Clinical trial NCT03749447
Conditions: Chronic Kidney Diseases Alport Syndrome Autosomal Dominant Polycystic Kidney
Keywords: Bardoxolone methyl CDDO-ME RTA 402 Alport Syndrome Autosomal Dominant Polycystic Kidney ADPKD
Sponsor: Biogen
Start date: 2019-03-08; Completion date: 2023-08-23
Enrollment: 270 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in qualified patients with chronic kidney disease (CKD) who previously participated in one of the qualifying clinical studies with bardoxolone methyl. Patients will remain in the study until bardoxolone methyl is available through commercial channels or until patient withdrawal, whichever is sooner.

Detailed description:

Arms: arm 1: Adult participants received bardoxolone methyl capsules, once daily (QD) at a starting dose of 5 milligrams (mg), followed by dose- escalation to 10 mg at Week 2 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility UACR \>300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study.

Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR \>300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.
Interventions: intervention 1: Bardoxolone methyl
Intervention descriptions: intervention 1: Bardoxolone methyl capsules

Protocol documents:
Prot_000.pdf: 
COVER PAGE 
 
Official Title: An Extended Access Program to Assess Long Term Safety of 
Bardoxolone Methyl in Patients With Chronic Kidney Disease (EAGLE) 
NCT Number: NCT03749447 
Document Date: 09 Nov 2022 
 


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RTA 402 
402-C-1803 
 
NCT NUMBER: 03729447 
EUDRACT NUMBER: 2018-003253-24 
 
AN EXTENDED ACCESS PROGRAM TO ASSESS LONG 
TERM SAFETY OF BARDOXOLONE METHYL IN 
PATIENTS WITH CHRONIC KIDNEY DISEASE 
(EAGLE) 
 
VERSION 4.0 - 09 NOVEMBER 2022 
Protocol History 
Version 4.1 Japan – 09 Nov 2022 
Version 3.1 Japan – 16 Sep 2021 
Version 3.0 – 30 Jun 2020 
Version 2.0 – 31 Jan 2019 
Version 1.0 – 04 Sep 2018 
The information contained herein is confidential and the proprietary property of Reata 
Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information without the prior 
written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 




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INVESTIGATOR’S AGREEMENT 
 
I have read the 402-C-1803 clinical study protocol and agree to conduct the study as outlined.  I 
have received and read the Investigator’s Brochure for bardoxolone methyl.  I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Medical and Scientific 
Leader 
, MD, MPH, MBA 
, 
 
Reata Pharmaceuticals, Inc. 
 
 
Office: 
 
Medical Monitor 
Medical Monitor Team 
Reata Pharmaceuticals, Inc. 
 
 
Office: 
 
Email: 
 
SAE Reporting 
 Facsimile:
 
E-mail: 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Product: 
Bardoxolone methyl 
Title of Study:  
An Extended Access Program to Assess Long Term Safety of Bardoxolone Methyl in Patients with 
Chronic Kidney Disease 
Study center(s): Approximately 230 study centers 
Studied period: Until commercial availability of 
bardoxolone methyl for each indication and region. 
Actual date first patient first visit: March 2019 
Estimated date last patient completed: Patient will 
remain in the study until bardoxolone methyl is 
available through commercial channels or until patient 
withdrawal, whichever is sooner 
The end of the study is defined as the last visit of the 
last patient. 
Phase of development:  
3a 
Primary Objectives:  To provide continuing open-label treatment with bardoxolone methyl as part of 
this extended access program while collecting ongoing safety and tolerability data of bardoxolone 
methyl.   
Safety Endpoints: Frequency, intensity, and relationship to study drug of adverse events (AEs) and 
serious adverse events (SAEs) and change from baseline in the following assessments: physical 
examinations, vital sign measurements, weight, urine albumin to creatinine ratio (ACR), and laboratory 
results. 
Methodology:  
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in 
qualified patients with chronic kidney disease (CKD) who previously participated in a qualifying, 
clinical study with bardoxolone methyl.  The CARDINAL study (402-C-1603, NCT03019185, 
EudraCT 2016-004395-22) and FALCON study (402-C-1808, NCT03918447, EudraCT 2018-004651-
20) are the only qualifying clinical studies at this time. 
The Day 1 visit of EAGLE is not required to be the same day as the End of Study visit of the prior 
qualifying study.  Lab assessments from the qualifying study will be used for EAGLE eligibility and 
maximum treatment dose assignment (Week 100 for CARDINAL or FALCON protocol versions 1 
through 5, and Week 108 [B] for FALCON versions 6 and newer) if those assessments were done ≤ 8 
weeks before Day 1.  In the event that the eligibility lab assessments were obtained > 8 weeks before 
the planned EAGLE Day 1 visit, a screening visit will be required for EAGLE enrollment.  
The maximum bardoxolone methyl dose will be determined by the proteinuria status based on the ACR 
value from the eligibility lab assessments from the prior qualifying study, or for patients requiring a 
screening visit, the maximum bardoxolone methyl dose will be determined based on the ACR values 
from the screening labs. Patients with ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, 


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and patients with ACR > 300 mg/g will be titrated to a maximum dose of 30 mg.  Adult patients 
(≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will 
dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if eligibility 
ACR > 300 mg/g) unless contraindicated clinically and approved by the medical monitor.  Patients 
under the age of 18 enrolling from CARDINAL  will start dosing at 5 mg every other day during the 
first week (from Day 1 through the Week 1 visit) and begin once-daily dosing with 5 mg during the 
second week of the study (following the Week 1 visit through the Week 2 visit), and then continue with 
once-daily dosing following the same aforementioned dose-titration scheme based on eligibility ACR 
at Weeks 2, 4, and 6.  Patients under the age of 18 enrolling from FALCON will follow the adult dose 
titration schedule.  Dose de-escalation is permitted during the study if indicated clinically, and 
subsequent dose re-escalation is also permitted.   
All patients in the study will follow the same visit and assessment schedule.  Patients will be scheduled 
to be assessed in person during treatment at Day 1, Weeks 1, 2, 4, 6, 8, 12, 24, and every 24 weeks 
thereafter.  Patients will also be assessed by telephone contact on Days 3, 10, 21, 31, 38, and 45. If the 
Day 1 visit for EAGLE is the same as the end-of-study visit for CARDINAL (all versions) or 
FALCON (protocol version 5 and older), the laboratory assessments required for both visits should 
only be completed once. If the Day 1 visit for EAGLE is the same as the end-of-study visit for 
FALCON (protocol version 6 and newer), the lab assessments required for both visits should be 
completed for each study individually.  If the Day 1 visit of EAGLE is not on the same day as the end-
of-study visit from prior qualifying study, lab assessments will be performed for Day 1 through the 
EAGLE central lab. 
The conduct of the study, according to protocol specifications, was impacted by the COVID-19 
pandemic.  As a result, and as of Version 3 of the protocol, modifications intended to address access to 
and administration of investigational product, and adherence to protocol-specified visits and laboratory 
assessments were implemented.  These modifications are described in Appendix 1 (COVID-19 
Mitigations). 
Number of patients (planned):  
Patient numbers will be determined by those who are currently participating or have previously 
participated in a qualifying clinical study with bardoxolone methyl.   


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Main criteria for inclusion: 
1. Patients who are participating (or who have participated) in qualifying studies and who have 
not been required to discontinue study treatment for protocol or safety reasons and who have 
completed required End-of-Treatment and/or Follow-up visits in a prior clinical study with 
bardoxolone methyl and who, according to the assessment of the investigator, have a potential 
positive benefit-risk assessment for participating in the trial.   
2. Meets the following eligibility criteria based on assessments from the prior qualifying study or 
from a screening visit, if applicable. 
a. Not expected to reach end stage kidney disease (ESKD) or nephrotic syndrome within 
12 weeks of study enrollment, in the investigator’s judgement; subjects with eGFR 
< 20 ml/min/1.73m2 should be discussed with the medical monitor before enrollment 
(eg, such subjects with an average rate of eGFR decline > 1.0 ml/min/1.73m2 per 
month in the 3 months prior to eligibility assessment may not be eligible);  
b. BNP < 200 pg/mL at the last on-treatment visit in the prior qualifying study or at a new 
screening visit, if applicable. 
c. No occurrence of a cardiovascular serious adverse event in the prior qualifying study 
or in the interval between the end of the qualifying study and the screening visit, if 
applicable. 
3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
study procedures; 
4. Evidence of a personally signed and dated informed consent document (and assent form if 
necessary) indicating that the patient (or a legally acceptable representative) has been informed 
of all pertinent aspects of the study prior to initiation of any protocol-mandated procedures.  
Major exclusion criteria: 
1. Participation in other investigational clinical studies involving interventional products 
being tested or used in a way different from the approved form or when used for an 
unapproved indication; 
2. Patients who have an ongoing SAE from a clinical study that is assessed by the investigator 
as related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners of 
childbearing potential and females of childbearing potential) while screening, taking study 
drug, and 30 days after the last study drug dose;  
4. Women who are pregnant or breastfeeding; 
5. Patient is, in the opinion of the investigator, unable to comply with the requirements of the 
study protocol or is unsuitable for the study for any reason; 
6. Known hypersensitivity to any component of the study drug. 
Investigational product, dosage, and mode of administration:  
Bardoxolone methyl will be administered at oral doses of 5, 10, 20, or 30 mg  
Reference therapy, dosage, and mode of administration:  
None. 
Criteria for evaluation: 


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Safety: Results of physical examination, laboratory results, ACR, vital sign measurements, weight, 
AEs, and SAEs. 
Statistical methods: 
Sample size: The aim of this long-term extended access study is primarily to provide continuing 
bardoxolone methyl treatment to patients and to assess long-term safety and tolerability hence no single 
primary variable has been identified.  Patient numbers will be determined by those who are 
participating (or who have previously participated) in a qualifying clinical study with bardoxolone 
methyl. 
Primary analysis of safety: As the extension is an open-label design with no comparator group, all 
statistical analyses will be descriptive.  
The summary tables will be presented for the overall group of patients, and also split by previous 
treatment groups (ie, bardoxolone methyl or placebo) in prior bardoxolone methyl clinical studies. 


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3. 
TABLE OF CONTENTS AND LIST OF TABLES 
1. 
TITLE PAGE ................................................................................................................1 
SPONSOR APPROVAL AND SIGNATURE PAGE .....................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................9 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Clinical Experience with Bardoxolone Methyl ..........................................................19 
5.1.1. 
Efficacy .......................................................................................................................19 
5.1.2. 
Safety and Tolerability ...............................................................................................21 
5.1.2.1. 
Fluid Overload ............................................................................................................21 
5.1.2.2. 
Transaminase and Gamma-Glutamyl Transpeptidase (GGT) Elevations ..................22 
5.1.2.3. 
Muscle Spasms ...........................................................................................................22 
5.1.2.4. 
Weight Loss ................................................................................................................23 
5.1.2.5. 
Hypomagnesaemia ......................................................................................................23 
5.1.2.6. 
Increases in Urinary Protein .......................................................................................24 
5.1.2.7. 
Growth and Development (Weight and Height) in Adolescents ................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................26 
6.1. 
Primary Objectives .....................................................................................................26 
6.2. 
Primary Safety Endpoints ...........................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Patients .....................................................................................................28 
7.3. 
Treatment Assignment ................................................................................................29 
7.3.1. 
Dose Escalation ..........................................................................................................29 
7.3.2. 
Dose De-Escalation and Re-Escalation ......................................................................29 
7.3.3. 
Interruption and Resuming of Study Drug .................................................................29 
7.3.4. 
Adolescent Dosing Rationale .....................................................................................30 
7.4. 
End of Study and Commercial Availability ................................................................31 
7.5. 
Criteria for Study Termination ...................................................................................31 


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7.6. 
Criteria for Premature Termination or Suspension of Investigational Sites ...............31 
7.7. 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites ..........................................................................31 
7.8. 
Schedule of Assessments ............................................................................................32 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................35 
8.1. 
Patient Inclusion Criteria ............................................................................................35 
8.2. 
Patient Exclusion Criteria ...........................................................................................36 
8.3. 
Screening Period .........................................................................................................36 
8.4. 
Patient Re-Screening & Re-Testing ............................................................................36 
8.4.1. 
Re-Screening ...............................................................................................................36 
8.4.2. 
Re-Testing ...................................................................................................................37 
8.5. 
Discontinuation ...........................................................................................................37 
9. 
TREATMENT OF PATIENTS ..................................................................................39 
9.1. 
Select Management Guidelines ..................................................................................39 
9.1.1. 
Management of Fluid Status .......................................................................................39 
9.1.2. 
Management of Elevated Aminotransferase Levels (ALT and/or AST) ....................40 
9.1.3. 
Management of Muscle Spasms .................................................................................41 
9.1.4. 
Weight Loss ................................................................................................................41 
9.1.5. 
Hypomagnesaemia ......................................................................................................41 
9.1.6. 
Management of Urinary Protein .................................................................................41 
9.1.7. 
Management of Blood Pressure ..................................................................................41 
9.1.8. 
Nausea .........................................................................................................................42 
9.1.9. 
End Stage Kidney Disease ..........................................................................................42 
9.1.10. 
Monitoring Growth and Sexual Development in Adolescents ...................................42 
9.2. 
Description of Study Drug ..........................................................................................43 
9.3. 
Concomitant Medications ...........................................................................................43 
9.3.1. 
Excluded and Prohibited Medications ........................................................................43 
9.3.2. 
Permitted Medications ................................................................................................44 
9.4. 
Treatment Compliance ................................................................................................45 
9.5. 
Randomization ............................................................................................................45 
9.6. 
Unscheduled Visits .....................................................................................................45 
9.7. 
Pregnancy ...................................................................................................................46 


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9.7.1. 
Women of Childbearing Potential and Fertile Males .................................................46 
9.7.2. 
Methods of Birth Control............................................................................................46 
9.7.3. 
Suspected Pregnancy ..................................................................................................47 
9.8. 
Serious Toxicities .......................................................................................................48 
9.9. 
Study Procedures ........................................................................................................48 
9.9.1. 
Informed Consent and Assent .....................................................................................48 
9.9.2. 
Inclusion/Exclusion ....................................................................................................49 
9.9.3. 
Prior and Current Concomitant Medications ..............................................................49 
9.9.4. 
Height .........................................................................................................................49 
9.9.5. 
Weight and Body Mass Index (BMI) .........................................................................49 
9.9.6. 
Vital Sign Measurements ............................................................................................49 
9.9.7. 
Physical Examination .................................................................................................50 
9.9.8. 
Pregnancy Test ............................................................................................................50 
9.9.9. 
Study Drug Administration .........................................................................................50 
9.9.10. 
Study Drug Dispensation and Collection ...................................................................50 
9.9.11. 
Telephone Contact ......................................................................................................51 
9.9.12. 
Adverse Event Collection ...........................................................................................51 
9.9.13. 
Clinical Chemistry ......................................................................................................51 
9.9.14. 
Hematology .................................................................................................................51 
9.9.15. 
eGFR ...........................................................................................................................51 
9.9.16. 
N-Terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) and Brain 
Natriuretic Peptide (BNP) ...........................................................................................52 
9.9.17. 
Urine Collection for Albumin to Creatinine Ratio (ACR) .........................................52 
9.9.18. 
Lipid Panel ..................................................................................................................52 
9.9.19. 
Medical History ..........................................................................................................53 
9.9.20. 
Tanner Staging ............................................................................................................53 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................54 
10.1. 
Study Drug ..................................................................................................................54 
10.2. 
Study Drug Packaging and Labeling ..........................................................................54 
10.3. 
Study Drug Storage .....................................................................................................54 
10.4. 
Study Drug Administration .........................................................................................54 
10.5. 
Study Drug Accountability .........................................................................................55 


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10.6. 
Study Drug Handling and Disposal ............................................................................55 
11. 
SAFETY ASSESSMENTS ........................................................................................56 
11.1. 
Safety Parameters .......................................................................................................56 
11.2. 
Adverse and Serious Adverse Events .........................................................................56 
11.2.1. 
Definition of Adverse Events .....................................................................................56 
11.2.1.1. 
Adverse Event .............................................................................................................56 
11.2.1.2. 
Serious Adverse Event ................................................................................................56 
11.3. 
Eliciting Adverse Event Information ..........................................................................57 
11.4. 
Assessment of Causality .............................................................................................58 
11.5. 
Assessment of Severity ...............................................................................................58 
11.6. 
Recording Adverse Events .........................................................................................58 
11.7. 
Reporting Serious Adverse Events .............................................................................59 
12. 
STATISTICS ..............................................................................................................61 
12.1. 
Sample Size ................................................................................................................61 
12.2. 
Study Variables ...........................................................................................................61 
12.2.1. 
Safety Variables ..........................................................................................................61 
12.3. 
Statistical Analyses .....................................................................................................61 
12.3.1. 
Primary Analysis of Safety .........................................................................................61 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................62 
13.1. 
Study Monitoring ........................................................................................................62 
13.2. 
Audits and Inspections ................................................................................................62 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 
14.1. 
Quality Assurance .......................................................................................................63 
14.2. 
Financial Disclosure ...................................................................................................63 
14.3. 
Sponsor Obligations ....................................................................................................63 
14.4. 
Investigator Documentation ........................................................................................63 
14.5. 
Clinical Study Insurance .............................................................................................64 
14.6. 
Use of Information ......................................................................................................64 
15. 
ETHICS ......................................................................................................................65 
15.1. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Review ........................................................................................................................65 
15.2. 
Ethical Conduct of the Study ......................................................................................65 


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15.3. 
Written Informed Consent ..........................................................................................65 
15.4. 
Confidentiality ............................................................................................................66 
15.5. 
Modification of the Protocol .......................................................................................66 
15.6. 
Protocol Deviations ....................................................................................................67 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
16.1. 
Retention of Records ..................................................................................................68 
16.2. 
Case Report Forms .....................................................................................................68 
17. 
PUBLICATION POLICY ..........................................................................................69 
18. 
REFERENCES ...........................................................................................................70 
19. 
APPENDICES ............................................................................................................72 
APPENDIX 1. COVID-19 MITIGATIONS ...............................................................................73 
1. 
SITE OPERATIONS AND PATIENT MANAGEMENT .........................................73 
2. 
COVID-19 INFECTED PATIENTS AND STUDY DRUG USE .............................73 
3. 
STUDY DRUG ACCESS ...........................................................................................74 
4. 
STUDY VISITS ..........................................................................................................74 
5. 
DOSE MANAGEMENT ............................................................................................75 
5.1. 
Dose De-escalation and Interruption for Missed Safety and Laboratory 
Assessments ................................................................................................................75 
5.2. 
Resuming or Dose-escalating IP after Interruptions or Changes ................................75 
6. 
DEVIATIONS ............................................................................................................76 
7. 
MONITORING ...........................................................................................................76 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 3: 
Cross-Study Comparison of Increases in eGFR, Inulin Clearance, and 
Creatinine Clearance with Bardoxolone Methyl Treatment .......................................20 
Table 4: 
Lab Assessments for Eligibility ..................................................................................27 
Table 5: 
Schedule of Assessments ............................................................................................33 
Table 6: 
Management of Elevated Aminotransferase Levels (ALT and/or AST) ....................40 
Table 7: 
Bardoxolone Methyl Drug Product Information ........................................................43 
 
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LIST OF FIGURES 
Figure 1: 
Schema for Study 402-C-1803 ...................................................................................28 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and special terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
ACE 
angiotensin converting enzyme 
ACR 
albumin to creatinine ratio 
ADPKD 
autosomal dominant polycystic kidney disease 
AE 
adverse event 
ALT 
alanine aminotransferase 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BNP 
B-type natriuretic peptide 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations (US) 
CKD 
chronic kidney disease 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ERA 
Endothelin Receptor Antagonist 
ESKD 
end stage kidney disease 
FDA 
Food and Drug Administration (US) 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transpeptidase 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
Nrf2 
nuclear factor erythroid 2-related factor 2 
NT-proBNP 
N-Terminal prohormone B-type natriuretic peptide   
PH 
pulmonary hypertension 
SAE 
serious adverse event 


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Abbreviation or Specialist Term 
Explanation 
T2D 
type 2 diabetes  
ULN 
upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 


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5. 
INTRODUCTION 
Bardoxolone methyl and its analogs are oleanolic acid-derived synthetic triterpenoid compounds 
that potently induce the nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) – Kelch-like 
ECH-associated protein 1 (Keap1) pathway (Wu, 2011; Rojas-Rivera, 2012).  Through 
interaction with the Nrf2 repressor molecule, Keap1, bardoxolone methyl and its analogs 
promote translocation of Nrf2 to the nucleus, where Nrf2 binds to antioxidant response elements 
in the promoter region of its target genes, leading to induction of many antioxidants and 
cytoprotective enzymes and related proteins (Lee, 2009; Dinkova-Kostova, 2005).  Bardoxolone 
methyl and its analogs are also potent inhibitors of the nuclear factor kappa-light-chain-enhancer 
of activated B-cells (NF-κB) inflammatory pathway through both direct (ie, inhibition of the 
inhibitor of nuclear factor kappa β kinase beta subunit [IKKβ] kinase activity) and indirect 
mechanisms (ie, detoxification of reactive oxygen species) (Osburn, 2008).  Because of this dual 
mechanism of action, bardoxolone methyl and its analogs are hypothesized to have potential 
therapeutic relevance in a variety of disease settings involving oxidative stress and inflammation.    
Multiple studies validate the renal protective effect of Nrf2 activation.  In contrast, Nrf2 gene 
ablation intensifies inflammation, oxidative stress, and renal injury in preclinical models.  Nrf2-
knockout mice exhibit a lupus-like autoimmune nephritis (Yoh, 2001) and histologic analyses of 
kidney tissue show enlarged glomeruli, mesangial cell proliferation, thickening of the glomerular 
basement membrane, and glomerulosclerosis (Ma, 2006).  Similarly, Nrf2-knockout mice are 
more susceptible to nephrotoxic insults and develop more severe renal impairment.  Mechanistic 
studies demonstrate that Nrf2-mediated protection against these effects is at least partially 
through inhibition of transforming growth factor-β1 and reduction of extracellular matrix 
production (Jiang, 2014).  Collectively, these data establish that Nrf2 plays an important role in 
maintaining the function and structure of the kidney and Nrf2 activation offers protection from 
renal injury and dysfunction.   
Chronic kidney disease (CKD) is a disease of decreased kidney function that can progress to 
kidney failure and end-stage kidney disease (ESKD).  Although GFR decline can be initiated by 
different pathogenic stimuli, the pathogenic role of inflammatory processes in disease 
progression and declining renal function is similar across different forms of CKD.  For example, 
genetic defects in the glomerular basement membrane in Alport syndrome, hypoglycemia in 
type 1 diabetes (T1D), abnormal immunoglobulin A (IgA) deposition and clearance in IgA 
nephropathy (IgAN), segmental scarring in focal segmental glomerulosclerosis (FSGS), and 
renal cyst formation in autosomal dominant polycystic kidney disease (ADPKD), all trigger a 
cascade of pathological inflammatory processes that, over prolonged periods, result in oxidative 
stress, mesangial matrix expansion, glomerulosclerosis and fibrosis, decreased surface area for 
filtration, and reduced renal function.   
More specifically, the chronic activation of pro-inflammatory pathways in kidney cells promotes 
glomerular filtration rate (GFR) loss by at least three mechanisms: (a) in glomerular endothelial 
cells, inflammation-associated reactive oxygen species (ROS) induce endothelial nitric oxide 
synthase (eNOS) uncoupling and the production of peroxynitrite, which depletes vasodilatory 
nitric oxide resulting in loss of endothelial function and reduced glomerular surface area for 
filtration (ie, decreases in the ultrafiltration coefficient, Kf); (b) inflammation-associated ROS 
induce a contractile response in mesangial cells resulting in reduced Kf and GFR; and (c) ROS-


