relevant AE/SAE information.
•
The Investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:  
•
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

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
57 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
•
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects
clinical status, or may require intensive therapeutic intervention.
Assessment of Causality 
•
The Investigator is obligated to assess the relationship between study intervention and
each occurrence of each AE/SAE. The Investigator will use clinical judgment to
determine the relationship.
•
A reasonable possibility of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot be
ruled out.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk
factors, as well as the temporal relationship of the event to study intervention
administration, will be considered and investigated.
•
For causality assessment, the Investigator will also consult the IB and/or product
information, for marketed products.
•
The Investigator must review and provide an assessment of causality for each
AE/SAE and document this in the medical notes There may be situations in which an
SAE has occurred, and the Investigator has minimal information to include in the
initial report to SAE contact. However, it is very important that the Investigator
always make an assessment of causality for every event before the initial transmission
of the SAE data to SAE contact.
•
The Investigator may change their opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory
reporting requirements.
Follow-up of AEs and SAEs 
•
The Investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by SAE
contact to elucidate the nature and/or causality of the AE or SAE as fully as possible.
This may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other health care professionals.
•
If a participant dies during participation in the study or during a recognized follow-up
period, the Investigator will provide SAE contact with a copy of any postmortem
findings including histopathology.
•
New or updated information will be recorded in the originally submitted documents.
•
The Investigator will submit any updated SAE data to SAE contact within 24 hours of
receipt of the information.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
58 
10.5.4. 
Reporting of SAEs 
SAE Reporting to SAE Contact Via an Electronic Data Collection Tool 
•
If the electronic system is unavailable, then the site will use the paper SAE data
collection tool (see next Section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as it becomes
available.
•
After the study is completed at a given site, the electronic data collection tool will be
taken offline to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated
data on a previously reported SAE after the electronic data collection tool has been
taken offline, then the site can report this information on a paper SAE form (see next
Section) or to the SAE contact by telephone.
•
Contacts for SAE reporting will be provided by the Sponsor.
SAE Reporting to SAE Contact Via Paper Data Collection Tool 
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 (Section 10.1.1) of this protocol or by fax to the number in the 
Investigator Site File without undue delay but not later than 24 hours after obtaining 
knowledge of the events, regardless of causal relationship.
•
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) will be provided by email to the SAE contact on the Study 
Contact Information page (Section 10.1.1) or by fax to the number in the Investigator 
Site File.
•
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 (Section 10.1.1) 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 subject/hospital 
records, discharge summaries, laboratory/test results, or autopsy reports.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. Initial notification via telephone does not replace the need for 
the Investigator to complete and sign the SAE data collection tool within the 
designated reporting timeframes.
•
If at any time after the subject has completed participation in the study, the 
Investigator or study staff becomes aware of an SAE that they suspect is related to the 
study medication, the event and any known details will be reported promptly by email

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
59 
to the SAE contact on the Study Contact Information page (Section 10.1.1) or by fax 
to the number in the Investigator Site File, following the reporting instructions in this 
section. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
60 
10.6. 
Appendix 6: Concomitant Medication Considerations 
A. While Taking Study Intervention (Starting from Day 1 to Week 24)
1. Prohibited Medications While Taking Study Intervention (Starting from Day 1 to Week
24)
•
Inhibitors of the RAAS.
−
Examples include (not all inclusive) the following: ACEIs, aldosterone blockers,
ARBs, ERAs and aliskiren.
•
Inhibitors of the endothelin system (eg, 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 Cytochrome P450 3A (CYP3A) inhibitors. For a detailed list of these
medications, see the P450 Drug Interaction table at:
http://medicine.iupui.edu/clinpharm/ddis/maintable.
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 intervention 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
participant case individually and use clinical judgment.
−
Sulfamethoxazole/trimethoprim (eg, Bactrim™ and Septra®), cimetidine,
pyrimethamine, cetirizine, cobicistat, probenecid, vandetanib, dolutegravir,
ranolazine, dronedarone, ritonavir, and telaprevir cannot be used within at least
7 days prior to any visit at which eGFR is assessed.
−
Fibrates.
2. Medications to be Used with Caution While Taking Study Intervention (Starting from
Day 1 to Week 24)
It is recommended that high dose systemic corticosteroid (defined as >10 mg/day prednisone 
or equivalent) and/or systemic immunosuppressive therapy for the treatment of IgAN be 
avoided for the duration of participation in the study. If, in the Investigator’s opinion, high 
dose systemic corticosteroid and/or systemic immunosuppressive therapy is warranted, such 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
61 
intervention may be provided in addition to study intervention at the discretion of the 
Investigator. Consultation with the Medical Monitor is recommended before starting 
interventional therapy, when possible. 