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mediated activation of inflammatory pathways leads to fibrosis, promoting structural alterations 
in the mesangium and glomerular basement membrane thickening that contributes to GFR 
decline.  GFR decline from these processes inevitably leads to ESKD.   
Through Nrf2 activation and inhibition of NF-κB, bardoxolone methyl and closely related 
structural analogs have been shown to improve renal function, reduce inflammation, and prevent 
structural injury in multiple models of renal injury and disease (Tanaka, 2008; Zoja, 2010; 
Wu, 2011; Aminzadeh, 2013; Ding, 2013).  In particular, several of these studies elucidate the 
effects of bardoxolone methyl and closely related analogs on the underlying disease processes 
that promote reduced GFR.  Specifically, bardoxolone methyl and analogs reverse endothelial 
dysfunction (Ferguson, 2010) and mesangial cell contraction, thereby increasing glomerular 
surface area (Kf) and GFR (Ding, 2013).  Further, data from animal models of chronic renal 
disease demonstrate that the compounds are anti-fibrotic and have protective effects on the renal 
interstitium in response to high protein (Zoja, 2010) and pressure overload in the setting of 
hyperfiltration (Aminzadeh, 2013).   
Bardoxolone methyl has consistently improved parameters of renal function in multiple clinical 
studies in patients with CKD associated with type 2 diabetes (T2D), cancer, and pulmonary 
hypertension (PH), with significant increases in inulin clearance, creatinine clearance, and 
estimated GFR (eGFR).  The changes in eGFR also correlate in reductions in other parameters 
such as blood urea nitrogen (BUN), uric acid, and phosphate, and not associated with validated 
markers of renal injury, providing corroboration that bardoxolone methyl treatment is associated 
with improvements in kidney function.   
The profile of eGFR increases with bardoxolone methyl reflects its multiple protective and 
anti-inflammatory effects.  Early improvements in eGFR evident within the first 4 weeks of 
bardoxolone methyl treatment are likely attributed to the reversal of acute and dynamic 
inflammation-mediated processes such as endothelial dysfunction and mesangial cell contraction 
resulting in glomerular filtration surface area increases.  These increases in eGFR are sustained 
for patients treated with bardoxolone methyl for up to one year, with retained eGFR increases 
from baseline event after withdrawal of drug treatment.  The magnitude and durability of these 
changes are quite different from the pattern observed with eGFR increases due to intraglomerular 
pressure or hyperfiltration.  Over 400 patients with T2D CKD have been treated with 
bardoxolone methyl for 1 year or longer, with no evidence of renal toxicity, as assessed by 
validated markers of renal injury, proportion of patients with clinically meaningful loss of eGFR, 
renal serious adverse events (SAEs) and ESKD.  Thus, the collective data support that 
bardoxolone methyl may have disease-modifying effects in the kidney (eg, reversal of mesangial 
expansion and interstitial fibrosis) that are beneficial and not deleterious.  On the basis of these 
results, bardoxolone methyl is currently being evaluated in a Phase 2/3 study in patients with 
Alport syndrome and in a Phase 2 study in patients with CKD due to T1D, IgAN, ADPKD, or 
FSGS. 
In patients with CKD, the potential impact of a sustained eGFR increase with bardoxolone 
methyl treatment is clinically meaningful and could provide a multi-year delay in disease 
progression to ESKD. 


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5.1. 
Clinical Experience with Bardoxolone Methyl 
Overall, bardoxolone methyl has been tested in multiple CKD studies enrolling almost  
6000 patients, and approximately 3,700 individuals have been exposed to bardoxolone methyl.     
5.1.1. 
Efficacy  
As seen in Table 3, improvements in renal function, including eGFR, creatinine clearance, and 
inulin clearance, have been observed with bardoxolone methyl treatment in multiple clinical 
studies, including those in CKD, cancer, and PH patients.  Bardoxolone methyl was originally 
considered for development in cancer patients, and in two Phase 1 studies, bardoxolone methyl 
was observed to reduce serum creatinine levels, corresponding to an increase in eGFR.  The 
reductions of serum creatinine levels and resultant increases in eGFR were time-dependent and 
manifested in a majority (82%) of the patients studied.  In subsequent studies that enrolled over 
2,700 patients with type 2 diabetes and CKD, bardoxolone methyl has been shown to 
consistently produce clinically and statistically significant improvements in eGFR that are 
durable for at least one year in treated patients.   
Study 402-C-0804 (BEAM) was a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, multi-dose, Phase 2b study designed to assess the efficacy and safety of 3 doses 
(25, 75, and 150 mg) of the crystalline formulation of bardoxolone methyl in patients with Stage 
3b-4 CKD (eGFR 20-45 mL/min/1.73 m2) and type 2 diabetes.  Analysis of the primary 
endpoint, the change in eGFR values from baseline at Week 24, demonstrated a clinically and 
statistically significant increase in eGFR relative both to the baseline value and to the change 
with placebo (p < 0.001) at each of the 3 tested dose levels (Pergola, 2011).  Mean eGFR 
increases were largely sustained through Week 52 and on average, patients treated with 
bardoxolone methyl experienced a net increase in eGFR of 7.4 ± 0.8 mL/min/1.73 m2 at 
Week 52 from a baseline of 32.4 mL/min/1.73 m2.   
Study 402-C-0903, titled “Bardoxolone Methyl Evaluation in Patients with Chronic Kidney 
Disease and Type 2 Diabetes: The Occurrence of Renal Events” (BEACON), was a Phase 3, 
randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study 
designed to compare the efficacy and safety of bardoxolone methyl to placebo in patients with 
Stage 4 CKD (eGFR 15 to 29 mL/min/1.73 m2) and Type 2 diabetes.  A total of 2185 patients 
were randomized 1:1 to once-daily administration of the amorphous SDD formulation of 
bardoxolone methyl (20 mg) or placebo.  The primary efficacy endpoint of the study was the 
time-to-first event in the composite endpoint defined as ESKD (need for chronic dialysis, renal 
transplantation, or renal death) or cardiovascular death.  Similar to prior studies, bardoxolone 
methyl patients had mean increases in eGFR that occurred by Week 4 of treatment and remained 
above baseline through Week 48 (overall mean increase of 5.5 mL/min/1.73 m2).  In contrast, 
placebo-treated patients experienced a mean decline in eGFR (−0.9 mL/min/1.73 m2, 95% CI 
−1.2 to −0.5 mL/min/1.73 m2), corresponding to a relative difference between groups of  
6.4 mL/min/1.73 m2 (95% CI 5.9 to 6.9 mL/min/1.73 m2, p<0.001) (de Zeeuw, 2013).   
Patients in Study 402-C-0804 and 402-C-0903 also participated in a four-week withdrawal 
period following the treatment period.  In 402-C-0804, analysis of the change in eGFR from 
baseline to Week 56 for patients who received study drug for 52 weeks showed that a portion of 
the increase in eGFR is retained following withdrawal of therapy.  Patients treated with 75 and 


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150 mg of bardoxolone methyl for 52 weeks had eGFR increases from baseline of 4.0 and 
4.3 mL/min/1.73 m2, respectively, at Week 56.  Similar results were observed in BEACON for 
patients that received at least 48 weeks of treatment.  These data support that the longer-term 
protective and anti-inflammatory effects of bardoxolone methyl may reverse some of the 
structural remodeling processes in the kidney associated with declining renal function, resulting 
in sustained eGFR improvement after withdrawal of drug. 
Notably, Reata’s Asian development partner, Kyowa Kirin Co., Ltd, demonstrated that 
bardoxolone methyl treatment resulted in a significant improvement in measured GFR, as 
assessed by insulin clearance in Japanese patients with CKD and type 2 diabetes.  Improvements 
in other measures of renal function, including BUN, uric acid, and phosphorus, have also been 
consistently observed, providing further evidence that observed changes in eGFR reflect true 
improvements in kidney function. Mostly recently, bardoxolone methyl has been shown to also 
significantly increase eGFR in patients with Alport syndrome (Study 402-C-1603) and 
autosomal dominant polycystic kidney disease (ADPKD; Study 402-C-1702).   
Table 3: 
Cross-Study Comparison of Increases in eGFR, Inulin Clearance, and 
Creatinine Clearance with Bardoxolone Methyl Treatment 
Study 
Phase/ 
Country 
Study  
Design 
Study 
Population 
# of 
Patients 
Treatment 
Duration 
Placebo-corrected 
∆eGFR 
(mL/min/1.73m2)1 
CKD Studies 
402-C-0801 
(Stratum 1) 
2a/ 
US 
Multicenter, Open-
Label, Dose-
Ranging, 
Randomized 
Age >=18, 
Diabetic 
nephropathy 
60 
28 days 
6.72 
(p<0.001) 
402-C-0801 
(Stratum 2) 
2b/ 
US 
Multicenter, Open-
Label, Dose-
Ranging, 
Randomized 
Age >=18, 
Diabetic 
nephropathy 
20 
56 days 
7.22 
(p<0.001) 
CrCl also sig. increased 
402-C-0804 
(BEAM) 
2/ 
US 
Multicenter, Double-
Blinded, 
Randomized, 
Placebo-Controlled 
Age >=18, 
T2D and CKD 
227 
52 weeks 
8.6 at WK52 
(p<0.001 vs PBO) 
402-C-0902 
2/ 
US 
Multicenter, Open-
Label, Randomized, 
Parallel-Group, 
Dose-Ranging 
Age >=18, T2D and 
CKD 
131 
85 days 
6.52 
(p<0.001) 
402-C-0903 
(BEACON) 
3/ 
Global 
Multinational, 
Multicenter, 
Randomized, 
Double-Blinded, 
Placebo-Controlled 
Age >=18, 
T2D and Stage 4 
CKD 
2185 
Median: 
7 months with 
522 patients 
through Week 
48 
6.4 
(p<0.001 vs PBO) 
CrCl also significantly 
increased 
402-C-1102 
1/US 
Multi-Dose, 
Multicenter, Open-
Label 
Age>=18, 
T2D and Stage 3b 
and 4 CKD 
24 
56 days 
9.0 
(p<0.05) 
RTA402-005 
(TSUBAKI) 
2/ 
Japan 
Randomized, 
Double-Blinded, 
Placebo-Controlled 
Age >=20,  
T2D and Stage 3 
and 4 CKD 
120 
16 weeks 
6.6 (inulin GFR) 
(p=0.008 vs PBO) 
402-C-1603 
2/US Multicenter,  
Open-label 
Age 12 to 65, 
Alport syndrome 
30 
48 weeks 
10.4 (p<0.001) 


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402-C-1603 
Year 1 
3/Global 
Randomized, 
Double-Blinded, 
Placebo-Controlled 
Age 12 to 70, 
Alport Syndrome 
157 
48 weeks 
9.5 (p<0.001 vs PBO) 
402-C-1702 
2/US Multicenter,  
Open-label 
Age ≥ 18, ADPKD 
31 
12 weeks 
9.3 (p<0.001) 
402-C-1702 
2/US Multicenter,  
Open-label 
Age 18 to 70, 
IgA Nephropathy 
26 
12 weeks 
8.0 (p<0.0001) 
402-C-1702 
2/US Multicenter,  
Open-label 
Age 18 to 70, 
T1D CKD 
28 
12 weeks 
5.5 (p=0.025) 
402-C-1702 
2/US Multicenter,  
Open-label 
FSGS 
18 
12 weeks 
7.8 (p=0.003) 
Non-CKD Studies 
402-C-0501 
1/ 
US 
Open-label, Dose-
escalation 
Age >=18, 
Advanced Solid 
Tumors or 
Lymphoid 
Malignancies 
47 
Median:  
56 days 
18.22 
(p<0.0001) 
402-C-0702 
½/ 
US 
Double-Blinded, 
Randomized 
Pancreatic Cancer 
34 
Median:  
56 days 
32.22 
(p=0.001) 
402-C-1302 
(LARIAT) 
2/ 
US 
Randomized, 
Double-Blinded, 
Placebo-Controlled 
Age 18 to 75 
PH (Baseline eGFR 
82 mL/min/1.73 m2) 
543 
16 weeks 
14.7 
(p<0.001 vs PBO) 
Abbreviations: ADPKD= autosomal dominant polycystic kidney disease; CKD=chronic kidney disease; 
CrCl=creatinine clearance; IgA=immunoglobulin A; eGFR=estimated glomerular filtration rate; FSGS=focal 
segmental glomerulosclerosis; PBO=placebo; PH=pulmonary hypertension; T1D=type 1 diabetes; T2D=type 2 
diabetes; US=United States; Wk=week 
1 Unless noted, data are differences between mean eGFR changes from baseline for bardoxolone methyl versus 
placebo groups and p-values calculated comparing the difference in means between bardoxolone methyl and placebo 
groups. 
2 Data are mean eGFR changes from baseline for bardoxolone methyl patients and p-values are calculated from two-
sided paired t-tests comparing eGFR change to 0. 
3 Number of patients enrolled Cohorts 1 and 2. 
5.1.2. 
Safety and Tolerability 
Please refer to the Investigator’s Brochure for a detailed discussion of safety findings for studies 
in healthy subjects, cancer, CKD, and PH patients with bardoxolone methyl. 
5.1.2.1. 
Fluid Overload 
Similar to endothelin receptor antagonists (ERAs) in certain patient populations, including 
bosentan in advanced congestive heart failure and avosentan in advanced CKD, bardoxolone 
methyl treatment was found to be associated with an increased risk for fluid overload and heart 
failure hospitalizations in the BEACON trial, which enrolled patients with Stage 4 CKD 
(eGFR 15 to 29 mL/min/1.73 m2) and type 2 diabetes.  The overall increased risk for fluid 
overload and heart failure events with bardoxolone methyl appeared to be limited to the first 
three to four weeks after initiation of treatment.  Elevated B-type natriuretic peptide (BNP) and 
prior hospitalization for heart failure were identified as risk factors that contributed to increased 
risk for these events.  The increased risk for these events from bardoxolone methyl treatment had 
not been observed in six previous CKD studies, which were conducted mostly in patients with 
Stage 3b CKD (eGFR of 30 to 44 mL/min/1.73 m2), patients with hepatic dysfunction, cancer 
patients, or healthy volunteers.  


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Review of admission notes and narrative descriptions for heart failure hospitalizations in 
BEACON indicates that heart failure in bardoxolone methyl-treated patients was often preceded 
by rapid fluid weight gain (several kilograms within the first weeks of treatment initiation) and 
was not associated with acute renal decompensation or acutely reduced left ventricular 
contractility.  Available data from BEACON and other studies suggest that bardoxolone methyl 
treatment can differentially affect hemodynamic status according to the clinical condition of 
patients and likely promotes fluid retention in patients with more advanced renal dysfunction and 
other recognized risk factors associated with heart failure at baseline.   
In a Phase 2 dose-ranging study of the efficacy and safety of bardoxolone methyl in patients with 
pulmonary hypertension (LARIAT), risk mitigation procedures were employed to reduce the 
potential for bardoxolone methyl-induced fluid overload; these procedures excluded patients 
with the identified risk factors and ensured close monitoring for fluid retention within the first 
month of treatment.  To date, the risk for acute fluid overload AEs with bardoxolone methyl in 
late-stage CKD patients has not been observed in PH patients.   
5.1.2.2. 
Transaminase and Gamma-Glutamyl Transpeptidase (GGT) Elevations  
In clinical studies of bardoxolone methyl, almost all patients had increases of transaminase 
enzymes above baseline upon initiation of treatment, which followed a consistent pattern.  These 
increases were not associated with elevations in bilirubin, and hepatotoxicity has not been 
observed.  In BEACON, fewer hepatobiliary SAEs were observed in the bardoxolone methyl 
arm than in the placebo arm.  The elevations begin immediately after initiation of treatment or an 
increase in dose; they peak approximately two to four weeks later.  In most patients, 
transaminase elevations were mild, but approximately 4% to 11% of patients experienced an 
elevation greater than 3X the upper limit normal (ULN).  The elevations resolved to levels less 
than the ULN in most patients with elevations, within two weeks after peak values while patients 
continued taking study drug.  Patients who experienced elevations to greater than 3X the ULN 
sometimes required additional time to resolve.  While some patients have had elevations to 
above 3X the ULN, persistent elevations to above 3X the ULN have not been observed, and the 
elevations did not recur once resolved, unless caused by other factors. 
Bardoxolone methyl regulates gamma-glutamyl transpeptidase (GGT), a known Nrf2 target gene 
protein.  In clinical studies, low level GGT elevations during treatment were common, mild, and 
typically lasted longer than alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) 
elevations.  Bilirubin levels in patients experiencing transaminase or GGT elevations due to 
treatment with bardoxolone methyl either remained at baseline levels or decreased.  The ALT, 
AST, and GGT elevations were generally self-limiting in patients who continued treatment with 
study drug.  
5.1.2.3. 
Muscle Spasms 
Muscle spasm was the most frequently reported AE in clinical trials of bardoxolone methyl in 
patients with CKD who also had type 2 diabetes.  The muscle spasms most often manifested in 
the first two months of treatment and resolved spontaneously or with empirical treatment.  They 
occurred mostly at night, in the lower extremities, and were generally mild to moderate in 
severity.  Muscle spasms have also been reported in bardoxolone methyl-treated PH patients but 
at lower incidences than that observed in prior CKD studies.  Moreover, the incidence of muscle 


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spasms is similar to that observed in placebo-treated PH patients.  Muscle spasms may result 
from improved insulin sensitivity and glucose uptake in skeletal muscle cells.  Increases in 
glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp procedure, were 
observed in response to bardoxolone methyl in a defined subset of patients enrolled in a Phase 2a 
study.  To date, in those cases where serum creatinine kinase (CK) levels have been measured, 
no association has been observed between muscle spasms and elevated CK levels in patients 
treated with bardoxolone methyl.  Clinical signs and laboratory findings associated with the 
reports of muscle spasms have not been consistent with muscle toxicity.  Bardoxolone methyl 
patients showed no increase in prominent laboratory findings associated with muscle toxicity, 
such as increased levels of serum markers, including creatinine, lactate dehydrogenase (LDH), 
BUN, uric acid, phosphorus, and potassium, which were monitored weekly during the first two 
months of a prior study (402-C-0804) when muscle spasms were most frequently reported.  
Increases in the whole-body glucose disposal rate have been observed in mice treated with 
bardoxolone methyl, as well.  Increased glucose uptake was observed in isolated calf muscles of 
the mice, but not in white adipose tissue (Saha, 2010).   
5.1.2.4. 
Weight Loss 
Decreases in weight and reports of anorexia/decreased appetite have been observed following 
treatment with bardoxolone methyl in patients with CKD who also had type 2 diabetes.  In 
studies of these patients, 17% of bardoxolone methyl patients reported AEs of weight decrease or 
decreased appetite (irrespective of relationship to treatment).  Weight reduction was more 
pronounced in patients treated with bardoxolone methyl than in those given placebo. 
Weight loss of approximately one kilogram per month was observed, with patients of higher 
body-mass index at baseline losing more weight (in absolute terms) than those of normal or 
moderately-elevated body-mass index.     
Bardoxolone methyl-treated PH patients have also had decreases in weight, with mean weight 
decreases of approximately 3 kg versus placebo at Week 16.  Weight loss in PH patients has not 
coincided with reports of decreased appetite or anorexia AEs. 
5.1.2.5. 
Hypomagnesaemia 
Hypomagnesaemia has not been commonly reported in PH patients to date but was reported as 
an AE for 15.5% of patients with CKD who also had type 2 diabetes who received bardoxolone 
methyl.  The AE of hypomagnesaemia (of any reported relationship to study drug) was more 
frequently reported in bardoxolone methyl-treated patients than in patients given placebo.  The 
investigators considered almost all reported events to be mild.  Additionally, patients treated with 
bardoxolone methyl had a greater decrease from baseline in serum magnesium levels than 
patients given placebo; the decrease was evident within 4 weeks and attenuated after 8 weeks of 
starting therapy.  In bardoxolone methyl clinical studies performed to date, a post-hoc analysis 
identified no correlation between hypomagnesaemia and either gastrointestinal AEs or cardiac 
AEs, including cardiac dysrhythmias and prolonged QTc.  The 24-hour urine collections from 
the BEACON ambulatory blood pressure monitoring sub-study showed no increase in urinary 
magnesium levels, indicating that renal loss of magnesium did not account for the reductions in 
serum magnesium observed with bardoxolone methyl treatment in CKD patients.  Notably, a 


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thorough QT study that tested doses of bardoxolone methyl up to 80 mg, bardoxolone methyl 
showed no increase in the QT interval.  
5.1.2.6. 
Increases in Urinary Protein 
Increases in urinary albumin have been observed in some patients treated with bardoxolone 
methyl with CKD and type 2 diabetes.  The increases are likely due to bardoxolone methyl’s 
pharmacological modulation of tubular protein reabsorption and have not been associated with 
interstitial fibrosis or injury.  In preclinical studies, bardoxolone methyl has been shown to 
downregulate the primary proteins involved in protein reabsorption in the proximal tubules: the 
megalin-cubilin complex.  Moreover, the magnitude of observed eGFR increases with 
bardoxolone methyl treatment is thought to reduce the residence time of protein in the proximal 
tubules, thereby reducing protein reuptake and increasing urinary protein levels.  Therefore, 
increased eGFR, together with decreased megalin expression, is thought to result in decreased 
fractional reabsorption of albumin and increased urinary excretion of albumin.  Consistent with 
bardoxolone methyl-mediated protection in preclinical models of protein-overload-induced 
nephropathy, these pharmacological effects are thought to reduce protein overload and secondary 
nephropathy caused by excessive albumin uptake and therefore are not associated with tissue 
injury and interstitial fibrosis. 
5.1.2.7. 
Growth and Development (Weight and Height) in Adolescents  
In study 402-C-1603 (CARDINAL) phase 3, due to the small number of patients and baseline 
differences in mean height and weight (placebo vs. bardoxolone methyl treated), a firm 
conclusion regarding effect on height and weight cannot be derived.  
In study 402-C-1603, a total of 23 adolescent patients (ages 12-17 years) with Alport syndrome 
were enrolled, where 11 and 12 were randomized to bardoxolone methyl and placebo, 
respectively.  In bardoxolone methyl treated adolescents, both weight and height at baseline were 
relatively higher than placebo treated adolescents. Bardoxolone methyl treated patients had a 
mean baseline weight of 65.50 kg (SD 10.193, median 63.90 kg, min/max 52.5/81.3 kg), while 
placebo treated adolescents had a mean baseline weight of 57.79 kg (SD 16.020, median 59.80 
kg, min/max 29.5/76.3 kg). A change from baseline using the last on treatment value available 
for weight showed a mean weight decrease of -1.41 kg (SD 5.260, median -2.30 kg, min/max -
10.9 to 6.8 kg) for bardoxolone methyl treated adolescents and a mean weight increase of +2.26 
kg (SD 4.153, median +2.25 kg, min/max -5.7 to +8.2 kg) for placebo treated adolescents. 
Bardoxolone methyl treated adolescents at baseline had a mean height of 171.7 cm (SD 5.90, 
median 172.0 cm, min/max 165/183 cm), while placebo treated adolescents had a mean height of 
166.3 cm (SD 14.94, median 169.5 cm, min/max 136/186 cm).  A change from baseline using 
the last on treatment value available showed a mean height increase of +1.1 cm (SD 1.13, 
median +1.0 cm, min/max 0 to 3 cm) for bardoxolone methyl treated adolescents, compared with 
a mean height increase of +2.4cm (SD 3.65, median 0.6 cm, min/max -1 to +11cm) for placebo 
treated adolescents. 
Bardoxolone methyl treated adolescents at baseline had a mean body mass index (BMI) of 
22.1 kg/m2 (SD 2.11, median 22.3 kg/m2, min/max 19/25 kg/m2), while placebo treated 
adolescents at baseline had a mean BMI of 20.5 kg/m2 (SD 3.63, median 20.3 kg/m2, min/max 


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16/26 kg/m2).  Overall, in bardoxolone methyl treated adolescents, BMI changes from baseline to 
last value on treatment showed a mean decrease of -0.5 kg/m2 (SD 1.40, median -0.8 kg/m2, 
min/max -3/+2 kg/m2), compared with a mean BMI increase in placebo treated adolescents of  
0.3 kg/m2 (SD 1.15, median 0.3 kg/m2, min/max -2/+2 kg/m2).   
Overall, no other concerning differences in the safety profile were identified in patients 12 to < 
18 years of age compared to adult patients randomized to receive bardoxolone methyl (total: 
n=77; adults: n=66) or to receive placebo (total: n=80; adults: n=68). 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objectives 
• To provide continuing open-label treatment with bardoxolone methyl as part of this 
extended access program while collecting ongoing safety and tolerability data of 
bardoxolone methyl.  
6.2. 
Primary Safety Endpoints 
• Frequency, intensity, and relationship to study drug of AEs and SAEs and change 
from baseline in the following assessments: physical examinations, vital sign 
measurements, weight, urine albumin to creatinine ratio (ACR), and laboratory 
results. 




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contraindicated clinically and approved by the medical monitor.  Patients under the age of 18 
enrolling from CARDINAL will start dosing at 5 mg every other day during the first week (from 
Day 1 through the Week 1 visit) and begin once-daily dosing with 5 mg during the second week 
of the study (following the Week 1 visit through the Week 2 visit), and then continue with once-
daily dosing following the same aforementioned dose-titration scheme based on eligibility ACR 
at Weeks 2, 4, and 6.   Patients under the age of 18 enrolling from FALCON will follow the adult 
dose titration schedule.  Dose de-escalation is permitted during the study if indicated clinically, 
and subsequent dose re-escalation is also permitted.
All patients in the study will follow the same visit and assessment schedule, as outlined in the 
study schema (Figure 1).  Patients will be scheduled to be assessed in person during treatment at 
Day 1, Weeks 1, 2, 4, 6, 8, 12, 24, and every 24 weeks thereafter.  Patients will also be assessed 
by telephone contact on Days 3, 10, 21, 31, 38, and 45. If the Day 1 visit for EAGLE is the same 
as the end-of-study visit from the prior qualifying study, the assessments required for both visits 
should only be completed once. If the Day 1 visit of EAGLE is not on the same day as the end-
of-study visit from prior qualifying study, lab assessments will be performed for Day 1 through 
the EAGLE central lab. 
Figure 1: 
Schema for Study 402-C-1803 
Abbreviations: ACR=albumin to creatinine ratio; D=day; W=week; eGFR=estimated glomerular filtration rate; 
Scr=screening
*Patients enrolling from CARDINAL (402-C-1603) that are under the age of 18 will receive bardoxolone methyl 
every other day during Week 1. Patients enrolling from FALCON (402-C-1808) that are under the age of 18 will 
receive bardoxolone methyl every day during Week 1  
Note: Screening visit will be scheduled for subjects whose last lab assessments are more than 8 weeks old. Refer to 
Section 8.3 for additional details. Subjects requiring a screening visit will be consented on the same visits
The conduct of the study, according to protocol specifications, was impacted by the COVID-19 
pandemic.  As a result, and as of Version 3 of the Protocol, modifications intended to address 
access to and administration of investigational product (IP), and adherence to protocol-specified 
visits and laboratory assessments were implemented.  These modifications are described in 
Appendix 1 (COVID-19 Mitigations).  
7.2.
Number of Patients
Patient numbers will be determined by those who are participating and have previously 
participated in a qualifying clinical study with bardoxolone methyl. 


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7.3. 
Treatment Assignment  
All patients will receive bardoxolone methyl in this study. 
7.3.1. 
Dose Escalation  
Adult patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing 
at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at 
Week 6 (only if eligibility ACR > 300 mg/g) unless contraindicated clinically and approved by 
the medical monitor.  Patients from the CARDINAL study under the age of 18 at the time of 
consent for participation in the EAGLE study will start dosing at 5 mg every other day during the 
first week (from Day 1 through the Week 1 visit) and begin once-daily dosing with 5 mg during 
the second week of the study (following the Week 1 visit through the Week 2 visit), and then 
continue with once-daily dosing following the same aforementioned dose-titration scheme based 
on eligibility ACR at Weeks 2, 4, and 6.  Patients from the FALCON study under the age of 18 
at the time of consent for participation in the EAGLE study will follow the adult dose titration 
schedule.  Dose escalation may proceed slowly if the patient experiences early elevation in 
ALT/AST over ULN eg, at Week 2 (See Section 9.1.2).  The dosing objective is to titrate 
patients to the maximum dose determined by eligibility ACR and maintain the maximum dose 
after initial dose-titration.  The investigator should discuss any reason for not dose-escalating at 
Weeks 2, 4, or 6 with the medical monitor.   
7.3.2. 
Dose De-Escalation and Re-Escalation 
The investigator may choose to decrease the patient’s dose to the prior dose (eg, 20 mg to 10 mg, 
or 10 mg to 5 mg), if clinically indicated.  Dose de-escalation may occur more than once, but the 
minimum dose permitted is 5 mg.  Reasons for dose de-escalation should be discussed with the 
medical monitor prior to changing the dose and must be documented.  After dose de-escalation, 
patients must return for an unscheduled, in-clinic visit within 4 weeks (± 3 days) to perform the 
assessments detailed in Section 9.6. 
If a patient’s dose has been reduced, dose re-escalation back to a higher dose is permitted to meet 
the dosing objective.  However, patients who dose re-escalate must have a telephone call 1 week 
(± 2 days) after dose re-escalation and an unscheduled, in-clinic visit 2 weeks (± 3 days) after 
dose re-escalation to perform the assessments detailed in Section 9.6. 
Patients who had a delayed initial dose-escalation should also have a telephone call 1 week 
(± 2 days) after each dose escalation and an in-clinic visit 2 weeks (± 3 days) after dose 
escalation to perform the assessments detailed in Section 9.6.  If these timepoints no longer 
coincide with scheduled study visits, unscheduled phone calls and in-clinic visits should occur.  
These do not replace the regularly scheduled study visits; they should be performed as well. 
7.3.3. 
Interruption and Resuming of Study Drug 
In addition to dose de-escalation and re-escalation, the study drug administration can be 
interrupted, if clinically indicated.  The term interruption refers to a temporary halt of study drug 
administration.  If there are any questions regarding study drug interruption, please consult the 
medical monitor. 


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Any patient who interrupts study drug for 14 consecutive days or more must have approval from 
the medical monitor prior to resuming study drug. 
When a patient resumes study drug after an extended interruption (eg, more than 14 days), the 
site should discuss the appropriate starting dose and visit frequency with the medical monitor.  
The duration of the interruption and the reason for interruption should be taken into 
consideration when determining how to safely resume study drug.   
Following an extended interruption, when the investigator deems it is safe for the patient to 
return to the site for an in-person visit, the investigator should conduct an evaluation to 
determine whether the patient is still eligible to receive study drug and to determine the 
appropriate does, in consultation with the medical monitor.  This should include a confirmation 
that the patient’s circumstances have not changed in a manner that would prohibit administration 
of the study drug (eg, the patient is now taking an excluded medication).  Once the investigator 
determines study drug administration is appropriate, dosing may proceed. 
Patients must have a telephone call approximately 1 week after resuming and an unscheduled, 
office visit 2 weeks (± 3 days) after resuming study drug to perform assessments detailed in 
Section 9.6.  
7.3.4. 
Adolescent Dosing Rationale 
Adolescents (12 ≤ age < 18) enrolling from FALCON will receive the same dosing regimen as 
adults. The maximum bardoxolone methyl dose will be determined by baseline proteinuria 
status.  Similar to the adult population, a dose de-escalation is permitted during the study if 
indicated clinically, and subsequent dose re-escalation is also permitted to meet the dosing 
objective of the highest tolerated dose. 
Although no adolescent (12 ≤ age < 18) patients with CKD due to ADPKD have been exposed to 
bardoxolone methyl, in CARDINAL and EAGLE, approximately 20 adolescent patients with 
Alport syndrome received bardoxolone methyl at a maximum dose of 20 mg for patients with 
baseline ACR ≤ 300 mg/g and a maximum dose of 30 mg for patients with baseline 
ACR > 300 mg/g. In CARDINAL phase 2/3 studies, the dose titration for adolescent patients 
was similar to adults, differing only during the first week, where adolescents administered study 
drug (at the 5 mg dose) every other day, while adults (also at the 5 mg dose) administered study 
drug daily. An overall safety/tolerability evaluation of adolescent patients from CARDINAL 
phase 2 (open-label, n=2) and Phase 3 (double-blind placebo-controlled, n=11) showed the 
dosing regimen was well tolerated and the adverse event profile in adolescent patients was 
similar to the adverse events profile observed in the adult patients. 
Additionally, a population pharmacokinetic (popPK) analysis was conducted for bardoxolone 
methyl using rich and sparse PK data from 8 clinical studies in healthy subjects and patients with 
Alport syndrome, PAH, T2D CKD, ADPKD, and other rare CKDs (Study REAT-BARD-PMX-
1532).  The effects of intrinsic factors on bardoxolone methyl PK were evaluated in the popPK 
analysis and showed that no dose adjustments based on sex, age, body weight, race, or renal 
function are needed.   To further support dosing recommendations based on age, simulations 
using the popPK model were performed to assess the potential effects of age on bardoxolone 
methyl steady-state exposures.  Simulations were conducted following 20 mg QD and used 
individual posthoc PK parameter estimates for all patients and subjects in the popPK analysis 


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dataset.  Model predictions demonstrate a lack of a clinically meaningful difference in exposures 
between patients and subjects < 18 years of age and patients and subjects ≥ 18 years of age (ratio 
of median exposures: 0.93 to 1.11).  In addition, the systemic clearance of bardoxolone methyl 
was not affected by disease state in the popPK analysis.  Therefore, there are no differences in 
systemic exposure (AUC) expected between patients with ADPKD and patients with Alport 
syndrome.  The popPK model predicted mean steady-state AUC for patients receiving 30 mg QD 
(n=16) in Study 402-C-1702 (rare CKDs, including ADPKD) is 222 ng*hr/ml (SD =  
134 ng*hr/ml), and is similar to the popPK model predicted mean steady-state AUCs of  
263 ng*hr/ml (SD = 135 ng*hr/ml) and 223 ng*hr/ml (SD = 155 ng*hr/ml) in Alport syndrome 
patients receiving 30 mg QD in the phase 2 (n=9) and  phase 3 (n=24) portions of CARDINAL), 
respectively.   
In summary, there were no differences in adverse event profiles in adolescent and adult patients 
who received bardoxolone in CARDINAL phase 2/3 studies, and a popPK analysis suggested 
there are no expected differences in systemic exposure (AUC) between ADPKD and Alport 
syndrome patients and no age dependent requirements for dose adjustments. Therefore, the same 
dosing regimen is proposed both for adolescent and adult ADPKD patients.   
7.4. 
End of Study and Commercial Availability 
Each patient will complete an End of Study visit that should occur within 30 days after 
bardoxolone methyl becomes available to the patient through commercial channels.  Commercial 
availability is defined as when the commercial drug is approved for use by the relevant 
regulatory authority and is made available through commercial channels to that patient.  The 
timing of commercial availability can vary by country, site and/or patient, depending on these 
factors.  The scheduled study visits and IP dispensation will continue for each patient until 
commercial availability or alternative drug supply arrangements are made.  More information on 
other scenarios for study closure are included in Section 7.5. 
7.5. 
Criteria for Study Termination 
The Sponsor reserves the right to discontinue the study at any time for clinical or administrative 
reasons, or if required by regulatory agencies.  If the Sponsor discontinues the study, all study 
drug will be discontinued and the investigator will be responsible for securing any alternative 
therapy to be administered, as appropriate. 
7.6. 
Criteria for Premature Termination or Suspension of Investigational 
Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of good clinical practice (GCP), protocol, or contractual 
agreement with Sponsor or the site is unable to ensure adequate performance of the study. 
7.7. 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Sites 
In the event that the Sponsor, an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), or regulatory authority elects to terminate or suspend the study or the 


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participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the Sponsor. 
7.8. 
Schedule of Assessments 
Table 5 lists the overall schedule of assessments for the study. 


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Table 5: 
Schedule of Assessments  
Study 
Week 
(Day±Days) 
Assessment 
Screening 
Visit
a 
Day 
1a,c 
Week 1 
(Phone) 
Day 3 ± 
2 Days 
Week 
1 Day 
7 ± 3 
Days 
Week 2 
(Phone) 
Day 10 
± 2 
Days 
Week 
2 Day 
14 ± 
3 
Days 
Week 3 
(Phone) 
Day 21 
± 2 
Days 
Week 
4 Day 
28 ± 
3 
Days 
Week 4 
(Phone) 
Day 31 
± 2 
Days 
Week 5 
(Phone) 
Day 38 
± 2 
Days 
Week 
6 
Day 
42 ± 
3 
Days 
Week 7 
(Phone) 
Day 45 
± 2 
Days 
Week 
8 
Day 
56 ± 
3 
Days 
Week 
12 
Day 
84 ± 3 
Days 
Week  24 
± 3 
Days, 
Every 24 
Weeks ± 
3 Days 
End 
of 
Study 
Visit
b 
Informed consent 
X
c 
X
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Weight at home 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight in-clinic 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Dispense Weight & Study Drug 
Diary 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Collect/Review Weight & Study 
Drug Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Physical examination 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Xe 
Xe 
Pregnancy testf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Dispense study drug 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Collect study drug 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Telephone contact 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
Adverse event collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Basic Lipid Panel 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Chemistries (incl. 
eGFR)g 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
BNP and NT-Pro BNP 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Urine collection for ACRh 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Tanner Stagingi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: AE=adverse event; BNP=B-type natriuretic peptide; eGFR=estimated glomerular filtration rate; NT-proBNP=N-terminal prohormone B-type natriuretic peptide; 
ACR=albumin to creatinine ratio; WOCBP=women of child-bearing potential 
a A screening visit will be conducted for subjects whose planned EAGLE Day 1 visit is not within 8 weeks of the eligibility lab assessments from the prior qualifying study.  Refer 
to Section 7.1 for additional details.  Subjects requiring a screening visit will be consented prior to the start of any screening assessments.  All other subjects will be consented at 
the start of the Day 1 visit, before any procedures are performed for this, or the prior study. 
b After the Week 24 visit, subjects will continue to be assessed in person every 24 weeks until the study ends. The End -of- Study visit should occur within 30 days after 
bardoxolone methyl becomes available to the subject through commercial channels.  For additional details, see Section 7.4.  Subjects who will be discontinued from the study prior 
to commercial availability of bardoxolone methyl must also complete all End-of-Study assessments as soon as possible (if possible, within 30 days of discontinuation).   


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c On Day 1, all procedures should be performed before study drug administration.  AE assessment on Day 1 should be performed following study drug administration. If the Day 1 
visit for EAGLE is the same as the end-of-study visit for CARDINAL (all versions) or FALCON (protocol version 5 and older), the laboratory assessments required for both visits 
should only be completed once.  
If the Day 1 visit for EAGLE is the same as the end-of-study visit for FALCON (protocol version 6 and newer), the lab assessments required for both visits should be completed 
for each study individually. 
d Demographics are to be performed on the earliest study visit, whether it be Day 1 or a Screening visit, if necessary. 
e Assessment should include a complete physical examination as described in Section 9.9.7.  
f A serum pregnancy test will be performed at any point in time if a pregnancy is suspected.  All other pregnancy assessments will be urine pregnancy tests.  Additional pregnancy 
assessments will be performed more frequently if required by local law or requested by local health authorities or IRBs/IECs.   
g eGFR will not be calculated by the central lab. 
h Urine albumin to creatinine ratio will be measured by first morning void spot urine collection.  Appropriate containers for the collection will be provided to the subject at the visit 
prior to collection. 
i Adolescent patients from the FALCON (402-C-1808) (12 ≤ age < 18 years at consent) will be assessed by Tanner staging at all specified timepoints. 


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Diagnosis and main criteria for inclusion:  
1. Patients who are participating (or who have participated) in qualifying studies and who 
have not been required to discontinue study treatment for protocol or safety reasons and 
who have completed required End-of-Treatment and/or Follow-up visits in a prior 
clinical study with bardoxolone methyl and who, according to the assessment of the 
investigator, have a potential positive benefit-risk assessment for participating in the trial; 
2. Meets the following eligibility criteria based on assessments from the prior qualifying 
study or from a screening visit, if applicable.   
a. Not expected to reach ESKD or nephrotic syndrome within 12 weeks of study 
enrollment, in the investigator’s judgement; subjects with eGFR < 20 ml/min/1.73m2 
should be discussed with the medical monitor before enrollment (eg, such subjects 
with an average rate of eGFR decline > 1.0 ml/min/1.73m2 per month in the 3 months 
prior to eligibility assessment may not be eligible); 
b. BNP < 200 pg/mL at the last on-treatment visit in the prior qualifying study or at a 
screening visit, if applicable, as shown in Section 7.1 and Table 5; 
c. No occurrence of a cardiovascular serious adverse event in the prior qualifying study 
or in the interval between the end of the qualifying study and the screening visit, if 
applicable. 
3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures; 
4. Evidence of a personally signed and dated informed consent document (and assent form 
if necessary) indicating that the patient (or a legally acceptable representative) has been 
informed of all pertinent aspects of the study prior to initiation of any protocol-mandated 
procedures.  


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8.2. 
Patient Exclusion Criteria 
All patients with any of the following conditions or characteristics must be excluded from the 
study: 
1. Participation in other investigational clinical studies involving interventional products 
being tested or used in a way different from the approved form or when used for an 
unapproved indication; 
2. Patients who have an ongoing SAE from a clinical study that is assessed by the 
investigator as related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners 
of childbearing potential and females of childbearing potential) while screening, taking 
study drug, and 30 days after last study drug dose;  
4. Women who are pregnant or breastfeeding; 
5. Patient is, in the opinion of the investigator, unable to comply with the requirements of 
the study protocol or is unsuitable for the study for any reason; 
6. Known hypersensitivity to any component of the study drug. 
8.3. 
Screening Period 
The Day 1 visit of EAGLE is not required to be the same day as the End of Study visit of the 
prior qualifying study.  As shown in Table 4, lab assessments from the qualifying study may be 
used for EAGLE eligibility and maximum treatment dose assignment (Week 100 for 
CARDINAL or FALCON protocol versions 1.0 through 5.0, and Week 108 [B] for FALCON 
versions 6.0 and newer) if those assessments were done ≤ 8 weeks before Day 1. In the event the 
eligibility lab assessments were obtained > 8 weeks before the planned EAGLE Day 1 visit, a 
screening visit will be required for EAGLE enrollment.  
Patients who previously were ineligible due to previous eGFR requirements may be rescreened 
once. 
The maximum bardoxolone methyl dose will be determined by proteinuria status based on the 
ACR value from the eligibility lab assessments from the prior qualifying study, or for patients 
requiring a screening visit, the maximum bardoxolone methyl dose will be determined based on 
the ACR values from the screening labs.  
Subjects requiring a screening visit will be consented prior to the start of any screening 
assessments.  All other subjects will be consented at the start of the Day 1 visit, before any 
procedures are performed for this, or the prior study.  
All screening procedures should be completed per the schedule of assessments in Table 5. 
8.4. 
Patient Re-Screening & Re-Testing 
8.4.1. 
Re-Screening 
Patients may repeat Screening once to qualify for the study (re-screening must occur at least 
2 weeks after the screen fail).  In rare circumstances, a second re-screening may be appropriate; 


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in these cases, the site must consult with the medical monitor for approval.  When a patient 
repeats screening, the patient keeps the same patient number while re-screening procedures are 
completed. No new patient number is generated, this ensures the patient number during EAGLE 
will match the one used in the prior qualifying study.   
8.4.2. 
Re-Testing 
In rare situations, a specific screening test (eg, BNP) may be repeated if the test value is 
inconsistent with the patient’s medical history and/or is considered by the investigator to be an 
anomaly.  Medical monitor approval must be obtained prior to re-testing any of the eligibility 
parameters for a patient. 
8.5. 
Discontinuation  
Discontinuation refers to a patient’s permanent stopping of administration of study drug and all 
study assessments and visits for a patient, site, or study.  Patients have the right to discontinue 
study drug and withdraw from the study at any time for any reason, without prejudice to their 
medical care.  Furthermore, the investigator may discontinue a patient from study drug and the 
sponsor may terminate a specific site or the entire study.  Consultation with the medical monitor 
should occur prior to study drug discontinuation and withdrawing a patient from the study.  The 
reason for a patient’s discontinuation from study drug or study termination will be recorded in 
the electronic case report form (eCRF).   
Patients who permanently discontinue from study drug will be asked to complete the End-of-
Study procedures noted in Table 5, and withdraw from the trial. 
If a patient reaches ESKD (defined as the initiation of maintenance dialysis for 12 weeks or more 
or kidney transplant), the patient must terminate from the study and should complete an end-of-
study visit.  The investigator should record the ESKD event as an adverse event and document 
the date of dialysis initiation or kidney transplantation.  
The reason for discontinuation will be recorded in the eCRF. Reasons for discontinuation may 
include the following. The standardized disposition term is provided, and details are listed in 
[brackets]: 
• ADVERSE EVENT [Occurrence of an AE or change in medical status that will lead 
the investigator to be concerned about the patient’s welfare]; 
• DEATH; 
• LOST TO FOLLOW-UP [Patient lost to follow-up]; 
• NON-COMPLIANCE WITH STUDY DRUG [Subject has not agreed with or 
followed the instructions related to the study medication]; 
• OTHER [Other specified reason for patient discontinuation]; 
• PHYSICIAN DECISION [Specified medical reason for patient discontinuation]; 
• PREGNANCY [Females who become pregnant during the study]; 
• PROTOCOL DEVIATION [Non-compliance with protocol]; 


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• PROTOCOL-SPECIFIED WITHDRAWAL CRITERIA MET [Reached ESKD 
(initiation of maintenance dialysis for 12 weeks or more or kidney transplant)]; 
• STUDY TERMINATED BY SPONSOR [Sponsor termination of the study]; 
• SITE TERMINATED BY SPONSOR [Premature termination or suspension of an 
investigational site]; 
• WITHDRAWAL BY SUBJECT [Administrative reasons (eg, inability to continue); 
Voluntary withdrawal; Withdrawal of consent]; 
Patients should temporarily interrupt study drug and the medical monitor should be contacted to 
discuss if permanent study drug discontinuation is required if any of the following occur. Refer 
to Section 9.1.2 for additional guidance 
• ALT or AST > 8X ULN; 
• ALT or AST > 5X ULN for more than 2 weeks; 
• ALT or AST > 3X ULN and (total bilirubin > 2X ULN or International Normalized 
Ratio [INR] > 1.5); 
• ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Select Management Guidelines 
The following guidelines apply to the management of study participants:   
9.1.1. 
Management of Fluid Status 
Specific risk mitigation procedures will be employed to reduce the potential for bardoxolone 
methyl-induced fluid overload.  Laboratory data will be used to monitor fluid status after 
enrollment.  Patients who experience a BNP > 100 pg/mL that represents a doubling (or more) of 
BNP levels from Day 1 should have an unscheduled telephone contact immediately.  If fluid 
retention is suspected, the patient should be instructed to stop taking study medication 
immediately and be medically evaluated by the investigator or a local physician within 1 to 
2 days. 
Additionally, after enrollment and starting study treatment, patients will be closely monitored for 
rapid weight gain suggestive of fluid overload. Patients will be given a Sponsor-provided scale to 
use at home to collect and record their weights daily during the first 8 weeks of the treatment 
period and weekly thereafter. In the event the Sponsor-provided scale is temporarily unavailable 
(eg, subject is traveling, replacement scale has not arrived to subject, etc.), subjects may use any 
available scale.  Use of a scale other than the Sponsor-provided scale should be documented in 
the subject diary.  During the first 8 weeks, patients who experience a five-pound (2.3 kg) or 
greater increase in weight in one week or 3 pounds (1.4 kg) in one day should have an 
unscheduled telephone contact immediately. Whether prompted by BNP elevations, sudden 
weight gain, or by the presence of clinical signs and symptoms the patient must be instructed to 
stop taking their study medication immediately and be medically evaluated by the investigator or 
a local physician within 1 to 2 days. 
Investigators are encouraged to start or increase doses of diuretics (thiazides, loop diuretics) 
early after recognition of edema. This can be done concurrently with temporary drug interruption 
and re-initiation. Patients may not restart their study medication until the investigator has 
completed and documented an assessment of fluid overload. 
After Week 8, patients who experience a five-pound (2.3 kg) or greater increase in weight in one 
week will be instructed to return to the clinic for an unscheduled physical examination and 
laboratory assessment by the investigator. Study medication should not be interrupted until the 
investigator has completed and documented an assessment of fluid overload. 
Investigators should advise patients to watch for signs and symptoms of fluid overload. Patients 
should be informed to notify their physicians immediately if they experience swollen feet, chest 
pain, shortness of breath with mild exertion or while lying down, or other relevant symptoms. 
The investigator should immediately assess symptoms of fluid overload and determine 
appropriate medical management, as necessary, including whether stopping drug administration 
is required. At the earliest sign of worsening or new onset peripheral edema or other signs and 
symptoms of acute volume overload, investigators will be expected to report if changes to a 
patient’s diuretic regimen have been required to manage edema. 