Similarly, it is recommended to avoid the introduction or change dose of patients receiving 
low dose systemic corticosteroids (defined as ≤10 mg/day prednisone or equivalent), enteric 
budesonide and/or mineralocorticoid receptor antagonists (eg. spironolactone, eplerenone, 
finerenone) for the duration of the study, unless, in the Investigator’s opinion, such 
introduction is warranted, and may be provided in addition to study intervention. Appropriate 
potassium monitoring should be conducted for patients receiving mineralocorticoid receptor 
antagonists. 
Consultation with the Medical Monitor is recommended before changing/starting 
interventional therapy, when possible.   
The medications in the categories below should be avoided or used with caution while taking 
study intervention.  
•
Strong P-glycoprotein (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
intervention 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 6.6.
−
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 intervention.
−
Examples relevant to the study population include (not all inclusive) the
following: bupropion, cyclophosphamide, ketamine, meperidine, and methadone.
•
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.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
62 
•
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.
−
International normalized ratio (INR) monitoring is recommended if warfarin is
used concomitantly with study intervention.
3. Additional Information
Additional medications potentially interacting with sparsentan (CYP3A inhibitors, P gp 
inhibitors, and CYP 2B6 substrates) can be found at: 
http://medicine.iupui.edu/clinpharm/ddis/main table/ 
B. Prohibited Medications Following Discontinuation of Study Intervention
(ie, Non-Treatment Period from Week 24 to Week 28)
•
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.
•
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™ and Septra®), cimetidine,
pyrimethamine, cetirizine, cobicistat, probenecid, vandetanib, dolutegravir,
ranolazine, dronedarone, ritonavir, and telaprevir cannot be used within at least
7◦days prior to any visit at which eGFR is assessed.
−
Fibrates.
C. Participants Who Have Permanently Discontinued Study Intervention Prior to Safety
Follow-Up Visit
•
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™ and Septra®), cimetidine,
pyrimethamine, cetirizine, cobicistat, probenecid, vandetanib, dolutegravir,
ranolazine, dronedarone, ritonavir, and telaprevir cannot be used within at least
7 days prior to any visit at which eGFR is assessed.
−
Fibrates.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
63 
10.7. 
Appendix 7: Contraceptive and Barrier Guidance 
10.7.1. 
Definitions 
Participants in the following categories are considered participants who can become pregnant: 
1. Following menarche
2. From the time of menarche until becoming postmenopausal unless permanently sterile
(see below)
•
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause.
•
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be
used to confirm a postmenopausal state in participants not using hormonal
contraception or hormonal replacement therapy (HRT). However, in the absence of
12 months of amenorrhea, confirmation with more than one FSH measurement is
required.
•
Participants on HRT and whose menopausal status is in doubt will be required to use
one of the non-estrogen hormonal highly effective contraception methods if they wish
to continue their HRT during the study. Otherwise, they must discontinue HRT to
allow confirmation of postmenopausal status before study enrollment.
•
Permanent sterilization methods (for the purpose of this study) include:
•
Documented hysterectomy.
•
Documented bilateral salpingectomy.
•
Documented bilateral oophorectomy.
•
For individuals with permanent infertility due to an alternate medical cause other than
the above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis),
Investigator discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
•
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle
cannot be confirmed before first dose of study intervention, additional evaluation
should be considered.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
64 
10.7.2. 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when 
used consistently and correctly. 
•
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc.
•
IUD.
•
Intrauterine hormone-releasing system (IUS)c.
•
Bilateral tubal occlusion.
•
Azoospermic partner (vasectomized or due to a to medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of
the participant who can become pregnant, and the absence of sperm has been confirmed. If not, an
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately
90 days.
Note: documentation of azoospermia can come from the site personnel’s review of the participant’s medical
records, medical examination, or medical history interview.
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently 
and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
1. oral
2. intravaginal
3. transdermal
4. injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc 
5. oral
6. injectable
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant 
a) Contraceptive use should be consistent with local regulations regarding the use of contraceptive methods for
those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those
when used consistently and correctly.
c) If hormonal contraception is used, one additional barrier method must also be used during sexual activity,
such as a diaphragm or diaphragm with spermicide (preferred), or male condom or male condom with
spermicide (preferred), from Day 1/Randomization until 30 days after the last dose of study intervention.
Hormonal implants do not require an additional barrier method to be used. If locally required, in accordance
with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to
those which inhibit ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction). 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
65 
10.8. 
Appendix 8: 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 of >5.5 mEq/L (5.5 mmol/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, rule out measurement errors or
likely reasons for the increase (eg, sample hemolysis, metabolic acidosis, discontinuation
of diuretic by the patient/lack of compliance, diet transgression).
a.