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9.1.2. 
Management of Elevated Aminotransferase Levels (ALT and/or AST) 
For all patients enrolled, nearly all instances of elevated aminotransferases due to bardoxolone 
methyl treatment are expected to be asymptomatic. Some patients may experience more rapid 
increases in ALT/AST values than others during the dose titration period.  Investigators may 
consider extending the time between each dose increase to manage ALT/AST elevations. 
If a patient’s transaminases are elevated, follow the instructions outlined in Table 6.   
Table 6: 
Management of Elevated Aminotransferase Levels (ALT and/or AST) 
ALT and/or AST Level(s) 
Dose 
Interruption 
(yes/no) 
Procedure 
> 8X ULN 
Yes 
 
Interrupt study drug temporarily  
 
Contact the medical monitor  
 
The study drug may be restarted with Sponsor 
approval after all the following criteria are met:  
• Ultrasound or MRI of the hepatobiliary tree*; 
• ALT and AST returned to ≤ ULN; 
• TBL is within normal range; 
• Other relevant labs (eg, albumin, INR, PT) are 
within normal range; 
• No clinical signs or symptoms of liver injury 
are present. 
 
*Based on imaging results, if additional 
tests/studies are warranted, this should be 
discussed with the medical monitor.  
> 5X ULN for more than 
2 weeks 
> 3X ULN with the 
appearance of fatigue, 
nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, 
and/or eosinophilia 
> 3X ULN and 
(TBL > 2X ULN or INR > 1.5) 
> 3X ULN 
No 
 
Check transaminase levels (as well as 
TBL, GGT, alkaline phosphatase [ALP], 
and International Normalized Ratio [INR]) 
within 48 to 72 hours 
Continue testing for ALT/AST every 72 to 
96 hours until transaminase levels are below 3X 
the ULN for at least 1 week 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
GGT=gamma-glutamyl transpeptidase; INR=international normalized ratio; MRI=magnetic resonance imaging; 
PT=prothrombin time; TBL=total bilirubin; ULN=upper limit of normal  
Patients restarting study drug after meeting these interruption criteria should start at the 5 mg 
dose level and dose titrate according to Section 7.3.2. 


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The hepatobiliary tree must be assessed by ultrasound or magnetic resonance imaging (MRI) for 
patients who meet temporary interruption criteria. Based on imaging results, if patient additional 
tests/studies are warranted, this should be discussed with the medical monitor.  
9.1.3. 
Management of Muscle Spasms 
Basic symptomatic relief is the first step in managing muscle spasm, including walking, adequate 
hydration, wearing socks, and stretching before bedtime. Assessment of levels of electrolytes 
such as magnesium, calcium, and potassium may indicate the need for replacement.  Serum 
vitamin D levels may be collected at the discretion of the investigator, in the management of 
muscle spasms.  If vitamin D levels are low, supplementation may be warranted.  Muscle 
relaxants may also help relieve symptoms. 
9.1.4. 
Weight Loss 
The investigator should evaluate adult patients for unexplained weight loss of 7% or greater from 
the Day 1 weight.   Ongoing assessments of other symptomology (for example: nausea, 
vomiting, abdominal pain, or poor appetite) to ensure that the patient is receiving adequate 
nutrition and consideration of other etiologies of weight loss may be warranted for patients 
receiving bardoxolone methyl.   
The investigator should evaluate adolescent patients for unexplained weight loss of 5% or greater 
from the Day 1 weight.  If observed, the investigator should temporarily stop study drug, and 
evaluate the patient for any symptomology (for example: nausea, vomiting, abdominal pain, or 
poor appetite) leading to weight loss, and/or other causes of weight loss.  The investigator should 
inform the medical monitor prior to stopping study drug, and the investigator and medical 
monitor should discuss management of the patient.  
9.1.5. 
Hypomagnesaemia 
In instances where a patient experiences hypomagnesaemia, defined as serum magnesium less 
than 1.3 mEq/L (0.65 mmol/L), consideration should be given to repletion of serum magnesium. 
9.1.6. 
Management of Urinary Protein 
Although increases in urinary protein with bardoxolone methyl have not been associated with 
renal injury or loss of kidney function, investigators should closely monitor patients if urinary 
albumin to creatinine ratios increase by more than 100% and exceed 1000 mg/g for proteinuria 
and should consult the medical monitor for appropriate measures.  
9.1.7. 
Management of Blood Pressure  
Investigators should attempt to maintain the blood pressure within the range recommended by 
the Kidney Disease Improving Global Outcomes (KDIGO) Blood Pressure Working Group:  
≤ 140 mmHg systolic and ≤ 90 mmHg diastolic for patients with urine ACR < 30 mg/g, and  
≤ 130 mmHg systolic and ≤ 80 mmHg diastolic for patients with urine ACR > 30 mg/g  
(KDIGO, 2012).   
Patients being treated with an angiotensin converting enzyme (ACE) inhibitor and/or angiotensin 
II receptor blocker (ARB) should be receiving the maximally tolerated labeled daily dose 
(MTLDD), defined as the dose at or below the labeled dose that does not exhibit any intolerable 


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adverse effects (eg, hypotension, hyperkalemia), based on the investigator's assessment.  
Diuretics may be titrated to help maintain blood pressure target levels.    
Any changes in ACE inhibitor or ARB use or diuretic therapy should be preceded by 
consideration of any relevant contraindications as per the local product information.  
9.1.8. 
Nausea 
Nausea may occur with higher doses of bardoxolone methyl.  Nausea AEs are typically mild and 
reversible within a few weeks after treatment initiation.  If symptoms do not resolve, dose de-
escalation, with consultation of the medical monitor, may be necessary.   
9.1.9. 
End Stage Kidney Disease 
Patients approaching ESKD should be closely monitored by the investigator to fully characterize 
their progression.  For patients with eGFR ≤ 15.0 mL/min/1.73 m2, initiate more frequent follow-
up to closely monitor safety assessments (ie, clinical chemistry (including eGFR), hematology, 
vital sign assessments (including weight), BNP and N-terminal prohormone B-type natriuretic 
peptide (NT-proBNP).  Similar frequent follow-up may also be implemented for patients with 
eGFR > 15.0 mL/min/1.73 m2 who, in the investigator’s opinion based on the anticipated 
progression of their disease, may be approaching ESKD.  Patient follow-up should be completed 
in-person or through a home health visit where in-person visits are not feasible, at least once 
every 4 weeks (± 2 weeks), until one of the following occurs: 
• Initiation of dialysis; 
• Receipt of transplant.   
Upon initiation of dialysis, study drug should be temporarily interrupted.  Because laboratory 
and vital sign assessments can be affected by receiving dialysis, those safety assessments should 
not be performed concurrently while a patient is receiving dialysis.  Patients receiving dialysis 
should continue to be followed for vital status and SAEs by phone or in-person according to the 
protocol scheduled visits.  Dialysis not lasting at least 12 weeks will be considered acute dialysis, 
and patients should be considered for re-initiation of study drug with medical monitor approval.  
After completing acute dialysis, such patients should continue to undergo frequent follow-up (ie, 
at least once every 4 weeks [± 2 weeks]) while eGFR ≤ 15.0 mL/min/1.73 m2. Study drug may 
be restarted following acute dialysis, with medical monitor approval. Dialysis lasting at least 
12 weeks will be confirmed as maintenance dialysis. Upon confirmation of maintenance dialysis, 
study drug should be permanently discontinued. Upon receipt of kidney transplant, study drug 
should be permanently discontinued. See Section 8.5 for description of follow-up options 
following permanent study drug discontinuation.  Initiation of dialysis (acute and/or 
maintenance) and receipt of kidney transplant due end stage kidney disease should be considered 
important medical events, and therefore recorded as SAEs.   
9.1.10. 
Monitoring Growth and Sexual Development in Adolescents 
Growth and sexual development will be assessed through an evaluation of height, weight, and 
Tanner Staging. See the Study Reference Manual for details on the Tanner staging. 
Body weight should be measured daily by patients/caregivers using a provided weighing scale. 
Weight and height will also be measured at all site visits, as outlined in Section 9.9.4  and 


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Section 9.9.5. Patients should be instructed to inform the site if there is an observed weight loss 
of more than 3 pounds (1.4 kg) in between clinic visits (Section 9.1.1 ). 
The medical monitor will routinely evaluate both weight and height entered into the clinical 
database of adolescents and will inform the investigator to initiate further evaluation if there is a 
weight loss of ≥ 5% or lack of expected growth per growth charts. 
Sexual maturity will be assessed by the investigator using Tanner Staging. If any abnormal 
patterns of sexual maturity are identified on evaluation of Tanner Staging, the medical monitor 
should be notified for additional discussion. 
9.2. 
Description of Study Drug 
Bardoxolone methyl (RTA 402) drug product information is shown in Table 7. 
Table 7: 
Bardoxolone Methyl Drug Product Information 
Description 
Bardoxolone methyl capsule (5 mg, 10 mg, 15 mg, 
20 mg) 
Ingredients 
Bardoxolone methyl 
Methacrylic Acid – Ethyl Acrylate Copolymer (1:1), 
Type A  
Silicified Microcrystalline Cellulose  
Hydroxypropyl Methylcellulose  
Lactose Monohydrate 
Sodium Lauryl Sulfate 
Colloidal Silicon Dioxide 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide (capsule pigment) 
Route of Administration 
Oral 
9.3. 
Concomitant Medications 
9.3.1. 
Excluded and Prohibited Medications 
9.3.1.1 Excluded Medications 
Patients taking these medications or treatments will be ineligible for enrollment: 
• Tolvaptan (patients on tolvaptan who have already enrolled under Version 3.0 of the 
protocol may remain in the trial); 
• Somatostatin analogues 
• Any other investigational drug or device as part of an interventional study within 
30 days prior to Day 1; 
• Chronic (> 2 weeks) immunosuppressive therapy, or need for corticosteroids, 
including therapies such as glucocorticoids, oncologic preparations, and anti-TNFα 


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agents (eg, infliximab [Remicade®], adalimumab [Humira®], certolizumab pegol 
[Cimzia®], etanercept [Enbrel®]) within 12 weeks prior to enrollment.  
Glucocorticoid intra-articular injections, inhaled products, topical preparations, and 
nasal preparations are allowed. 
If a patient takes an excluded medication during the study, the investigator should consult with 
the medical monitor immediately to discuss if there is need for study drug interruption or 
discontinuation.  
9.3.1.2 Prohibited Medications 
Concomitant use with strong or moderate CYP3A4 inhibitors or inducers is prohibited; switching 
to alternate allowed medication should be considered. If a strong or moderate CYP3A4 inhibitor 
or inducer is medically necessary, discuss with medical monitor.  Subjects who are using these 
medications prior to screening should have a washout for at least 5-half-lives or 30 days, 
whichever is longer. 
Concomitant use with Chronic (> 2 weeks) immunosuppressive therapy, corticosteroids, 
including therapies such as glucocorticoids, oncologic preparations, and anti-TNFα agents (eg, 
infliximab [Remicade®], adalimumab [Humira®], certolizumab pegol [Cimzia®], etanercept 
[Enbrel®]) is prohibited.  
Concomitant use with tolvaptan (patients on tolvaptan who have already enrolled under Version 
3 of the protocol may remain in the trial), somatostatin analogues, and any other investigational 
drug or device is prohibited. Concomitant dosing with prohibited medications is not allowed and 
will not be approved by the medical monitor.  If a site becomes aware of a patient administering 
a prohibited medication, the medical monitor should be notified immediately to determine 
whether study drug should be permanently discontinued or whether an interruption is 
appropriate.   
Importantly, the administration of any medications listed in this section should be recorded in the 
concomitant medication page of the electronic data capture (EDC) independent of the patient’s 
study drug status or duration since the patient’s last dose of study drug, to ensure accurate 
interpretation of safety and efficacy data.  
9.3.2. 
Permitted Medications 
Allowed concomitant medications include the following: 
• Antibiotics, including (but not limited to) fluoroquinolones and trimethoprim-
sulfamethoxazole (if the antibiotic being prescribed is a moderate or strong CYP3A4 
inhibitor or inducer, see Section 9.3.1. 
• Daily multivitamins or recommended daily supplements; 
• Other medications intended to manage concurrent diseases, as authorized by the 
treating physician; 
• Statins (eg, pravastatin or rosuvastatin), in the Czech Republic and globally; 
• Pain management: acetaminophen, and other adjuvant analgesics and opioids may be 
used as deemed appropriate by the investigator, in the Czech Republic and globally; 


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• Oral, implantable, or injectable contraceptives. 
Patients taking medication chronically, including ACE inhibitors, ARBs, and SGLT2 inhibitors 
should be maintained on those same doses and dose schedules throughout the study period and 
should not have additions or changes made to their medications, unless medically indicated.   
The list presented above is meant to serve as a broad guideline and is not exhaustive. Drugs not 
listed here, but which are deemed medically necessary, may be used provided if they do not fall 
under the excluded medications described in Section 9.3.1. Questions about permitted 
medications should be directed to the medical monitor.  
9.4. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to patients enrolled in the study in accordance with the protocol.  Patients should administer 
study drug exactly as instructed by the site.  Non-compliance is defined as taking less than 80% 
or more than 110% of expected study medication during any evaluation period (visit to visit).  A 
lack of treatment compliance during any evaluation period (visit to visit) should be entered as a 
protocol deviation.   
Patients should record in the patient diary all administered and missed doses of study drug.  A 
missed dose includes inadvertent missed doses as well as study drug interruptions and 
discontinuations. Patients will be asked to return all unused study drug (study drug bottles and 
any unused capsules). The study drug must not be used for reasons other than that described in 
the protocol. 
9.5. 
Randomization 
Not applicable 
9.6. 
Unscheduled Visits 
Unscheduled visits may be performed at any time and for any reason, including those not 
specifically mentioned in this section, as deemed necessary by the investigator. 
• Unscheduled visits conducted for the following reasons should include collection of 
AEs, clinical chemistry, BNP/NT-proBNP, hematology, concomitant medication 
collection, and vital signs;  
• Assessment of weight gain per Section 9.1.1; 
• Management of an AE or SAE; 
• Performance of additional laboratory tests for clinically abnormal laboratory test 
values or to confirm a possible pregnancy; 
• Dose re-escalation; 
• Dose de-escalation; 
• Resuming study drug following an extended interruption; 
• eGFR ≤ 15.0 per Section 9.1.9; 


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• patient safety evaluation. 
Unscheduled visits conducted for the following reasons do not require additional assessments 
unless deemed necessary by the investigator. 
 
Study drug dispensation; 
 
Any operational need that would require the patient to return to the site between 
scheduled visits. 
9.7. 
Pregnancy 
9.7.1. 
Women of Childbearing Potential and Fertile Males 
Women of childbearing potential (WOCBP) are those who have experienced menarche and are 
not surgically sterile (no history of bilateral tubal ligation, hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy), do not have fallopian inserts with confirmed blockage (eg, x-ray, 
ultrasound), have not had reproductive potential terminated by radiation, and are not 
postmenopausal (defined as no menses for at least 1 year without an alternative medical cause). 
For patients enrolled in United Kingdom, women with bilateral tubal ligation are considered as 
WOCBP and will be required to use other types of birth control measures specified in 
Section 9.7.2. 
Fertile males are those who have entered puberty or reached physical maturation (after puberty) 
and are not surgically sterile (no history of bilateral orchiectomy or vasectomy at least 6 months 
earlier with the appropriate post-procedure documentation of surgical success). 
Pregnancy using frozen embryos of subject or subject partner is not permitted in the study. 
Czech Republic Only: 
Women of childbearing potential (WOCBP) are those who have experienced menarche and are 
not surgically sterile (no history of bilateral tubal ligation, hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy), and are not postmenopausal (defined as no menses for at least 1 year 
without an alternative medical cause). 
Fertile males are those who have entered puberty or reached physical maturation (after puberty) 
and are not surgically sterile (no history of bilateral orchiectomy). 
9.7.2. 
Methods of Birth Control 
During Screening, while taking study drug, and until 30 days following administration of the 
final dose of study medication, WOCBP must practice one of the following acceptable methods 
of birth control: 
• Use double barrier contraception method defined as male use of a condom and female 
use of a barrier method (eg, contraceptive sponge, spermicidal jelly or cream, 
diaphragm [always use with spermicidal jelly/cream]). Double-barrier methods are 
not allowed for patients at participating sites in Germany and Australia; 
• Use of hormonal contraceptives (oral, parenteral, intravaginal, or transdermal) for at 
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• Use of an intrauterine device; 
• Vasectomized partner (with vasectomy performed at least 6 months prior to screening 
(if necessary) or day 1 with the appropriate post-procedure documentation of surgical 
success).  Partner must be the sole partner for that patient; 
• Abstain from sexual intercourse completely.  Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
During Screening, while taking study drug and until 30 days following administration of the final 
dose of study medication, fertile males who have female partners of childbearing potential must 
practice one of the following acceptable methods of birth control: 
• Have had a vasectomy (performed at least 6 months prior to screening (if necessary) 
or day 1 with the appropriate post-procedure documentation of surgical success); 
• Use double barrier contraception method, defined as male use of a condom and 
female use of a barrier method (eg, contraceptive sponge, spermicidal jelly or cream, 
diaphragm [always use with spermicidal jelly/cream]).  Double-barrier method is not 
allowed for patients at participating sites in Germany and Australia; 
• Have had a vasectomy (with vasectomy performed at least 6 months prior to 
screening with the appropriate post-procedure documentation of surgical success) 
(not permitted in the United Kingdom) 
• Partner contraception methods; must be the sole partner for that patient: 
− Use of an intrauterine device; 
− Use of hormonal contraceptives (oral, parenteral, intravaginal, or transdermal) for 
at least 60 days prior to start of study drug administration; 
− Surgically sterile partner (bilateral tubal ligation, hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy); fallopian inserts with confirmed 
blockage (eg, x-ray, ultrasound) (not permitted in the Czech Republic); 
− Reproductive potential has been terminated by radiation; (not permitted in the 
Czech Republic) 
− Postmenopausal (defined as no menses for at least 1 year) without an alternative 
medical cause. 
• Abstain from sexual intercourse completely.  Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
9.7.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (eg, late or missed menstrual period).  Male patients must be 
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If a WOCBP patient or investigator suspects that the patient may be pregnant, the study drug 
must be withheld until the results of a serum pregnancy test are available.  If the serum 
pregnancy test confirms the pregnancy, the WOCBP patient must discontinue taking study drug. 
A patient must also discontinue study drug if their partner becomes pregnant. The investigator 
must immediately report to the medical monitor a pregnancy associated with study drug 
exposure.  The early discontinuation protocol-required procedures outlined for End-of-treatment 
and Follow-up visits must be performed on the patient.  
Pregnancy is not considered an AE; however, the investigator must follow a pregnant patient, or 
the pregnant female partner of a male patient (if she consents to be followed), and report follow-
up information regarding the course of the pregnancy, including perinatal and neonatal outcome.  
Infants resulting from such pregnancies should be followed for a minimum of 8 weeks.  Reata or 
designee may contact the investigator to request additional information throughout the course of 
the pregnancy. 
The following pregnancy outcomes must be considered SAEs and will require additional 
reporting in the eCRF and reported as a serious AE: 
• Congenital anomaly/birth defect; 
• Stillbirth; 
• Spontaneous miscarriage. 
9.8. 
Serious Toxicities 
In the case of serious toxicities, the investigator may choose to interrupt treatment with 
bardoxolone methyl.  Dose reductions are permitted to manage tolerability issues.  Patients who 
resume therapy after an interruption will follow the originally planned study schedule.  
9.9. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 5.  All Day 1 procedures, except AE assessments, should be completed prior to 
administration of first dose of study drug. 
9.9.1. 
Informed Consent and Assent 
Written informed consent (see Section 15.3) must be obtained from the patient before any 
study-related procedures are performed.  Re-consenting will be required when there is an update 
or change in the study procedures, safety information, or any other information that may affect 
the patient’s willingness to participate. 
For adolescent patients, informed consent will be obtained from the parent(s) or legal guardian in 
accordance with regional laws or regulations.  In addition, dependent upon the patient’s age and 
IRBs, IEC, and/or local requirements, assent of the patient must also be obtained.  Adolescent 
patients may be asked to personally sign and date either a separately designed, written assent 
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9.9.2. 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Section 8.  Patients must meet 
all the inclusion and none of the exclusion criteria for entry in the study.  Investigators should 
contact the medical monitor with any questions regarding eligibility prior to enrolling the patient 
on Day 1. 
9.9.3. 
Prior and Current Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking.  
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug names 
should be used where possible.  Prior and concomitant medications (ie, medications that the 
patient is taking or has taken within 30 days prior to Day 1) will be reviewed as indicated in 
Table 5 and all changes will be recorded. 
9.9.4. 
Height 
Height should be measured without footwear or prosthetics as indicated in Table 5.  
Height should be recorded in centimeters, and where height is measured in inches, the following 
formula should be used to convert inches to centimeters: 
Height (in inches) x 2.54 = Height (in centimeters) 
Any conversions of units should be documented in the source documents. 
9.9.5. 
Weight and Body Mass Index (BMI) 
Weight must be measured as indicated in Table 5.  BMI will be calculated in the eCRF each time 
the weight is recorded.  The Sponsor will provide each patient with a scale to use at home to 
measure weight, and a diary will be provided to record the at-home weight measurements.  
Weights recorded in patient diaries will not be entered in the eCRF.  Weights should be taken at 
approximately the same time each day and recorded in a patient diary.  During the first eight 
weeks, weights will be recorded daily; weekly weights will be recorded thereafter.  Patients will 
be instructed to stop administering study drug and contact the investigator if their daily weight 
increases per the criteria outlined in Section 9.1.1.  Patients will be provided instructions within 
the Informed Consent Form and/or Assent Form to help ensure consistent weight collection 
throughout the study.  
Weight should be recorded in kilograms, and where weight is measured in pounds, the following 
formula should be used to convert pounds to kilograms: 
Weight (in pounds) ÷ 2.205 = Weight (in kilograms) 
Any conversions of units should be documented in the source documents. 
9.9.6. 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), respiration rate, blood pressure, and body temperature.  Blood pressure should be 
taken after the patient has rested in a sitting position for at least 5 minutes.  The same arm 


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(usually the non-dominant arm) and the appropriate size cuff should be used for each 
measurement.  Vital sign measurements should be taken as indicated in Table 5 .  
9.9.7. 
Physical Examination 
A physical examination must be performed by a physician, physician assistant, or registered 
nurse practitioner as indicated in Table 5 and as documented within the table footnotes.  A 
complete physical examination is required at Day 1, Week 1, Week 2, Week 4, Week 6, Week 8, 
Week 12, Week 24, every 24 weeks thereafter, and at the end of study, and must include the 
following organ or body system assessments: head, eyes, ears, nose, throat, musculoskeletal, 
cardiovascular, lymphatic, respiratory, abdomen, skin, extremities, and neurological.  Clinically 
significant findings at Day 1 must be recorded as medical history if there was a time delay 
between this study and the prior qualifying study and this finding was not captured in the 
previous study.  Following the examination on Day 1, new or changed physical examination 
findings meeting the criteria for an adverse event must be recorded as an adverse event.  The 
investigator or his/her appointed designee is primarily responsible to perform the physical exam.  
If the appointed designee is to perform the physical exam, he/she must be permitted by local 
regulations and his/her name must be included on any globally and locally required documents 
(eg, individual must be added for all sites on a United States (US) Food and Drug Administration 
[FDA] Form 1572).  Whenever possible, the same individual should perform all physical exams.  
9.9.8. 
Pregnancy Test 
WOCBP (see Section 9.7) will complete a pregnancy test as indicated in Table 5, or at any time 
if pregnancy is suspected.  Negative test results are required on Day 1 before study drug 
administration.  Any patient who becomes pregnant during the study must discontinue taking 
study drug immediately.  See Section 9.7.3 for a description of procedures to be followed in case 
of pregnancy.   
9.9.9. 
Study Drug Administration 
Patients should self-administer one dose orally as indicated in Section 7.3.1 . Each dose of study 
drug should be administered at approximately the same time each day.  
Study drug administration should be recorded in a patient diary. 
A vomited dose must not be replaced.  A double dose (e.g., missed dose from previous day and 
dose for current day) must not be taken. 
9.9.10. 
Study Drug Dispensation and Collection 
Study drug will be dispensed and collected from the patient as indicated in Table 5.  The patient 
will be dispensed the appropriate number of treatment kits at each timepoint: Day 1, Week 2, 
Week 4, Week 6, Week 8, Week 12, Week 24, and every 24 weeks thereafter for the duration of 
the study.  If the patient is provided more than one kit, only one treatment kit should be opened 
at a time.  Dispensed treatment kits from each visit (including unscheduled visits) should be 
returned to the site for collection at the subsequent visit.  


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If the appropriate number of treatment kits (eg, a 3-month supply) cannot be dispensed as 
outlined in Table 5, a partial supply may be provided to the patient.  The remainder may be 
provided separately to the patient.  Every effort should be made to avoid interruptions in dosing. 
9.9.11. 
Telephone Contact 
Patients will be contacted by telephone as indicated in Table 5.  Patients will be asked about their 
body weight and other signs of fluid retention, as well as AEs and any changes to concomitant 
medications.  If fluid retention is suspected, the patient should be instructed to stop taking study 
medication immediately and be medically evaluated by the investigator or a local physician 
within 1 to 2 days, as detailed in Section 9.1.1. 
9.9.12. 
Adverse Event Collection 
Patients will be observed for general appearance, presence of illness or injury, or signs indicative 
of a concurrent illness as indicated in Table 5.  Patients must be instructed to volunteer any 
information regarding AEs on or after the first dose of study drug or sites may query the patients 
with an open question regarding any AEs they may be experiencing (eg, “How have you been 
feeling since your last visit?”).  Any findings are to be documented.  Patients must be asked if 
they have been hospitalized, had any accidents, used any new medications, or changed 
concomitant medication regimens (including prescription drugs, over-the-counter medications, 
vitamins, herbal products, and minerals).  Responses must be documented in the source 
documents.  AEs should be reported from the time of the first dose through 30 days after the last 
dose (or the End of Study visit, whichever is earlier). 
See Section 11 for more detail regarding adverse events. 
9.9.13. 
Clinical Chemistry 
Samples will be collected for clinical chemistry analyses as indicated in Table 5. These include 
albumin, alkaline phosphatase, ALT, AST, bicarbonate, bilirubin direct, bilirubin total, 
BUN/urea, calcium, chloride, creatine kinase (CK), creatinine, eGFR, ferritin, GGT, glucose, 
LDH, magnesium, phosphorus, potassium, protein total, sodium, and uric acid. 
9.9.14. 
Hematology 
Complete blood count (CBC) collection will be performed following the visit schedule indicated 
in Table 5.  The CBCs will be offered optionally on the unscheduled visits. The tests include: 
hematology; anisocytosis, basophils, basophils absolute, eosinophils, eosinophils absolute, 
hematocrit, haemoglobin, hypochromasia, lymphocytes, lymphocytes absolute, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular 
volume (MCV), microcytosis, monocytes, monocytes absolute, neutrophils, neutrophils absolute, 
platelet count, red blood cell (RBC) count, teardrop cells, and white blood cell (WBC) count. 
9.9.15. 
eGFR 
The eGFR value will not be calculated by the central lab.  The equation used to calculate eGFR 
for each patient throughout the study will be based on the patient’s age on the date of 
consent/assent in the original, qualifying study.  For patients consented at age 18 years and older, 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation will be used: 


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eGFR (mL/min/1.73 m2) = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age ×  
1.018 [if female] × 1.159 [if black] 
For patients consented at age 12 to 17, the Bedside Schwartz equation will be used: 
eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Scr  
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scr/κ or 1 and max indicates the 
maximum of Scr/κ or 1.  Age indicates age at time of serum creatinine lab collection. 
In the absence of any clinically significant event or other medical conditions, the investigator 
should consider re-testing eGFR if the most recent value is significantly different from the prior 
value.  
9.9.16. 
N-Terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) and Brain 
Natriuretic Peptide (BNP)  
Samples will be collected for NT-proBNP and BNP as indicated in Table 5.  As recent exercise 
may affect BNP and NT-proBNP levels, patients should be allowed to rest for approximately one 
hour following arrival at the clinic and prior to obtaining this blood sample.  This sample must be 
taken with the patient in the same position at all appropriate visits, eg, sitting or semi-recumbent. 
Detailed instructions on collection, storage and shipment of the sample will be provided in a 
separate central laboratory manual provided to the investigator.   
9.9.17. 
Urine Collection for Albumin to Creatinine Ratio (ACR) 
Albumin/creatinine ratio will be measured by first morning void spot urine collection as 
indicated in Table 5.  Appropriate containers for the collection will be provided to the patient at 
the visit prior to the collection. 
Patients should be instructed how to properly capture a sample of their first morning void. 
defined as their first urination on the day of collection.  Following Day 1, if a patient presents for 
a visit and has forgotten to collect (or bring) the urine sample(s) for that visit, they may return 
within 7 days to submit the sample(s) collected that day.   
9.9.18. 
Lipid Panel 
Samples will be collected for the following lipid assessments as indicated in Table 5: Total 
Cholesterol, Low-Density Lipoprotein (LDL), High-Density Lipoprotein (HDL), and 
Triglycerides. 
The lipid panel was added to the schedule of assessments through a protocol amendment.  Sites 
should collect these samples from patients once the central laboratory kits and database enable 
collection.  Until such time the site can collect this test, failure to collect it is not considered a 
protocol deviation. 


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9.9.19. 
Medical History 
If the patient delays their study enrollment from the last day of the prior qualifying study, they 
should complete an entry into the Medical History eCRF to capture any events that occurred 
during the time period between the studies. 
9.9.20. 
Tanner Staging 
Gender appropriate Tanner staging will be performed on all ADPKD patients if the patient 
enrolls in the study as an adolescent. Tanner staging should be performed as outlined in Table 5, 
to monitor and assess sexual maturity.  All assessments must be performed even if a patient 
reaches 18 years of age while participating in the study.  Tanner staging may be performed only 
by a physician (specifically, the principal investigator or sub-investigator). 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 5 mg (size #4), 10 mg (size #2), 15 mg (size #1), and 20 mg 
(size #0) may be used in this study.  The 30 mg dose will be given as two 15 mg capsules.   
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied as either individual bottles (5, 10, 20 mg dose) or in tamper-
evident kits containing high-density polyethylene (HDPE) bottles.  Each bottle will utilize foil 
induction-seal liners and a child-resistant closure.  Each bottle of study drug will contain 30 or 
90 capsules of 5 mg, 10 mg, 15 mg, or 20 mg strength bardoxolone methyl.  Each bottle will also 
contain desiccant insert(s) that must not be ingested.  Labeling on each kit bottle will contain at 
minimum the following information: 
• Medication ID number; 
• Protocol 402-C-1803; 
• Caution Statement: New Drug – Limited by Federal Law to Investigational Use.  
Keep out of reach of children; 
• Control or lot number; 
• Store at 15° – 25°C (59° – 77°F)  
• Reata Pharmaceuticals, Inc., Irving, TX. 
When applicable, a double-panel label will be presented on the treatment kit carton containing 
this and other information.  Additionally, labeling, in the relevant local languages for IP for use 
and distribution in the European Union (EU) shall adhere to current Eudralex, Volume 4 Annex 
13 guidance and requirements. 
In the event the IP is not packaged as intended or may not adhere to current good manufacturing 
practices (cGMP), a complaint should be filed with the Sponsor.  Attention should be given to 
ensure the patient number is not submitted within the complaint documentation. 
10.3. 
Study Drug Storage 
The stability of the drug product has been and is currently being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location with room 
temperature conditions of 15° to 25°C (59° to 77°F).   
If the investigational product is stored outside of the designated conditions, a temperature 
excursion notification should be submitted to the Sponsor for review and approval for use of the 
affected IP. 
10.4. 
Study Drug Administration 
Please refer to Section 9.9.9 for details on study drug administration.  It is the responsibility of 
the investigator or designee to provide clear instructions to the patient regarding the number and 


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type of capsules to be ingested at each study drug administration time point listed in Table 5.  
Patients must be instructed to continue taking study drug once daily unless: (1) the patient has 
been otherwise instructed by the investigator or (2) the patient has been formally discontinued 
from study treatment. 
10.5. 
Study Drug Accountability 
Study drug bottles and any unused capsules should be returned to the study staff for eventual 
disposition by the Sponsor.  The investigator, or designee, will maintain a record of all study 
drug received, dispensed, and returned.  The number of capsules returned at each visit will be 
recorded by the site for each bottle in the kit.  The site will make these records available for 
Sponsor or designee review. 
10.6. 
Study Drug Handling and Disposal 
At any time during the conduct of the study, the Sponsor or its designee will direct the site 
regarding the final disposition of study drug.  No study drug shall be destroyed by the clinical 
site unless agreed upon in writing by the Sponsor.  Documentation of study drug disposition will 
be retained with the investigator.  Refer to the IP Handling Manual for detailed instructions on 
study drug handling and disposal. 


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11. 
SAFETY ASSESSMENTS 
11.1. 
Safety Parameters 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all safety assessments.  Safety 
parameters include vital sign measurements, AEs, SAEs, weight, and laboratory test results.  
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Event 
An AE is defined as any untoward medical occurrence in a patient regardless of its causal 
relationship to study drug.  An AE can be any unfavorable and unintended sign (including any 
clinically significant abnormal laboratory test result), symptom, or disease temporally associated 
with the use of the study drug, whether or not it is considered to be study-drug related.  Included 
in this definition are any newly-occurring events or previous conditions that have increased in 
severity or frequency since the administration of study drug. 
All AEs that are observed or reported by the patient during the study (from administration of the 
first dose until End of Study Visit as indicated in Table 5) must be reported, regardless of their 
relationship to study drug or their clinical significance.   
For patients who discontinue study drug early, AEs should be reported through 30 days 
following the date of last dose of study drug or through the End of Study Visit, whichever is 
earlier.  In addition, as noted in Section 11.2.1.2, death, kidney disease, or initiation of transplant 
should be reported as SAEs through the End of Study visit.  
AEs that are related to study procedures should be reported independent of the patient’s study 
status or duration since the patient’s last dose of study drug. SAEs, if considered related to study 
drug, can be reported at any time during the study duration.  
11.2.1.2. Serious Adverse Event 
An SAE is any AE occurring at any dose and regardless of causality that: 
• Results in death; 
• Is life-threatening; 
• Requires hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Is a congenital anomaly or birth defect in an offspring of a patient taking study drug; 
• Is an important medical event.  


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The term "life-threatening" refers to an event in which the patient was at immediate risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Initiation of dialysis (acute and/or maintenance) and receipt of kidney transplant due end stage 
kidney disease, as defined Section 9.1.9, should be considered important medical events.  
Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of the first dose of study drug until the final visit 
indicated in Table 5, as appropriate).  Certain pregnancy outcomes will require submission as an 
SAE (see Section 9.7). 
The investigator is responsible for reporting to Reata or designee all AEs and SAEs that are 
observed or reported by the patient during the study (from the time of administration of the first 
dose of study drug until the final visit indicated in Table 5, as appropriate), including events 
resulting from protocol-associated procedures as defined in relevant legislation, and regardless of 
their relationship to study drug or their clinical significance.  For patients who discontinue study 
drug early, SAEs should be reported through 30 days following the date of last dose of study 
drug.  SAEs, if considered related to study drug, should be reported at any time during the study.  
In addition, death, kidney transplant, or initiation of dialysis, should be reported through the End 
of Study visit on the appropriate eCRF (see Section 11.7).  The Sponsor may request additional 
information from the investigator to ensure the timely completion of accurate safety reports. 
All SAEs reported or observed during the study must be followed to resolution or until the 
investigator deems the event to be chronic or the patient to be stable.  Reata or designee may 
contact the investigator to obtain additional information on any SAE which has not resolved at 
the time the patient completes the study. 
11.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, non-directed question, such as, “How 
have you been feeling since your last visit?” to elicit any medically related changes in their 
well-being.  They may also be asked if they have been hospitalized, had any accidents, used any 
new medications, or changed concomitant medication regimens (including prescription drugs, 
over-the-counter medications, vitamins, herbal products, and minerals).  Responses must be 
documented in the source documents. 
In addition to patient observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, or from 
other documents that are relevant to patient safety. 


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11.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Not Related: This relationship suggests that there is no association between the study drug and 
the reported event. 
Unlikely Related: This relationship suggests that the temporal sequence of the event with study 
drug administration makes a causal relationship improbable and/or other factors also provide 
plausible explanations. 
Possibly Related: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence from the time 
of study drug administration, and/or, follows a known response pattern to the study drug, but 
could have been produced by other factors. 
Probably Related: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
Definitely Related: This relationship suggests that a definite causal relationship exists between 
the drug administration and the AE, and other conditions (eg, concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
For regulatory reporting purposes, an adverse event is considered to be related when the 
causality evaluation is either “Definitely Related, Probably Related, or Possibly Related.”  An 
adverse event is considered to be not related when the causality evaluation is either “Unlikely 
Related or Not Related.” 
11.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities 
Severe: Symptoms causing inability to perform usual social and functional activities  
11.6. 
Recording Adverse Events 
All conditions present prior to the administration of the first dose of study drug (Day 1) should 
be documented as adverse events in the prior trial with bardoxolone methyl.  Any new 
event/condition that starts during the gap between prior qualifying study and Day 1 of EAGLE 
should be recorded as medical history in EAGLE.  AEs should be reported from the time of the 
first dose through 30 days after the last dose or the End of Study visit, whichever is earlier. 


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Information to be collected includes type of event, date of onset, date of resolution, investigator-
specified assessment of severity and relationship to study drug, seriousness, as well as any action 
taken.  
For guidance on how to handle AEs that change in severity (eg, worsening or improving) see the 
eCRF Completion Guidelines.  All drug-related (possibly, probably, or definitely related, see 
Section 11.4) AEs and clinically significant abnormal laboratory test results reported or observed 
during the study must be followed to resolution (either return to baseline, within normal limits, 
or stabilization).  All non-drug related AEs or clinically significant abnormal laboratory results 
will be followed through the 30 days after the last dose of study drug. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Preexisting conditions 
(present before the start of the AE collection period) are considered concurrent medical 
conditions and should NOT be recorded as AEs.  However, if the patient experiences a 
worsening or complication of such a concurrent condition, the worsening or complication should 
be recorded as an AE.  Investigators should ensure that the AE term recorded captures the 
change in the condition (eg, “worsening of…”).  Any improvement in condition should be 
documented per Section 9.9.7. 
Each AE should be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values) or symptoms should NOT be recorded as additional AEs.  If a 
diagnosis is unknown, sign(s) or symptom(s) should be recorded as an AE(s).  Changes in 
laboratory test values are only considered AEs if they are judged to be clinically significant (ie, if 
some action or intervention is required or if the investigator judges the change to be beyond the 
range of normal physiological fluctuation).  If abnormal laboratory test values are the result of 
pathology for which there is an overall diagnosis (eg, increased creatinine levels in renal failure), 
only the diagnosis should be reported as an AE. 
Elective procedures (surgeries or therapies) that were scheduled prior to the start of AE 
collection are not considered AEs.  These elective procedures should not be recorded as AEs, but 
should be documented in the patient’s source documents as elective (eg, elective periodontal 
surgery).  However, if a pre-planned procedure is performed early (eg, as an emergency) because 
of a worsening of the preexisting condition, the worsening of the condition should be captured as 
an AE. 
11.7. 
Reporting Serious Adverse Events 
Any AE the investigator considers serious according to the previously described criteria must be 
reported within 24 hours from the time the site personnel first learn about the event.  
To report the SAE, fax/email the completed SAE form 
 
 within 24 hours of awareness. 


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 Facsimile: 
or 
 
 
E-mail: 
 
For questions regarding SAE reporting, contact your study manager, medical monitor, or 
. 
Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
subject dies. 
Within 24 hours of receipt of new information, the updated follow-up SAE form, along with any 
supporting documentation (eg, subject discharge summary or autopsy reports), should be faxed 
or emailed to 
. 
The Sponsor or designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible but no later than 
7 calendar days after the initial receipt of the information.  Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency.  For other 
SAEs that do not meet the fatal or life-threatening unexpected criteria, but are reported to be 
associated with the use of the study drug, Reata or designee will notify the appropriate regulatory 
agencies in writing within the timeframe established by those regulatory agencies.  Reata or 
designee will provide copies of any reports to regulatory agencies regarding serious and 
unexpected SAEs to the investigators for review and submission to their IRB or IEC, as 
appropriate.  
Principal investigators are responsible for informing their IRB/IEC of any SAEs at their site.  
SAE correspondence with regulatory authorities or IRBs/IECs must be submitted to the Sponsor 
or designee for recording in the study file. 
Note that the following SAEs which are commonly observed in this patient population as part of 
CKD progression will not be reported to regulatory authorities as individual expedited reports, 
except in unusual circumstances: 
• Initiation of dialysis due to end stage kidney disease; 
• Kidney transplant due to end stage kidney disease. 
These events will be reviewed on a regular basis in aggregate and will be reported in an 
expedited manner if a safety signal is detected.  Regular safety study updates will be reported to 
regulatory authorities according to local guidelines. 


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12. 
STATISTICS 
12.1. 
Sample Size 
The aim of this long-term extended access study is primarily to provide continuing bardoxolone 
methyl treatment to patients and to assess long term safety and tolerability, hence no single 
primary variable has been identified.  Patient numbers will be determined by those who are 
participating (or who have previously participated) in a qualifying clinical study with 
bardoxolone methyl. 
12.2. 
Study Variables 
12.2.1. 
Safety Variables 
The safety variables include results of physical examinations, laboratory test results, ACR, vital 
sign measurements, height, weight, AEs, and SAEs. 
12.3. 
Statistical Analyses 
A statistical analysis plan (SAP) detailing the analyses will be developed prior to database lock.  
All statistical analyses and data summaries will be performed using SAS® (Version 9.3 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized using descriptive statistics.  Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, relevant quartiles, 
standard deviation, coefficient of variation, and geometric mean (where applicable).  Categorical 
data will be summarized using frequency counts and percentages.  
12.3.1. 
Primary Analysis of Safety 
As the extension is an open-label design with no comparator group, all statistical analyses will be 
descriptive.   
The summary tables will be presented for the overall group of patients, and also split by previous 
treatment groups (ie, bardoxolone methyl or placebo) in prior bardoxolone methyl clinical 
studies.   