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 BP 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 BP, eGFR, sodium, and potassium within
1 week after starting the diuretic.
b. 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
BP permit). Assess the patient’s tolerability and measure their BP, eGFR, sodium,
and potassium within 1 week after increasing the dose. Consider correction of
metabolic acidosis, if relevant.
3. In both scenario 2a and 2b, adjust the dose of diuretic accordingly after 1 week. If the
patient’s serum potassium value is still >5.5 mEq/L (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 mEq/L (5.5 mmol/L), reduce the dose of study intervention by 50%. For long-
term prevention of hyperkalemia, consider treatment with patiromer or sodium zirconium
cyclosilicate.
4. If hyperkalemia persists or recurs, study intervention must be discontinued permanently.

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
66 
10.9. 
Appendix 9: Liver Safety: Suggested Actions and Follow-up 
Assessments and Study Intervention Rechallenge Guidelines 
Abnormal liver function test results that meet at least one of the following criteria below will be 
considered AEOIs and must be reported to the Sponsor’s Medical Monitor within 24 hours of 
awareness: 
•
The abnormality represents a new elevation in ALT or AST >3 times ULN, with or
without an elevation of total serum bilirubin >2 times ULN.
•
The abnormality represents a 2-fold increase in ALT or AST above the baseline value
for the study period (ie, Day 1) in participants who had elevated values prior to
starting study intervention.
In such instances, the following steps should be taken: 
1. Temporarily discontinue study intervention.
2. Perform repeat testing of ALT, AST, liver specific alkaline phosphatase (ALP), and total
bilirubin within 48 to 72 hours to confirm the abnormalities.
3. If the abnormality is confirmed by repeat results, the following should be done:
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
SAE Contact Information page (Section 10.1.1) of this protocol.
b. Monitor liver enzymes and serum bilirubin 2 or 3 times weekly. The frequency of
retesting can decrease to once weekly or less if the abnormalities stabilize and the
participant is asymptomatic.
c.
Perform additional testing to evaluate liver function, as appropriate (eg, INR and
direct bilirubin).
4. Do not resume study intervention until monitoring indicates abnormalities have resolved
or stabilized.
Participants are not allowed to resume study intervention if they have the following: 
•
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 of >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).
Management of such participants 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; 
nonalcoholic steatohepatitis; biliary tract disease or exposure to hepatotoxic medications or 
environmental chemical agents). Additionally, participants who demonstrate elevated liver 
enzymes a second time after re introduction of the study intervention may continue in the clinical 
study; however, they will not receive study intervention for the remainder of the trial. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
67 
Cases of increased liver function tests will always be considered serious (ie, medically 
important) if they meet both the following criteria: 
•
Study intervention is suspected to have caused hepatocellular injury, generally shown
by a confirmed elevation of 3-fold or greater above ULN in ALT or AST.
•
The ALT or AST elevations are accompanied by a total bilirubin >2 times the ULN
or INR of >1.5 without initial findings of cholestasis (elevated serum liver specific
ALP).

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
68 
11.
REFERENCES
Aucella F, Netti GS, Piemontese M, Cincione IR, Infante B, Gesualdo L. Proteinuria in the 
prognosis of IgA nephropathy. Minerva Urol Nefrol 2009 Sep;61(3):235-48. 
Baigent C, Emberson J, Haynes R, Herrington W, Judge P, Landray M, et al. Impact of diabetes 
on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative 
meta-analysis of large placebo-controlled trials. Lancet 2022; 400:1788-801. 
Berthoux F, Mohey H, Laurent B, Mariat C, Afiani A, Thibaudin L. Predicting the risk for 
dialysis or death in IgA nephropathy. J Am Soc Nephrol 2011 Apr;22(4):752-61. 
Choy BY, Chan TM, Lai KN. Recurrent glomerulonephritis after kidney transplantation. Am J 
Transplant 2006 Nov;6(11):2535-42. 
Coppo R, Peruzzi L, Amore A, Piccoli A, Cochat P, Stone R, et al. IgACE: a placebo-controlled, 
randomized trial of angiotensin-converting enzyme inhibitors in children and young people with 
IgA nephropathy and moderate proteinuria. J Am Soc Nephrol 2007;18:1880-8. 
Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002b Sep 5;347(10):738-48. 
Floege J, Eitner F. Current therapy for IgA nephropathy. J Am Soc Nephrol 2011;22:1785-94. 
Galla JH. IgA nephropathy. Kidney Int 1995 Feb;47(2):377-87. 
Geddes CC, Rauta V, Gronhagen-Riska C, Bartosic LP, Jardine AG, Ibels LS, et al. A 
tricontinental view of IgA nephropathy. Nephrol Dial Transplant 2003 Aug;18(8):1541-8. 
Hall YN, Fuentes EF, Chertow GM, Olson JL. Race/ethnicity and disease severity in IgA 
nephropathy. BMC Nephrol 2004 Sep2;5:10. 