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
The study monitor, as a representative of the Sponsor, is obligated to follow the study conduct 
closely.  In doing so, the monitor will visit the principal investigator and study facilities 
periodically and will maintain necessary telephone and letter contact.  The monitor will maintain 
current knowledge of the study activity of the investigator and his/her staff through observation, 
review of study records and source documentation, and discussion of the conduct of the study 
with the investigators and staff. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Council for Harmonisation for Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guideline E6(R2): Good Clinical 
Practice: Consolidated Guideline and current standard operating procedures. 
Each investigator is expected to make a reasonable effort to accommodate the monitor when 
monitoring visits are necessary and to be available during the site visit.  Furthermore, the 
monitor should be provided direct access to source data and documents for trial-related 
monitoring and internet during the visit. 
In case that study sites are closed for any visitors and monitors over a certain period of time 
during the COVID-19 pandemic, a risk-based approach to monitoring will be taken, focusing on 
certain sites, certain data points and certain processes that are critical to ensure the rights, safety 
and well-being of trial participants and the integrity of the trial (and trial data).  The results of 
adjusted monitoring/review measures and their impact will be reported to the Sponsor in 
monitoring reports and in the clinical study report, where applicable.  Adjusting monitoring 
activities may include a combination of on-site and off-site monitoring, where permitted by local 
regulations.  Remote source data verification may also be taken into consideration, where 
permitted by local regulations. 
13.2. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/IEC review, and regulatory inspections, by providing direct access 
to all study records.  In the event of an audit, the principal investigator agrees to allow the 
Sponsor, representatives of the Sponsor, the US FDA, and other relevant regulatory authorities 
access to all study records. 
The principal investigator should promptly notify the Sponsor or designee of any audits 
scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the Sponsor or designee. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Reata may conduct a quality assurance audit of the investigator’s clinical site, including CTM/IP 
storage facilities.   
14.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for one year following the completion 
of the study. 
No potential investigator who has a vested financial interest in the success of this study may 
participate in this study. 
14.3. 
Sponsor Obligations  
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the Screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or designee is not financially responsible for treatment of 
the patient’s underlying disease. 
14.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R2) 
8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents 
to the Sponsor or designee, which include but are not limited to the following: 
• An original investigator-signed investigator agreement page of the protocol;  
• The IRB/IEC approval of the protocol; 
• The IRB- or IEC-approved informed consent (and assent, if applicable), samples of 
site advertisements for recruitment for this study, and any other written information 
regarding this study that is to be provided to the patient or legal guardians; 
• A Form FDA 1572 or equivalent statement of investigator, fully executed, and all 
updates on a new fully executed Form FDA 1572; 
• Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
are accurate and current; 
• Completed financial disclosure forms (Section 14.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 


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designee a commitment to update this information promptly if any relevant changes 
occur during the course of the investigation and for 1 year following the completion 
of the study; 
• Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study. 
14.5. 
Clinical Study Insurance 
In accordance with the respective national drug laws, the Sponsor has taken out patient liability 
insurance for all patients who give their consent and enroll in this study.  This insurance covers 
potential fatalities, physical injuries, or damage to health that may occur during the clinical 
study. 
14.6. 
Use of Information  
All information regarding bardoxolone methyl supplied by the Sponsor to the investigator is 
privileged and confidential.  The investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor.  Furthermore, the 
investigator is obligated to provide the Sponsor with complete data obtained during the study.  
The information obtained from the clinical study will be used towards the development of 
bardoxolone methyl and may be disclosed to regulatory authorities, other investigators, corporate 
partners, or consultants as required. 


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15. 
ETHICS 
15.1. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Review 
The protocol and the proposed informed consent form (and assent if applicable) must be 
reviewed and approved by a properly constituted IRB/IEC before study start.  Each investigator 
must provide the Sponsor or its designee a signed and dated statement that the protocol and 
informed consent (and assent, if appliable) have been approved by the IRB/IEC for that site 
before consenting patients.  Prior to study initiation, the investigator is required to sign a protocol 
signature page confirming agreement to conduct the study in accordance with this protocol and 
to give access to all relevant data and records to the Sponsor, its designee, and regulatory 
authorities as required. 
The IRB/IEC chairperson or designee must sign all IRB/IEC approvals and must identify the 
IRB/IEC by name and address, the clinical protocol, and the date approval and/or favorable 
opinion was granted. 
The principal investigator is responsible for obtaining reviews of the clinical research at intervals 
specified by the IRB/IEC, but not exceeding 1 year.  The principal investigator must supply the 
Sponsor or designee with written documentation of reviews of the clinical research. 
15.2. 
Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (eg, US Code of Federal Regulations Title 21, European Directive 2001/20/EC), and 
with the ethical principles laid down in the Declaration of Helsinki.   
The principal investigator agrees to conduct the study in accordance with the ICH Guidance for 
Industry on GCP ICH E6(R2)] and the principles of the Declaration of Helsinki 
[https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-
research-involving-human-subjects/]. The principal investigator must conduct all aspects of this 
study in accordance with all national, state, and local laws or regulations. 
15.3. 
Written Informed Consent 
Because the study will be conducted under a United States Investigational New Drug 
Application, a signed informed consent form (or assent form if necessary), in compliance with 
Title 21 of US CFR Part 50, will be obtained from each patient before the patient enters the 
study.  For sites outside of the United States, the signed consent will be obtained in accord with 
local regulations, ICH E6 (R2), and principles of the Declaration of Helsinki.  An informed 
consent template may be provided by the Sponsor or designee to the investigators.  The consent 
must be reviewed by the Sponsor or designee before IRB/IEC submission.  Once reviewed, the 
consent will be submitted by the principal investigator to his or her IRB/IEC for review and 
approval before the start of the study.  If the informed consent form is revised during the course 
of the study, all participants affected by the revision must sign the revised IRB/EC-approved 
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Before enrollment, each prospective patient will be given a full explanation of the study and be 
allowed to read the approved informed consent form.  Once the principal investigator or designee 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent (or assent as required) to participate in the study by signing the 
informed consent form (or assent form, if necessary).  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.  Informed consent and 
assent, if necessary, must be obtained before conducting any study-specific procedures (ie, all of 
the procedures described in the protocol).  The process of obtaining informed consent (and 
assent, if necessary) must be documented in the patient source documents. 
For adolescent patients, informed consent will be obtained from the parent(s) or legal guardian in 
accordance with regional laws or regulations.  In addition, dependent upon the patient’s age and 
IRBs, IEC, and/or local legal requirements, assent of the patient must also be obtained.  
Adolescent patients may be asked to personally sign and date either a separately designed, 
written assent form, or the written informed consent. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/IEC, and a copy of the approved version and the 
notice of approval must be provided to the Sponsor’s designated monitor after IRB/IEC 
approval. 
In person (in-clinic) informed consenting must be performed during the initial screening or 
enrollment visits. All other informed consenting will be allowed to be performed remotely, if 
permitted by your local regulations.  The principal investigator or designee will provide a copy 
of the informed consent form and/or assent form as necessary (signed copy to be provided per 
applicable law) to the patient and/or legal guardian.  The original form will be maintained in the 
patient’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/IEC. 
The principal investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to them for the purpose of the study.  Prior 
written agreement from the Sponsor or designee must be obtained for the disclosure of any said 
confidential information to other parties. 
15.5. 
Modification of the Protocol 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments.  The FDA or other applicable regulatory agencies must be notified of protocol 
amendments.  The changes will become effective only after approval of the Sponsor, the 


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investigator, the IRB/IEC, and where necessary, the applicable regulatory agency.  In cases when 
the protocol is modified to enhance patient safety, changes may be implemented, and the 
amendment must be immediately submitted to the IRB/IEC. 
The investigator is responsible for informing the IRB/IEC of all problems involving risks to 
patients according to national legislation.  In case of urgent safety measures, the Sponsor will 
immediately notify the investigators and relevant regulatory agencies, including FDA in accord 
with 21 CFR 312.32. 
15.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviation.  The IRB/IEC 
must be notified of all protocol deviations in a timely manner by the principal investigator or 
designee as appropriate.  Protocol deviations will be documented by site personnel and the 
responsible monitor during monitoring visits, and those observations will be communicated to 
the investigator.  Protocol deviations will be reviewed and any that are a serious breach of GCP 
and/or the protocol will be reported to the relevant regulatory agency, as required.  Protocol 
waivers are not allowed for sites in the United Kingdom, and protocol waivers will not be 
granted by the Sponsor in any participating countries. 
If there is an immediate hazard to a patient the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/IEC approval.  The Sponsor and IRB/IEC must be 
notified of the deviation. 
Deviations will be reported, evaluated, and discussed according to the Protocol Deviation Plan 
and in the final study report. 
All protocol deviations due to the impacts of COVID-19 will be identified and documented 
accordingly by the site and the Sponsor.  When visits are completed remotely (due to COVID-19 
or other reasons), sites should ensure the completion of at least those assessments listed in 
Appendix 1 Section 4.  Where these study procedures are completed remotely, any additional 
study procedures that cannot be completed will be noted as missing and will not be considered as 
a protocol deviation.  The failure to complete the minimally required procedures outlined in 
Appendix 1 Section 4, will be considered a protocol deviation.    


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Retention of Records 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).  Records will be retained for at least 2 years after the last marketing application 
submission or 2 years after formal discontinuation of the clinical development of the 
investigational product, or for the duration required by local regulations, whichever is longer.  If 
the investigator withdraws from the responsibility of keeping the study records, custody must be 
transferred to a person willing to accept the responsibility.  The Sponsor must be notified in 
writing if a custodial change occurs.  
16.2. 
Case Report Forms 
All case report form data will be entered in paper or electronic forms at the investigational site.  
A 21 CFR Part 11 compliant EDC system will be used to capture data electronically for all 
patients enrolled in the study. 


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17. 
PUBLICATION POLICY 
The Sponsor supports communication and publication of study results whatever the findings of 
the study. 
The Sponsor reserves the right to review all planned communications and manuscripts based on 
the results of this study.  This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but to allow the Sponsor to confirm the 
accuracy of the data, to protect proprietary information, and to provide comments based on 
information that may not yet be available to the study investigators.  The Sponsor also 
encourages disclosure of any conflict of interest from all authors or investigators when 
manuscripts are submitted for publication.  Those individuals who have contributed greatly to 
this study, including lead external advisors and select principal investigators, may serve on any 
potential publications committee for the study. 


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18. 
REFERENCES 
Aminzadeh MA, Reisman SA, Vaziri ND, et al. The synthetic triterpenoid RTA dh404 (CDDO-
dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney 
disease.  Redox Biol. 2013;1(1):527-31. 
de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 
chronic kidney disease.  N Engl J Med. 2013;369(26):2492-503. 
Ding Y, Stidham RD, Bumeister R, et al. The synthetic triterpenoid, RTA 405, increases the 
glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial 
cells.  Kidney Int. 2013;83(5):845-54. 
Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci USA. 2005;102(12):4584-9. 
Ferguson DA, Wigley WC, Heiss E. Bardoxolone methyl (BARD) improves markers of 
endothelial function in cultured cells.  Poster American Society of Nephrology (ASN) 2010. 
Jiang T, Tian F, Zheng H, et al. Nrf2 suppresses lupus nephritis through inhibition of oxidative 
injury and the NF-kB-mediated inflammatory response.  Kidney Int. 2014;85(2):333-43. 
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 
Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney 
Disease. Kidney Int Suppl  2012;2:337–414. 
Lee D-F, Kuo H-P, Liu M, et al. KEAP1 E3 ligase-mediated downregulation of NF-kB signaling 
by targeting IKKß.  Mol Cell. 2009;36(1):131-40. 
Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmune inflammation, enhanced 
lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the 
antioxidant-activated transcription factor Nrf2. Am J Pathol. 2006;168(6):1960-74. 
Osburn WO and Kensler TW. Nrf2 signaling: an adaptive response pathway for protection 
against environmental toxic insults. Mutat Res. 2008;659(1-2):31-9. 
Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with 
type 2 diabetes. N Engl J Med. 2011;365(4):327-36. 
Rojas-Rivera J, Ortiz A, Egido J. Antioxidants in kidney diseases: The impact of bardoxolone 
methyl. Int J Nephrol. 2012;2012:1-11. 
Saha P, Reddy V, Konopleva M, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-
oic-acid methyl ester has potent antidiabetic effects in diet-induced diabetic mice and 
Lepr(db/db) mice. J Biol Chem. 2010;285(52):40581-92. 
Tanaka Y, Aleksunes LM, Goedken MJ, et al. Coordinated induction of Nrf2 target genes 
protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity. Toxicol Appl Pharmacol. 
2008;231(3):364-73. 
Wu QQ, Wang Y, Senitko M, et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and 
increases expression of protective genes Nrf2, PPARgamma, and HO-1. Am J Physiol Renal 
Physiol. 2011;300(5):F1180-92. 


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Yoh K, Itoh K, Enomoto A, et al. Nrf2-deficient female mice develop lupus-like autoimmune 
nephritis. Kidney Int. 2001;60(4):1343-53. 
Zoja C, Corna D, Locatelli M, et al. Targeting Keap1-Nrf2 Pathway Ameliorates Renal 
Inflammation and Fibrosis in Mice with Protein-Overload Proteinuria.  Poster American Society 
of Nephrology Meeting 2010. 


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19. 
APPENDICES 


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APPENDIX 1. COVID-19 MITIGATIONS 
This appendix outlines the mitigation strategies adopted to protect the health of participants in 
the study, while maintaining compliance with good clinical practice (GCP) and minimizing the 
risk to trial integrity during the COVID-19 (Coronavirus Disease 2019) pandemic.   
The mitigations will be in place as long as COVID-19 has an impact on trial conduct.  
All measures/mitigations undertaken will be done in accordance with the applicable regional and 
national guidelines of the health authorities (for example, the Guidance on the Management of 
Clinical Trials During the COVID-19 (Coronavirus) Pandemic by the European Medicines 
Agency [EMA] and the FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency). 
COVID-19 impacts to the conduct of study assessments and data collection are noted within the 
clinical database. 
1. 
SITE OPERATIONS AND PATIENT MANAGEMENT 
If study sites close or restrict access to study teams during the COVID-19 pandemic, study teams 
must maintain open lines of communication with active study participants.  Additionally, the 
Sponsor is to be regularly updated on changes to the site’s status regarding closures, access 
limitations, contact information or other important information.  Sites are encouraged to provide 
alternate contact information to their patients and the Sponsor.  Updates may be sent to the 
Sponsor study team (COVID19@reatapharma.com). 
2. 
COVID-19 INFECTED PATIENTS AND STUDY DRUG USE 
If a patient enrolled in the study tests positive for severe acute respiratory syndrome coronavirus 
2 (SARS-CoV-2), study drug must be temporarily interrupted.  The sponsor must be notified 
immediately for additional guidance. 
Study dug may be resumed when the patient no longer presents an active infection (defined as 
resolution of symptoms or a negative SARS-CoV-2 test), as assessed by the Investigator and/or 
the patient’s physician(s).  If COVID-19 symptoms persist (eg, loss of taste or smell), the patient 
should be encouraged to repeat SARS-CoV-2 testing to minimize the duration of study drug 
interruption. 
Patients who interrupt study drug due to a positive COVID-19 test may resume study drug 
without an in-clinic visit, at the investigator’s discretion, if COVID-19 symptoms are mild, and if 
the duration of interruption did not exceed 14 days. 
The maximum duration of treatment interruption due to COVID-19 infection must be determined 
based on the patient’s symptoms and the investigator’s discretion.  Instructions for how to 
resume study drug (ie, appropriate dose for restarting and appropriate visit schedule) are 
contained in Section 7.3.3. 


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3. 
STUDY DRUG ACCESS 
To maintain dosing continuity during the COVID-19 pandemic, study drug may be shipped from 
the sites to patients using couriered tracking services, when a patient is not able or willing to 
travel to the study site.  Drug will not be shipped directly from the Sponsor to patients.  Stability 
information for study drug shipments is contained in the “Guidance for Direct-to-Patient 
Shipping of RTA-402 Drug Product Capsules during the Coronavirus (COVID-19) Pandemic” 
(Attachment 1).  For shipments anticipated to exceed a 48-hour transit time, sites will be 
supplied with temperature monitors upon request.  When a shipment exceeds this transit time, the 
Sponsor should be notified immediately via the COVID-19 Investigational Product Temperature 
Excursion Form.  The Sponsor will assess whether the product is fit for use.  During this 
assessment period, the patient should be informed to not take the Study drug until further notice 
from the site.  Study drug dispensation should be recorded in the appropriate drug accountability 
logs and all study drug receipts of delivery should be filed in the Investigative Site File.  patient 
4. 
STUDY VISITS 
If sites foresee upcoming closures or other issues impacting the patient’s ability to come in for 
frequent visits (first 8 weeks), consider postponing the patient’s enrollment. The Day 1 visit of 
EAGLE will not be required to occur on the same day as the end-of-study visit of prior 
qualifying study.  
For continued patient safety oversight, patients should continue with protocol-specified visits.  
Where inadvisable for the patient to be seen for an in-person, in- clinic visit or if a patient is 
unwillingly to come to the clinic, alternate visit completion methods should be considered, such 
as by phone, telemedicine, home health visits and/or local laboratory monitoring of safety labs.  
Visits conducted over the phone (or via telemedicine, if available), at a minimum should include 
the following assessments: 
• Adverse-event assessment 
• Prior and concomitant medication assessment 
In-home visits at a minimum should include the following assessments: 
• Safety labs (may also be done by local laboratories)  
− Clinical chemistry (including eGFR) 
− BNP and NT-proBNP 
− Hematology 
− Urine collection for ACR 
− Urine pregnancy test for WOCBP 
• Vital signs  
• Weight at home 
• Adverse event assessment 


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• Prior and concomitant medication assessment 
5. 
DOSE MANAGEMENT 
5.1. 
Dose De-escalation and Interruption for Missed Safety and 
Laboratory Assessments 
If no scheduled in -clinic visit is completed and remote assessments/laboratory samples cannot 
be collected within the protocol allowed time window for that visit, the IP dose must be de-
escalated to the previous dose within 6 days of the protocol visit window.  For patients on 5 mg, 
the lowest dose, that dose may be maintained, and no de-escalation is required.  All efforts 
should then be made to collect laboratory samples.  However, if laboratory samples cannot be 
collected within 14 days from the date of dose de-escalation (for visits through Week 12) and 
within 28 days (for visits beyond Week 12), IP must be temporarily interrupted until safety lab 
values can be evaluated and it is deemed appropriate to restart.  Appendix 1 Section 5.2 describes 
the procedure for resuming and dose-escalating IP following drug interruption.  
5.2. 
Resuming or Dose-escalating IP after Interruptions or Changes 
Patients who interrupt study drug due to a positive COVID-19 test may resume study drug 
without an in-clinic visit, at the investigator’s discretion, of COVID-19 symptoms are mild. 
When the investigator deems that it is safe for the patient to return to the site for an in-person 
visit, the investigator should conduct an evaluation to determine whether the patient is still 
eligible to receive IP and to determine the appropriate dose.  This should include a confirmation 
that the reason for interruption was not a per protocol specified reason and that the patient’s 
circumstances have not changed in a manner that would prohibit administration of the 
investigational drug (eg, the patient is now taking an excluded medication).  Once the 
investigator determines IP administration is appropriate, dosing may proceed as recommended in 
the table below. 
IP Status 
Dosing Recommendation 
IP temporarily interrupted for any reason (eg, COVID-
19, delays in obtaining safety lab, AEs) 
Resume IP at last administered dose 
IP dose not escalated as required per COVID-19 
mitigation plan 
Continue last administered dose; 
consider escalating dose, if appropriate 
IP de-escalated for any reason (eg, due to delays in 
obtaining safety labs, AEs) 
Continue last administered dose; 
consider escalating dose, if appropriate 
If the patient is not at the target dose, dose escalation to a higher dose is permitted.  Patients who 
dose escalate must have a telephone call 1 week after dose escalation and an office in-clinic visit 
(or unscheduled visit, if necessary) 2 weeks (± 3 days) after dose escalation to collect clinical 
chemistry, BNP, and NT-proBNP.  Unscheduled visits due to dose escalation should also include 
assessments detailed in Section 9.6 of the protocol.  Once the target dose has been reached and 
2-week follow-up completed, the Schedule of Assessments may be resumed. 


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6. 
DEVIATIONS  
Any study procedures that cannot be conducted remotely will be noted as missing.  All 
deviations due to the impacts of COVID-19 will be identified and documented accordingly by 
the site and the Sponsor.  The failure to complete a protocol visit will not be considered as a 
reason for study discontinuation and will not be considered as a major deviation.  Deviations will 
be reported, evaluated, and discussed according to the Protocol Deviation Plan and in the final 
study report. 
7. 
MONITORING  
In case that study sites are closed for any visitors and monitors over a certain period of time 
during the COVID-19 pandemic a risk-based approach to monitoring will be taken, focusing on 
certain sites, certain data points and certain processes that are critical to ensure the rights, safety 
and well-being of trial participants and the integrity of the trial (and trial data).  The results of 
adjusted monitoring/review measures and their impact will be reported to the Sponsor in 
monitoring reports and in the clinical study report, where applicable.  A CRF form has been 
updated to collect data for COVID-19 impact. Adjusting monitoring activities may include a 
combination of on-site and off-site monitoring.  Remote source data verification may also be 
taken into consideration. 


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AMENDMENT CHANGE DOCUMENT 
CLINICAL STUDY PROTOCOL 402-C-1803 
Study Title: AN EXTENDED ACCESS PROGRAM TO ASSESS LONG TERM SAFETY OF BARDOXOLONE METHYL IN PATIENTS 
WITH CHRONIC KIDNEY DISEASE (EAGLE) 
 
Protocol History 
Version 01 
Version 02 
04 September 2018 
31 January 2019 
Version 03 
30 June 2020 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc.  Any unauthorized use or disclosure 
of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 
 
72


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SUMMARY OF CHANGES 
 
The following document outlines the changes that have been made to Version 2 to produce the text of Version 3.  Additionally, the following 
points are provided: 
 
• 
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not 
described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the new version of the protocol. 
 
 
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AMENDMENT CHANGE DOCUMENT 
CLINICAL STUDY PROTOCOL 402-C-1803 
Study Title: AN EXTENDED ACCESS PROGRAM TO ASSESS LONG TERM SAFETY OF BARDOXOLONE METHYL IN PATIENTS 
WITH CHRONIC KIDNEY DISEASE 
 
Protocol History 
Version 01 
Version 02 
04 September 2018 
31 January 2019 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc.  Any unauthorized use or disclosure 
of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited.
147


 
 
 
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Amendment – Study Protocol 402-C-1803 
 
 
 
 
Version 02 
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Confidential 
 
 
SUMMARY OF CHANGES 
 
The following document outlines the changes that have been made to Version 1 to produce the text of Version 2.  Additionally, the following 
points are provided: 
 
 
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough. 
 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not 
described. 
 
Grammatical corrections and minor editorial changes are not described. 
 
Section numbers refer to the numbers in the new version of the protocol. 
148



SAP_001.pdf: 
COVER PAGE 
 
Official Title: An Extended Access Program to Assess Long Term Safety of 
Bardoxolone Methyl in Patients With Chronic Kidney Disease (EAGLE) 
NCT Number: NCT03749447 
Document Date: 25 Aug 2023 
 


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STATISTICAL ANALYSIS PLAN 
402-C-1803 
 
VERSION: 3.0  
DATE OF PLAN:  
25 AUG 2023 
 
BASED ON: 
Protocol Version 4.0 (09 Nov2022) 
 
STUDY DRUG: 
RTA 402, BARDOXOLONE METHYL 
PROTOCOL NUMBER: 
402-C-1803 
STUDY TITLE: 
An Extended Access Program to Assess long term safety of Bardoxolone Methyl in patients with 
Chronic Kidney Disease (“EAGLE”) 
 
SPONSOR: 
Reata Pharmaceuticals, Inc.  
5320 Legacy Drive 
Plano, Texas 75024 (972) 865-2219 
 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 




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TECHNICAL SUMMARY REPORT (TSR) 
Name of 
Sponsor/Company 
Reata Pharmaceuticals, 
Inc. 
Individual 
Study 
Table Referring to 
Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
Bardoxolone methyl capsules 
Page: 
Name of Active Ingredient: 
Bardoxolone methyl 
Title of Study: An Extended Access Program to Assess Long-Term Safety of Bardoxolone 
Methyl in Patients with Chronic Kidney Disease  
Study Center(s): Approximately 230 
Studied period (years): 
Actual date first patient first visit: March 2019 
Estimated last patient last completed: Patient will remain in the 
study until bardoxolone methyl is available through commercial 
channels or until patient withdrawal, whichever is sooner 
The end of the study is defined as the last visit of the last 
patient. 
Phase of development: 3a 
Objectives: 
To provide continuing open-label treatment with bardoxolone methyl as part of this 
extended access program while collecting ongoing safety and tolerability data of 
bardoxolone methyl. 
Methodology: 
This extended access study will assess the long-term safety and tolerability of bardoxolone 
methyl in qualified patients with chronic kidney disease who previously participated in a 
qualifying, clinical study with bardoxolone methyl.  The CARDINAL study (402-C-1603, 
NCT03019185, EudraCT 2016-004395-22) and FALCON study (402-C-1808, NCT03918447, 
EudraCT 2018-004651-20) are the only qualifying clinical studies at this time. 
The Day 1 visit of EAGLE is not required to be the same day as the End of Study visit of the 
prior qualifying study.  Lab assessments from the qualifying study will be used for EAGLE 
eligibility and maximum treatment dose assignment (Week 100 for CARDINAL or FALCON 
protocol versions 1 through 5, and Week 108 [B] for FALCON versions 6 and newer) if those 
assessments were done ≤ 8 weeks before Day 1.  In the event that the eligibility lab assessments 
were obtained > 8 weeks before the planned EAGLE Day 1 visit, a screening visit will be 
required for EAGLE enrollment.  
The maximum bardoxolone methyl dose will be determined by the proteinuria status based on 
the albumin/creatinine ratio (ACR) value from the eligibility lab assessments from the prior 
qualifying study, or for patients requiring a screening visit, the maximum bardoxolone methyl 
dose will be determined based on the ACR values from the screening labs. Patients with 
eligibility ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with 


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eligibility ACR > 300 mg/g will be titrated to a maximum dose of 30 mg.  Adult patients 
(≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and 
will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only 
if eligibility ACR > 300 mg/g) unless contraindicated clinically and approved by the medical 
monitor.  Patients under the age of 18 enrolling from CARDINAL will start dosing at 5 mg 
every other day during the first week (from Day 1 through the Week 1 visit) and begin 
once-daily dosing with 5 mg during the second week of the study (following the Week 1 visit 
through the Week 2 visit), and then continue with once-daily dosing following the same 
aforementioned dose-titration scheme based on eligibility ACR at Weeks 2, 4, and 6.  Patients 
under the age of 18 enrolling from FALCON will follow the adult dose titration schedule.  
Dose de-escalation is permitted during the study if indicated clinically, and subsequent dose 
re-escalation is also permitted.   
All patients in the study will follow the same visit and assessment schedule.  Patients will be 
scheduled to be assessed in person during treatment at Day 1, Weeks 1, 2, 4, 6, 8, 12, 24, and 
every 24 weeks thereafter.  Patients will also be assessed by telephone contact on Days 3, 10, 
21, 31, 38, and 45. If the Day 1 visit for EAGLE is the same as the end-of-study visit for 
CARDINAL (all versions) or FALCON (protocol version 5 and older), the laboratory 
assessments required for both visits should only be completed once. If the Day 1 visit for 
EAGLE is the same as the end-of-study visit for FALCON (protocol version 6 and newer), the 
lab assessments required for both visits should be completed for each study individually.  If the 
Day 1 visit of EAGLE is not on the same day as the end-of-study visit from prior qualifying 
study, lab assessments will be performed for Day 1 through the EAGLE central lab. 
The conduct of the study, according to protocol specifications, was impacted by the COVID-19 
pandemic.  As a result, and as of Version 3 of the protocol, modifications intended to address 
access to and administration of investigational product, and adherence to protocol-specified 
visits and laboratory assessments were implemented.  These modifications are described in the 
protocol Appendix 1 (COVID-19 Mitigations). 
Number of Patients (planned): Patient numbers will be determined by those who are currently 
participating or have previously participated in a qualifying clinical study with bardoxolone 
methyl and meet eligibility requirements.   
Diagnosis and main criteria for inclusion (see protocol Section 8.1): 
1. Patients who are participating (or who have participated) in qualifying studies and who 
have not been required to discontinue study treatment for protocol or safety reasons and 
who have completed required End-of-Treatment and/or Follow-up visits in a prior 
clinical study with bardoxolone methyl and who, according to the assessment of the 
investigator, have a potential positive benefit-risk assessment for participating in the trial. 
2. Meets the following eligibility criteria based on assessments from the prior qualifying 
study or from a screening visit, if applicable. 
a. Not expected to reach end-stage kidney disease or nephrotic syndrome within 
12 weeks of study enrollment, in the investigator’s judgement; subjects with 
estimated glomerular filtration rate < 20 ml/min/1.73m2 should be discussed with 
the medical monitor before enrollment (eg, such subjects with an average rate of 
estimated glomerular filtration rate decline > 1.0 ml/min/1.73m2 per month in the 
3 months prior to eligibility assessment may not be eligible);  


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b. B-type natriuretic peptide < 200 pg/mL at the last on-treatment visit in the prior 
qualifying study or at a new screening visit, if applicable. 
c. No occurrence of a cardiovascular serious adverse event in the prior qualifying 
study or in the interval between the end of the qualifying study and the screening 
visit, if applicable. 
3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures; 
4. Evidence of a personally signed and dated informed consent document (and assent form 
if necessary) indicating that the patient (or a legally acceptable representative) has been 
informed of all pertinent aspects of the study prior to initiation of any protocol-mandated 
procedures.  
Diagnosis and main criteria for exclusion (see protocol Section 8.2): 
1. Participation in other investigational clinical studies involving interventional 
products being tested or used in a way different from the approved form or when 
used for an unapproved indication; 
2. Patients who have an ongoing serious adverse event from a clinical study that is 
assessed by the investigator as related to bardoxolone methyl. 
3. Unwilling to practice acceptable methods of birth control (both males who have 
partners of childbearing potential and females of childbearing potential) while 
screening, taking study drug and 30 days after the last study drug dose. 
4. Women who are pregnant or breastfeeding. 
5. Patient is, in the opinion of the investigator, unable to comply with the requirements 
of the study protocol or is unsuitable for the study for any reason. 
6. Known hypersensitivity to any component of the study drug. 
Test product, dose and mode of administration: Bardoxolone methyl will be administered at 
oral doses 5, 10, 20, or 30 mg. Each dose of study drug is administered at approximately the 
same time each day, preferably in the morning. 
Duration of treatment: Until bardoxolone methyl is available through commercial channels or 
until patient withdrawal or study termination, whichever is sooner.  
Reference therapy, dose and mode of administration: No reference therapy 
Criteria for evaluation (see protocol Section 6.2): Safety: Results of physical examination, 
laboratory results, ACR, vital sign measurements, weight, AEs, and SAEs. 
Statistical methods: 
Sample size: The aim of this long-term extended access study is primarily to provide 
continuing bardoxolone methyl treatment to patients and to assess long-term safety and 
tolerability, hence no single primary variable has been identified. Patient numbers will be 
determined by those who are participating (or who have previously participated) in a 
qualifying clinical study with bardoxolone methyl and meet eligibility requirements.   
Primary analysis of safety: As the extension is an open-label design with no comparator group, 
all statistical analyses will be descriptive.  The summary tables will be presented for the overall 
group of patients and split by previous treatment groups (ie, bardoxolone methyl or placebo) in 
prior bardoxolone methyl clinical studies. 


Page 6 of 35 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS .......................................................................................9 
2. 
INTRODUCTION ......................................................................................................10 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
3.1. 
Study Objectives .........................................................................................................11 
3.1.1. 
Primary Objective .......................................................................................................11 
3.2. 
Study Endpoints ..........................................................................................................11 
3.2.1. 
Primary Endpoints ......................................................................................................11 
4. 
STUDY DESIGN .......................................................................................................12 
4.1. 
Summary of Study Design ..........................................................................................12 
4.2. 
Definition of Study Drugs...........................................................................................12 
4.3. 
Sample Size Considerations........................................................................................13 
4.4. 
Randomization ............................................................................................................13 
4.5. 
Treatment Analysis Group Assignment ......................................................................13 
4.6. 
Clinical Assessments ..................................................................................................13 
5. 
PLANNED ANALYSES ............................................................................................16 
5.1. 
Planned Interim Analyses ...........................................................................................16 
5.2. 
Final Analyses and Reporting .....................................................................................16 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................17 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........17 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................17 
6.3. 
Analysis Populations ..................................................................................................17 
6.3.1. 
Safety Population ........................................................................................................17 
6.3.2. 
402-C-1603 to 402-C-1803 Safety Population ...........................................................18 
6.3.3. 
402-C-1808 to 402-C-1803 Safety Population  ..........................................................18 
6.4. 
Baseline Definition .....................................................................................................18 
6.5. 
Derived and Transformed Data ...................................................................................18 
6.5.1. 
Baseline Age ...............................................................................................................18 
6.5.2. 
Study Day ...................................................................................................................18 
6.5.3. 
Change from Baseline .................................................................................................18 
6.5.4. 
Visit Windows ............................................................................................................19 


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6.5.5. 
Laboratory Evaluations ...............................................................................................19 
6.5.6. 
Estimated Glomerular Filtration Rate .........................................................................20 
6.5.7. 
Urine Albumin to Creatinine Ratio .............................................................................20 
6.5.7.1. 
Baseline Urine Albumin to Creatinine Ratio Categorical Status ................................20 
6.5.7.2. 
ACR Category used in Stratification ..........................................................................21 
6.5.8. 
Natural log (ACR)/eGFR ............................................................................................21 
6.6. 
Handling of Missing Data ...........................................................................................21 
6.6.1. 
Missing Endpoints ......................................................................................................21 
6.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................21 
6.6.3. 
Missing Start and Stop Dates for Adverse Events ......................................................21 
6.6.4. 
Missing End of Treatment Date ..................................................................................22 
7. 
STUDY POPULATION .............................................................................................23 
7.1. 
Subject Disposition .....................................................................................................23 
7.2. 
Screen Failures ............................................................................................................23 
7.3. 
Protocol Deviation ......................................................................................................24 
7.4. 
Demographic and Baseline Characteristics ................................................................24 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................25 
7.6. 
Medical History ..........................................................................................................25 
8. 
SAFETY AND TOLERABILITY ..............................................................................26 
8.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............26 
8.1.1. 
Missing and Partial AE Onset Dates ..........................................................................27 
8.1.2. 
Summaries of Adverse Events ....................................................................................27 
8.2. 
Exposure and Compliance ..........................................................................................27 
8.3. 
Concomitant and Other Medications ..........................................................................28 
8.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........29 
8.4. 
Clinical Laboratory Evaluations .................................................................................29 
8.4.1. 
Continuous Summaries of Laboratory Results ...........................................................29 
8.4.1.1. 
Urine Albumin/Creatinine Ratio .................................................................................30 
8.4.1.2. 
Continuous eGFR .......................................................................................................30 
8.4.1.3. 
Natural log (ACR)/eGFR ............................................................................................30 
8.4.2. 
Categorical Summaries of Laboratory Results ...........................................................30 
8.4.2.1. 
Transaminases .............................................................................................................31 


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8.4.2.2. 
Frequency of End Stage Kidney Disease, eGFR decline ≥ 30%, or eGFR 
< 15 .............................................................................................................................32 
8.5. 
Vital Signs ..................................................................................................................32 
8.5.1. 
Body Weight ...............................................................................................................32 
8.6. 
Pregnancy ...................................................................................................................32 
9. 
PHARMACOKINETICS ...........................................................................................33 
10. 
COVID-19 IMPACT ..................................................................................................34 
10.1. 
Operational Impact .....................................................................................................34 
10.2. 
Safety ..........................................................................................................................35 
APPENDIX 1 .................................................................................................................................35 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................14 
Table 2: 
Visit Window (Days) ..................................................................................................19 
Table 3: 
Pre-specified Threshold Levels for Transaminases ....................................................31 
 
LIST OF FIGURES 
Figure 1: 
Schema for Study 402-C-1803 (EAGLE) ...................................................................12 
 


Page 9 of 35 
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1. 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ACR 
albumin/creatinine ratio 
ADPKD 
autosomal dominant polycystic kidney disease  
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (drug classification system)  
AYAME 
name for study RTA 402-006 
BARD 
Bardoxolone methyl 
Bard 
bardoxolone methyl  
BNP 
B-type natriuretic peptide 
CARDINAL 
name for Study 402-C-1603 
CSR 
clinical study report 
DBL 
database lock 
EAGLE 
name for Study 402-C-1803 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ESKD 
end-stage kidney disease 
FALCON 
name for Study 402-C-1808 
FMV 
first morning void 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
LLD 
lower limit of detection 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCr 
serum creatinine 
SDT 
study drug termination 
SOC 
System Organ Class 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


Page 10 of 35 
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2. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the planned analyses and data 
displays to be included in the clinical study report (CSR) for Protocol 402-C-1803. 
This SAP was developed in accordance with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 guidelines.. All decisions 
regarding final analysis, as defined in this SAP document, will be made prior to the initial 
database lock (DBL) of the study data. Since the trial is an open-label extension study, analyses 
will be re-run based on subsequent database locks as needed for regulatory reporting and/or 
submissions so long as data continue to accrue. Further information can be found in the protocol. 
The SAP is based on: 
• Protocol 402-C-1803, Version 4, dated 09 NOV 2022 
• ICH guidelines E4 (Dose-Response Information to Support Drug Registration) and 
E9 (Statistical Principles for Clinical Trials) 
This SAP describes the study populations, how variables are derived, how missing data are 
handled, and details concerning the statistical methods to be used to analyze the safety and 
efficacy data in the 402-C-1803 study. Should the SAP and the protocol be inconsistent with 
respect to the planned analyses, the language of the SAP is governing. 
The SAP version 1 dated 12 SEP 2019 was finalized and placed on file before the 1st DBL on 
22 NOV 2019.  This current version of the SAP describes the analyses planned prior to the DBL.  
Unless otherwise specified, these analyses are summarized in the CSR. The CSR will describe 
any deviations from the planned analyses.  
In May 2023, Kyowa Kirin Co., Ltd. (Kyowa Kirin) announced results from AYAME (402-006), 
a Phase 3, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the 
efficacy and safety of bardoxolone methyl (bardoxolone) for patients with diabetic kidney 
disease. The study enrolled 1013 patients who were treated with 5 mg to 15 mg of bardoxolone 
or placebo for 3 to 4 years. 
The AYAME (402-006) study met the primary endpoint and key secondary endpoint; however, 
there was no separation in the occurrence of end-stage kidney disease (ESKD) events between 
the 2 groups. Based on the AYAME (402-006) efficacy results, Kyowa Kirin and Reata 
Pharmaceuticals, Inc. have decided to discontinue clinical development of bardoxolone. 
This decision was communicated to all sites on 10 MAY 2023, which is referred to as the study 
drug termination (SDT) date.  
 


Page 11 of 35 
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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
To provide continuing open-label treatment with bardoxolone methyl as part of this extended 
access program while collecting ongoing safety and tolerability data of bardoxolone methyl. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse 
events (SAEs) and change from baseline in the following assessments: physical examinations, 
vital sign measurements, weight, urine albumin/creatinine ratio (ACR), and laboratory results. 


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4.
STUDY DESIGN
4.1.
Summary of Study Design
This extended access study will assess the long-term safety and tolerability of bardoxolone 
methyl in qualified patients with chronic kidney disease who previously participated in a 
qualifying clinical study with bardoxolone methyl. 
The Day 1 visit of 402-C-1803 is not required to occur on the same day as the last visit of the 
prior qualifying study (either 402-C-1603 or 402-C-1808).  Details for determining eligibility 
and lab assessment requirements are provided in Protocol Section 7.
All patients in the study will follow the same visit and assessment schedule (Figure 1). Patients 
will be assessed in person during treatment at Day 1, Weeks 1, 2, 4, 6, 8, 12, 24, and every 24 
weeks thereafter. Patients will also be assessed by telephone contact on Days 3, 10, 21, 31, 38, 
and 45. If the Day 1 visit for 402-C-1803 is the same as the end-of-study visit from the prior 
qualifying study, the assessments required for both visits should only be completed once. If the 
Day 1 visit of 402-C-1803 is not on the same day as the end-of-study visit from prior qualifying 
study, lab assessments are performed for Day 1 through the 402-C-1803 central lab.
Figure 1: 
Schema for Study 402-C-1803 (EAGLE)
4.2.
Definition of Study Drugs
Capsules containing bardoxolone methyl at the 5 mg, 10 mg, 15 mg, and 20 mg strengths will be 
used to titrate to a maximum dose of 20 or 30 mg/day are used in this study. 
Abbreviations: ACR=albumin to creatinine ratio; D=day; W=week; eGFR=estimated glomerular filtration rate; 
Scr=screening
*Patients in CARDINAL (402-C-1603) that are under the age of 18 will receive bardoxolone methyl every other day 
during Week 1. Patients in FALCON (402-C-1808) that are under the age of 18 will receive bardoxolone methyl 
every day during Week 1.
Note: Screening visit will be scheduled for subjects whose last lab assessments are more than 4 weeks old. Refer to
protocol Section 8.3 for additional details. Subjects requiring visit will be consented on the same visits


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4.3. 
Sample Size Considerations 
The 402-C-1803 study is not powered to show efficacy or safety effects, and there is no placebo 
comparator in this open-label trial. Patient numbers are determined by those who are 
participating (or who have previously participated) in a qualifying clinical study with 
bardoxolone methyl and meet eligibility criteria.  
4.4. 
Randomization 
This is a non-randomized, open-label study that includes patients who completed previous 
qualifying clinical study. The CARDINAL study (402-C-1603, NCT03019185, EudraCT 2016-
004395-22) and FALCON study (402-C-1808, NCT03918447, EudraCT 2018-004651-20) are 
the only qualifying clinical studies at this time. 
As no randomization or blinding is performed, all patients enrolled in 402-C-1803 are assigned 
to bardoxolone methyl. 
4.5. 
Treatment Analysis Group Assignment 
The treatment analysis groups for the 402-C-1803 study consist of: 
1. Placebo  Bardoxolone (Bard): placebo-bardoxolone methyl patients (patients 
previously randomized to placebo in 402-C-1603 Phase 3 or 402-C-1808 who started 
receiving bardoxolone methyl in 402-C-1803), 
2. Bard  Bard: bardoxolone methyl patients (patients previously randomized to 
bardoxolone methyl in 402-C-1603 Phase 3 or 402-C-1808 who started receiving 
bardoxolone methyl in 402-C-1803). Data from 402-C-1603 or 402-C-1808 must be 
unblinded to be included in either treatment analysis group. 
4.6. 
Clinical Assessments 
All patients in the study follow the same visit and assessment schedule for the duration of the 
trial.  Table 1 lists the overall schedule of assessments for the study.


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Table 1: 
Schedule of Assessments 
 
Study 
Week 
(Day±Days) 
Assessment 
Screening
Visita 
Day 1 a,cWeek 1 
(Phone)
Day 3 
± 2 
Days 
Week 1 
Day 7 
± 3 
Days 
Week 2 
(Phone)
Day 10 
± 2 
Days 
Week 2 
Day 14 
± 3 
Days 
Week 3 
(Phone) 
Day 21 
± 2 
Days 
Week 4 
Day 28 
± 3 
Days 
Week 4 
(Phone)
Day 31 
± 2 
Days 
Week 5 
(Phone) 
Day 38 
± 2 
Days 
Week 6 
Day 42 
± 3 
Days 
Week 7 
(Phone) 
Day 45 
± 2 
Days 
Week 8 
Day 56 
± 3 
Days 
Week 
12 Day 
84 ± 3 
Days 
Week  24 ± 
3 Days, 
Every 24 
Weeks  
± 3 Days 
End of 
Study 
Visitb 
Informed consent 
X
c 
X
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographicsd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Weight at home 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight in-clinic 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Dispense Weight & Study Drug 
Diary 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Collect/Review Weight & Study 
Drug Diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital sign measurements 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Physical examination 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Xe 
Xe 
Pregnancy testf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Dispense study drug 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
Collect study drug 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Telephone contact 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
Adverse event collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Basic Lipid Panel 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Chemistries 
(includedeGFR)g 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
BNP and NT-proBNP 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Urine collection for ACRh 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
Tanner Stagingi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: ACR=albumin/creatinine ratio; AE=adverse event; BNP=B-type natriuretic peptide; CARDINAL=name for Study 402-C-1603; EAGLE=name 
for Study 402-C-1803; eGFR=estimated glomerular filtration rate; FALCON=name for Study 402-C-1808; IEC=Independent Ethics Committee; 
IRB=Institutional Review Board; NT-proBNP=N-terminal prohormone B-type natriuretic peptide 
a A screening visit will be conducted for subjects whose planned EAGLE Day 1 visit is not within 8 weeks of the eligibility lab assessments from the prior 
qualifying study.  Subjects requiring a screening visit will be consented prior to the start of any screening assessments.  All other subjects will be consented at the 
start of the Day 1 visit, before any procedures are performed for this, or the prior study. 


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b After the Week 24 visit, subjects will continue to be assessed in person every 24 weeks until the study ends. The End-of-Study visit should occur within 30 days 
after bardoxolone methyl becomes available to the subject through commercial channels.  Subjects who will be discontinued from the study prior to commercial 
availability of bardoxolone methyl must also complete all End-of-Study assessments as soon as possible (if possible, within 30 days of discontinuation).   
c On Day 1, all procedures should be performed before study drug administration.  AE assessment on Day 1 should be performed following study drug 
administration. If the Day 1 visit for EAGLE is the same as the end-of-study visit for CARDINAL (all versions) or FALCON (protocol version 5 and older), the 
laboratory assessments required for both visits should only be completed once.  
If the Day 1 visit for EAGLE is the same as the end-of-study visit for FALCON (protocol version 6 and newer), the lab assessments required for both visits 
should be completed for each study individually. 
d Demographics are to be performed on the earliest study visit, whether it be Day 1 or a Screening visit, if necessary. 
e Assessment should include a complete physical examination as described in the protocol.  
f A serum pregnancy test will be performed at any point in time if a pregnancy is suspected.  All other pregnancy assessments will be urine pregnancy tests.  
Additional pregnancy assessments will be performed more frequently if required by local law or requested by local health authorities or IRBs/IECs.   
g eGFR will not be calculated by the central lab. 
h Urine ACR will be measured by first morning void spot urine collection.  Appropriate containers for the collection will be provided to the subject at the visit 
prior to collection. 
i Adolescent patients from the FALCON (402-C-1808) (12 ≤ age < 18 years at consent) will be assessed by Tanner staging at all specified timepoints. 


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5. 
PLANNED ANALYSES 
5.1. 
Planned Interim Analyses 
Interim analyses are based on locked data. A DBL plan will describe the details of each DBL. All 
outputs identified in this SAP and planned for the final analysis will be prepared for each interim 
analysis, and an interim CSR will be prepared. 
At the time of each planned interim analysis, no individual patient’s data are considered fully 
locked; therefore, interim results are interpreted as preliminary. 
5.2. 
Final Analyses and Reporting 
All final, planned analyses identified in this SAP will be performed after the last patient has 
completed the study and the database has been locked.  