Heerspink H, Stefansson B, Correa-Rotter R, Chertow G, Greene T, Hou F, et al. Dapagliflozin 
in Patients with Chronic Kidney Disease. N Engl J Med 2020 Oct;383(15):1436-46.  
Herrington W, Staplin N, Wanner C, Green J, Hauske S, Emberson J, et al. Empagliflozin in 
Patients With Chronic Kidney Disease. N Engl J Med 2022 Nov.  
Inker L, Heerspink H, Tighiouart H, Chaudhari J, Miao S, Diva U, et al. Association of 
Treatment Effects on Early Changes in Urine Protein and Treatment Effects on GFR Slope in 
IgA Nephropathy: An Individual Participant Meta-analysis. Am J Kidney Dis 2021 
Mar;78(3):340-9. 
Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New Creatinine-and 
Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med 2021 
Nov;385(19):1737.  
Inker LA, Mondal H, Greene T, Masachi T, Locatelli F, Schena FP, et al. Early change in urine 
protein as a surrogate end point in studies of IgA nephropathy; an individual-patient 
meta-analysis. Am J Kidney Dis 2016;68(3):392-401. 
Knoppova B, Reily C, Maillard N, Rizk DV, Moldoveanu Z, Mestercky J, et al. The origin and 
activities of IgA1-containing immune complexes in IgA nephropathy. Front Immunol 
2016 Apr 12;7:117. 
KDIGO (2021). “Chapter 2: Immunoglobulin A nephropathy (IgAN)/immunoglobulin A 
vasculitis (IgAV).” Kidney Int Suppl (2021):100(4S):115-27. 

Travere Therapeutics, Inc.  
sparsentan (RE-021) 
TVTX-RE021-204 (SPARTACUS) Original Protocol 
Confidential and Proprietary 
69 
Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C, et al. Long-term renal survival and related risk 
factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult 
population. Nephrology Dialysis Transplantation 2011 Sep;27(4):1479-85.  
Locatelli F, Pozzi C, Andrulli S. IgA nephritis: ACE inhibitors, steroids, both, or neither? 
Nephrol Dial Transplant 2006;21:3357-61. 
Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, et al. For the ASCEND 
Study Group. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol 2010 
Mar;21(3):527-35. 
Manno C, Strippoli GF, D’Altri C, Torres D, Rossini M, Schena FP. A novel simpler histological 
classification for renal survival in IgA nephropathy: a retrospective study. Am J Kidney Dis 
2007 Jun;49(6):763-75. 
Moriyama T, Tanaka K, Iwasaki C, Oshima Y, Ochi A, Kataoka H, et al. Prognosis in IgA 
nephropathy: 30-year analysis of 1,012 patients at a single center in Japan. PloS One 
2014 Mar 21;9(3):e91756. 
Praga M, Gutiérrez E, González E, Morales E, Hernández E. Treatment of IgA nephropathy with 
ACE inhibitors: a randomized and controlled trial. J Am Soc Nephrol 2003;14:1578-83. 
Reich H, Troyanov S, Scholey J, Cattran D. Remission of proteinuria improves prognosis in IgA 
nephropathy. Toronto Glomerulonephritis Registry 2007 Dec;18(12):3177-83.  
Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: 
outcomes and response to treatment in a prospective cohort of 352 patients with different 
patterns of renal injury. Am J Kidney Dis 2000 Jun;35(6):1155-65. 
Thompson A, Carroll K, Inker L, Floege J, Perkovic V, Boyer-Suavet S, et al. Proteinuria 
Reduction as a Surrogate End Point in Trials of IgA Nephropathy. Clin J Am Soc Nephrol. 2019 
Mar;14(3):469-81.  
Topham PS, Harper SJ, Furness PN, Harris KP, Walls J, Feehally J. Glomerular disease as a 
cause of isolated microscopic haematuria. Q J Med 1994 Jun;87(6):329-35. 
Wheeler D, Toto R, Stefansson B, Jongs N, Chertow G, Greene T, et al. A pre-specified analysis 
of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney 
events in patients with IgA nephropathy. Kidney Int Suppl (2021):100: 215-24. 

Signature Page for VV-CLIN-008052 v1.0
Signature Page for VV-CLIN-008052 v1.0
Approval
Clinical
16-Feb-2023 22:56:40 GMT+0000
Approval
Pharmacovigilance
16-Feb-2023 23:24:56 GMT+0000
Approval
Medical
16-Feb-2023 23:48:07 GMT+0000
Approval
Regulatory
16-Feb-2023 23:59:49 GMT+0000
Approval
Biostatistics
21-Feb-2023 19:19:14 GMT+0000
Approval
Medical
21-Feb-2023 19:38:16 GMT+0000