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
Results are summarized by the treatment analysis groups described in Section 4.5. Patient listings 
of all analysis data that support summary tables and figures are provided. The summary tables do 
not include measurements from patients excluded from the pre-defined analysis sets or extra 
measurements (such as unscheduled or repeat assessments) not closest to the target study day 
unless specified otherwise, but the patient listings do include these data. Missing data are not 
imputed, unless otherwise specified. In general, patient listings are sorted by patient number and 
assessment date (time and parameter, as applicable). 
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Results of statistical analyses are reported using summary tables, figures, and listings. All tables, 
figures, and listings use ICH numbering conventions. 
Analyses described in this SAP are based on data collected in 402-C-1803 and data collected in 
402-C-1808 and 402-C-1603 per eligibility requirements described in Protocol Section 7.1. All 
analyses and summaries are produced using Statistical Analysis Software® version 9.3 (or higher). 
6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Unless otherwise specified, descriptive statistics for continuous variables include the number of 
patients with data (N), mean, SD, median, minimum, and maximum. The same number of decimal 
places as in the observed value are presented when reporting minimum and maximum; 1 more 
decimal place than in the observed value is presented when reporting mean and quartiles; and 
2 more decimal places than in the observed value is presented when reporting SD. 
Categorical (qualitative) data are presented using frequency counts and percentages. All 
percentages are rounded to 1 decimal place, unless otherwise specified. Percentages equal to 100 
are presented as 100% and no percentages are presented for zero frequencies. Where individual 
variable values are missing, summaries of categorical data are based on reduced denominators (ie, 
only patients with available data are included in the denominators). For summaries of AEs and 
concomitant medications, the percentages are based on the number of patients who received study 
drug within each summary group. 
6.3. 
Analysis Populations 
Analysis populations defined in this section pertain to patients enrolled in the 402-C-1803 study. 
6.3.1. 
Safety Population 
The safety population includes all patients who received at least 1 dose of bardoxolone methyl in 
402-C-1803 study. The safety population is used for evaluation of safety variables. 


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6.3.2. 
402-C-1603 to 402-C-1803 Safety Population 
The 402-C-1603 to 402-C-1803 safety population includes all patients previously enrolled in 
402-C-1603 study who received at least 1 dose of bardoxolone methyl in 402-C-1803 study.  
6.3.3. 
402-C-1808 to 402-C-1803 Safety Population  
The 402-C-1808 to 402-C-1803 safety population includes all patients previously enrolled in 
402-C-1808 study who received at least 1 dose of bardoxolone methyl in 402-C-1803 study.  
Subgroup analyses will not be conducted due to termination of the bardoxolone methyl program. 
However, summaries based on the parent studies (402-C-1808 and 402-C-1603) will be provided 
along with a pooled analysis. 
6.4. 
Baseline Definition 
The last measurement on or prior to the date of first study drug administration is considered the 
402-C-1803 Day 1 measurement for the calculation of baseline. If baseline is missing, the last 
available value in prior qualified studies will be used as baseline. 
6.5. 
Derived and Transformed Data 
6.5.1. 
Baseline Age 
Subject’s age in years is the age collected at 402-C-1803 Day 1. 
6.5.2. 
Study Day 
Study day is the day relative to the date of first study drug kit dispensation in 402-C-1803, which 
may precede the date of first dose of study drug. 
Assessments that occur after 402-C-1803 study drug dispensation, but on or before the date of first 
study drug administration are considered to occur on study Day 1.  
For visits (or events) after the date of drug dispensing, day is calculated as: 
• Study day = visit (or event) date - date of drug dispense + 1 
For visits (or events) before the date of drug dispensing, day is calculated as: 
• Study day = visit (or event) date - date of drug dispense 
For listings (such as for AEs) the quantity ‘days since first (or last dose)’ is defined as: 
• Days since first dose = event date – date of first dose + 1 
• Days since last dose = visit (or event) date - date of last dose 
For summaries that present distribution of time expressed in weeks and months, weeks will be 
defined as days divided by 7 and months as days divided by 30.4. 
6.5.3. 
Change from Baseline 
Change from baseline is calculated as the result minus baseline, using the baseline value 
(Section 6.4) and the result assessed closest to the target study day for each analysis visit 
(Section 6.5.4). 


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6.5.4. 
Visit Windows 
Table 2: 
Visit Window (Days) 
Analysis Visit 
Label 
Target Study Day Analysis Window 
0 
Day 1 
1 
1 
1 
Week 1 
7 
2 ≤ Study Day ≤ 10 
2 
Week 2 
14 
11 ≤ Study Day ≤ 21 
4 
Week 4 
28 
22 ≤ Study Day ≤ 35 
6 
Week 6 
42 
36 ≤ Study Day ≤ 49 
8 
Week 8 
56 
50 ≤ Study Day ≤ 70 
12 
Week 12 
84 
71 ≤ Study Day ≤ 126 
24 
Week 24 
168 
127 ≤ Study Day ≤ 210 
48 
Week 48 
336 
308 ≤ Study Day ≤ 364 
72 
Week 72 
504 
476 ≤ Study Day ≤ 532 
96 
Week 96 
672 
644 ≤ Study Day ≤ 700 
120, 144, etc. 
Week 120, Week 144, 
Every 24 Weeks 
Thereafter 
Analysis Visit × 7 
([Analysis Visit × 7] 
- 28) ≤ Study Day ≤ 
([Analysis Visit × 7] 
+28) 
FU 
Follow-up 
28 days after 
last dose 
14 ≤ Days after 
last doseª ≤ 35 
ª For safety analyses, last dose for patients completing the treatment or permanently discontinuing study drug that 
occur on the date of last dose or less than 14 days after last dose are considered on treatment. 
The safety follow-up is based on days since last dose. If more than one assessment exists during the 
follow-up after last dose, the one closest to 28 days following the date of the last study drug 
administration is used for analysis and summary. 
If a parameter is assessed or measured more than once within a visit window, the one that is closest 
to the protocol-scheduled time point (or target study day) is used for the purposes of data analysis 
and summary. If two assessments are equidistant from a target study day, the earlier assessment is 
used. If the visit used for analysis includes two assessments on the same day, the average of 
assessments will be used for non-laboratory parameters. For laboratory parameters, if both an 
original and retest result are available in the laboratory dataset, the original result will be used and 
the second (ie, “retested”) result will be ignored. Records from visits not closest to the target study 
day, and therefore not used in analyses, are presented in by-subject data listings.   
6.5.5. 
Laboratory Evaluations 
Any laboratory assessments less than the lower limit of detection (LLD) are imputed as LLD/2. If 
no LLD is available, then the imputed value is the minimum numeric value listed divided by 2 (eg, 


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< 25 is 25/2=12.5). Laboratory assessments above the upper limit of detection are imputed as the 
upper limit of detection. If the lab result is qualitative but presented as > X, then the value X is used 
in the analysis. 
6.5.6. 
Estimated Glomerular Filtration Rate 
The formula used to calculate estimated glomerular filtration rate (eGFR) is based on the patient’s 
age at the date of 402-C-1803 consent. The formula will not change throughout the study. 
However, note that the formula used in the prior study may be different if the patient was < 18 in 
prior study and at least 18 in 402-C-1803. The Chronic Kidney Disease - Epidemiology 
Collaboration equation is used for adult patients (age at consent at least 18 years): 
• eGFR (mL/min/1.73 m2) = 141 × min (Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 
1.018 [if female] × 1.159 [if black] 
The Bedside Schwartz equation is used for pediatric patients (age at consent of 12 to 17): 
• eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Scr 
where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males. Min indicates the minimum of Scr/κ and 1, and max indicates the 
maximum of Scr/κ and 1. Age indicates age at time of serum creatinine collection. Height indicates 
height at time of serum creatinine collection. Estimated glomerular filtration rate (eGFR) will not 
be calculated by the central lab.   
6.5.7. 
Urine Albumin to Creatinine Ratio (ACR) 
Albumin/creatinine ratio is provided in the central laboratory database as the ratio of urine albumin 
to urine creatinine from the first morning void (FMV) urine collection. The ACR value is reported 
in the central laboratory database as missing when the FMV urine albumin result is < LLD. Urine 
albumin results < LLD and the corresponding ACR missing values is imputed as follows: 
• If urine albumin result = < LLD, then 
− Imputed urine albumin result (mg/dL) = LLD/2 
− Imputed ACR (mg/g) = (imputed urine albumin result in mg/dL) / [(urine creatinine 
in mg/dL) /1000] 
The ACR results are log-transformed for analysis to produce data that are more normally 
distributed. Any imputed ACR result where ACR=0 is considered to be 0.1 mg/g for purposes of 
calculating the geometric mean. 
6.5.7.1. 
Baseline Urine Albumin to Creatinine Ratio Categorical Status 
Baseline ACR status will also be grouped by the following categories using baseline ACR: 
• < 30 mg/g 
• 30 mg/g ≤ ACR ≤ 300 mg/g 
• 300 mg/g < ACR ≤ 1000 mg/g 
• 1000 mg/g < ACR ≤ 3500 mg/g 


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• ACR > 3500 mg/g 
6.5.7.2. 
ACR Category used in Stratification 
The ACR category used for stratification  with the following categories: 
• ACR ≤ 300 mg/g 
• ACR > 300 mg/g 
6.5.8. 
Natural log (ACR)/eGFR 
To evaluate ACR after adjusting for filtration rate, ln(ACR)/eGFR (Section 6.5.7 and Section 6.5.6) 
is calculated. 
6.6. 
Handling of Missing Data 
6.6.1. 
Missing Endpoints 
Missing data are not imputed. 
6.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Missing start dates for concomitant medications are not imputed. 
Concomitant medications with incomplete end dates are considered concomitant medications if: 
• Day and month are missing, and the year is equal to or after the year of the first date of 
study drug administration; 
• Day is missing and the year is after the year of the first date of study drug 
administration; 
• Day is missing and the year is equal to the year of the first date of study drug 
administration and the month is equal to or after the month of the first date of study drug 
administration; or 
• Year is missing. 
6.6.3. 
Missing Start and Stop Dates for Adverse Events 
Treatment-emergent adverse events (TEAEs) are events that either: 
• Had a date of onset on or after the date of the first dose of study drug and not more than 
30 days after the date of the last dose of study drug, or 
• Had no recorded date of onset with a stop date after the first dose of study drug, or 
• Had no recorded date of onset or stop date. 
Adverse events with incomplete start dates are considered after the date of first dose if: 
• Day and month are missing, and the year is equal to or after the year of the first date of 
study drug administration; 
• Day is missing and the year is after the year of the first date of study drug 
administration; 


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• Day is missing and the year is equal to the year of the first date of study drug 
administration and the month is equal to or after the month of the first date of study drug 
administration; or 
• Year is missing. 
Adverse events with incomplete start dates are considered on or within 30 days of last dose, if: 
• Day and month are missing, and the year is equal to or before the year of the date of last 
dose of study drug plus 30 days; 
• Day is missing and the year is equal to or before the year of the date of last dose of 
study drug plus 30 days, and month is equal to or before the month of the date of last 
dose of study drug plus 30 days; 
• Year is missing. 
6.6.4. 
Missing End of Treatment Date 
For patients without a full end of treatment date (i.e., missing day, month, or year), the last study 
drug dispensation date will be used as the end of treatment date for purposes of analysis. 


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7. 
STUDY POPULATION 
Data are summarized for the safety population (Section 6.3.1) 
7.1. 
Subject Disposition 
A disposition summary includes the number and percentage of patients in the following categories: 
• Patients with prior participation in 402-C-1603 phase 2 
• Patients with prior participation in 402-C-1603 phase 3 and randomized to placebo 
• Patients with prior participation in 402-C-1603 phase 3 and randomized to bardoxolone 
methyl 
• Patients with prior participation in 402-C-1808 phase 3 and randomized to placebo 
• Patients with prior participation in 402-C-1808 phase 3 and randomized to bardoxolone 
methyl 
• Patients completed study when the study was terminated 
• Continuing (or complete) treatment 
• Terminate early from the treatment 
− Reason for terminating treatment 
− Terminated early from the treatment due to COVID-19 
• Continuing (or complete) study 
• Terminate early from the study 
− Reason for terminating study 
− Terminated early from the study due to COVID-19  
− Study week at study termination  
− Terminated prior to SDT  
− Terminated after SDT 
Results will be summarized by analysis population (Section 6.3). A listing of disposition is 
provided for all patients. 
7.2. 
Screen Failures 
Lab assessments from the qualifying study will be used for EAGLE eligibility and maximum 
treatment dose assignment (Week 100 for CARDINAL or FALCON protocol versions 1 through 5, 
and Week 108 [B] for FALCON versions 6 and newer) if those assessments were done ≤ 8 weeks 
before Day 1.  In the event that the eligibility lab assessments were obtained > 8 weeks before the 
planned EAGLE Day 1 visit, a screening visit will be required for EAGLE enrollment. Subjects 
who previously were ineligible due to previous eGFR requirements may be rescreened once. 
Screen failures are not summarized. 


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7.3. 
Protocol Deviation 
Protocol deviations for major protocol deviations and protocol deviations related to COVID-19 are 
summarized. 
Major protocol deviations include but not limited to: 
• Protocol deviations for patients who entered the study even though they did not satisfy 
all entry criteria. 
• Patients who received an incorrect dose.  
All protocol deviations are listed. 
7.4. 
Demographic and Baseline Characteristics 
Summaries of demographic and other baseline characteristic data are presented by treatment 
analysis group (Section 4.5) for all the safety populations.  
The demographic and other baseline characteristics include: 
• Age, Age category at the date of informed consent (< 18, ≥ 18) 
• Race 
• Ethnicity: Non-Hispanic/Latino; Hispanic/Latino 
• Sex: (female; male) 
• Weight (kg), body mass index (kg/m2) 
• Geographic location: United States; Other 
• Diastolic and systolic blood pressure (mmHg), Heart rate (bpm) 
• SCr, eGFR, eGFR categorical status (< 60, ≥ 60 mL/min/1.73 m2) 
• ACR (geometric mean), ACR categorical status (< 30 mg/g; ≤ 300 mg/g; > 300 mg/g; 
• > 1000 mg/g), 
• Angiotensin converting enzyme-inhibitor treatment and/or Angiotensin II receptor 
blocker (yes/no) 
• Genetic subtype: X-linked Alport syndrome; Non-X-linked Alport syndrome (for Alport 
patients only)  
• Chronic kidney disease etiology:  Alport syndrome; autosomal dominant polycystic 
kidney disease (ADPKD) 
• Family history of ADPKD (for ADPKD patients only) 
• Use of tolvaptan (for ADPKD patients only) 
− Currently using tolvaptan 
− Previously used tolvaptan  
− Never received tolvaptan 


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• Prior study:  402-C-1603 phase 2, 402-C-1603 phase 3, 402-C-1808 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria 
A listing of enrolled patients who did not meet inclusion or exclusion criteria is generated. 
7.6. 
Medical History 
Medical history is summarized by treatment analysis group (Section 4.5). If medical history values 
are not recorded in 402-C-1803, then medical history values recorded at the 
402-C-1603/402-C-1808 screening visit are used for analysis. Medical history is coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Medical history items are summarized by 
MedDRA System Organ Class (SOC) and preferred term (PT). Patient listings are also provided. 


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8. 
SAFETY AND TOLERABILITY 
Safety and tolerability are evaluated by AEs, SAEs, clinical laboratory test results, body weight, 
vital signs, and physical examination. All analyses of the safety data are performed using the safety 
analysis set. Descriptive statistics are presented by treatment analysis group (Section 4.5) 
assignment in the all analysis populations. No formal statistical testing is performed for safety 
analyses. Any results not included in summaries based on analysis visit window definitions are 
presented in data listings. 
8.1. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
Adverse events are summarized by treatment as defined by the safety analysis set. General 
considerations for AE summaries and calculations are: 
• Multiple events by PT and SOC are counted once only per patient for summaries of AE 
incidence. 
• For summaries of AE incidence by severity, only the most severe event is counted per 
patient. 
• For summaries of AE incidence by relationship, only the most related event is counted 
per patient. 
• An AE with a missing resolution date or incomplete date that is not identified as 
continuing is assumed to be continuing and no duration is calculated. 
• Only TEAEs are included in summaries. 
Adverse events are coded using MedDRA version 21.1. In MedDRA, each verbatim term is 
mapped to a PT and high-level term, which is then mapped to an SOC. Tables and listings will 
present data at the SOC and PT level. 
Treatment emergent adverse events (TEAEs) are events that either: 
• Have a date of onset on or after the date of the first dose in the 402-C-1803 study and 
not more than 30 days after the date of the last dose of study drug in the 402-C-1803 
study, or 
• Have no recorded date of onset with a stop date after the first dose of study drug, or 
• Have no recorded date of onset or stop date 
Adverse events with a date of onset in a prior study that continued during the 402-C-1803 study are 
not considered TEAEs. 
In addition, AEs that occurred >30 days after the date of last dose of study drug are summarized as 
late-onset AEs. These are AEs that had a date of onset more than 30 days after the date of the last 
dose of study drug in 402-C-1803 study. 
The investigator grades the severity of the AEs as mild, moderate, or severe as defined in the study 
protocol Section 11.5. The investigators graded association or relatedness to the study medication 
according to criteria specified in Section 11.4 of the study protocol. 


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As defined in the protocol, an SAE is an AE that results in any of the following: 
• Death; 
• A life-threatening adverse drug experience; 
• Patient reaches ESKD (defined as the initiation of maintenance dialysis for 12 weeks or 
more or kidney transplant) 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Results in a congenital anomaly or birth defect in an offspring of a patient taking study 
drug; 
• Is an important medical event. 
8.1.1. 
Missing and Partial AE Onset Dates 
Rules for handling missing or partial AE onset dates are included in Section 6.6.3.   
8.1.2. 
Summaries of Adverse Events 
For each treatment analysis group, SOC, and PT, the number and percentage of patients reporting 
an event is calculated. In summary tables, SOC is presented alphabetically and events within SOC 
are presented by decreasing frequency count. 
Summary tables (number and percentage of patients and events) of AEs (by SOC and PT) are 
provided by treatment analysis group as follows: 
• All TEAEs 
• All treatment-emergent related AEs (definitely, probably, or possibly related) 
• All TEAEs by severity 
• All treatment-emergent SAEs (including deaths) 
• All related treatment-emergent SAEs (including deaths) 
• All TEAEs leading to permanent discontinuation of study drug 
Listings are provided showing: 
• All AEs 
• SAEs (including deaths) 
• AEs leading to permanent discontinuation of study drug 
8.2. 
Exposure and Compliance 
The duration of study drug exposure is defined as the number of days on treatment from the first 
dose of 402-C-1803 study drug until the last dose of study drug (last dose – first dose + 1). Study 
drug exposure is summarized by descriptive statistics. Summaries include the total dose (mg) 
received (based on the number of pills returned), study drug compliance, and duration (days) of 


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exposure during the study treatment period. In addition, a summary of the number and percentage 
of patients by dose (5 mg, 10 mg, 20 mg, 30 mg) and by visit window (Section 6.5.4) is generated. 
If a patient received more than one dose during a visit window, the duration of the longest dose 
exposure is used to calculate study drug dose during a given visit window. 
Total number of doses dispensed and total dose (mg) dispensed is calculated from total number of 
kits (bottles) recorded on the Study Drug Dispensation electronic case report form (eCRF). Total 
number of doses received is calculated from information on the eCRF of Study Drug Return and 
Study Drug Dispensation, as the (total number of doses dispensed – total number of doses 
returned). Study drug compliance (%) is calculated as 100 × total number of doses received / total 
number of study days of study participation. For patients who remain on study treatment at the time 
of an interim or final data cut, the last kit dispensed date is considered the date of last dose.  Any 
dispensation of drug after a subject has his or her end of treatment visit will not be used in any 
calculation. 
8.3. 
Concomitant and Other Medications 
Concomitant medications are coded using the World Health Organization drug dictionary (B3 
Global September 2018) for anatomical therapeutic chemical (ATC) classification and preferred 
drug name. Patients who used multiple medications are counted only once for each ATC and 
preferred drug name. Anatomical therapeutic chemical (ATC) and preferred drug name within each 
ATC are sorted alphabetically. Coded concomitant medications are summarized by treatment 
analysis group (Section 4.5). Percentages are based on the number of patients in the safety analysis 
set. 
A concomitant medication is any medication taken at the time of first study treatment during the 
402-C-1803 study or a medication that was started after the start of 402-C-1803 study drug dosing. 
Specifically, concomitant medications are medications: 
• That are continued from 402-C-1603 or 402-C-1808 and continued after the first study 
drug dosing, or 
• That have start dates within the 402-C-1803 treatment period. 
Concomitant medications are summarized for each treatment analysis group by World Health 
Organization ATC class and preferred name. Patients may have more than 1 medication per ATC 
class and preferred name. At each level of patient summarization, a patient is counted once if 
he/she reported one or more medications at that level. Each summary is ordered by descending 
order of incidence of ATC class and preferred name within each ATC class. 
Concomitant medications include those with an end date after the first study drug administration as 
well as medications without an end date. Medications with an end date on or prior to the date of 
first study drug administration in 402-C-1803 study are not considered concomitant medications. 


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Patients who take the following excluded medications (defined in the Protocol Section 9.3.1) 
during the study are listed. 
• Any other investigational drug 
• Tolvaptan (patients on tolvaptan who have already enrolled under Version 3.0 of the 
protocol may remain in the trial) 
• Somatostatin analogues 
• Chronic (> 2 weeks) immunosuppressive therapy, or need for corticosteroids, 
including therapies such as glucocorticoids, oncologic preparations, and anti-tumor 
necrosis factor α agents [eg, infliximab (Remicade®), adalimumab (Humira®), 
certolizumab pegol (Cimzia®), etanercept (Enbrel®)]. (Glucocorticoid intra- articular 
injections, inhaled products, topical preparations, and nasal preparations are allowed.) 
In addition, patients who take the following concomitant medications (defined in the 
Protocol Section 9.3.2) during the study are listed. 
• Antibiotics; 
• Daily multivitamins or recommended daily supplements; 
• Other medications intended to manage concurrent diseases, as authorized by the 
treating physician; 
• Statins, in the Czech Republic and globally 
• Pain management medications 
• Oral, implantable, or injectable contraceptives 
8.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
Missing and partial concomitant medication start and stop dates are detailed in Section 6.6.2  
8.4. 
Clinical Laboratory Evaluations 
Laboratory data are summarized at baseline and at each time point by treatment analysis group 
(Section 4.5). 
8.4.1. 
Continuous Summaries of Laboratory Results 
Selected laboratory evaluations and change from baseline are summarized by treatment analysis 
group (Section 4.5), laboratory category (hematology, chemistry), test, and study visit using 
continuous statistics. The eGFR results are calculated using formulas described in Section 6.5.6. 
Box plots and line graphs are generated for selected laboratory test results, such as eGFR, ACR, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBL), B-type 
natriuretic peptide (BNP), blood urea nitrogen, uric acid, magnesium, creatinine, and creatine 
kinase. Line graphs include mean ± SE over time for both the observed values and for change 
from baseline. 


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Due to the nature of urinalysis parameters, summaries of continuous statistics are not provided 
unless otherwise specified. The one exception is the ACR from the FMV urine collection. 
Qualitative lab results, including urinalysis, are included in the listings, but are not summarized. 
Laboratory results that are above or below normal limits are flagged in the listings. 
8.4.1.1. 
Urine Albumin/Creatinine Ratio 
Summaries of ACR (Section 6.5.7) will use the geometric mean with 95% confidence intervals 
instead of the arithmetic mean and will display ACR results in original units of mg/g. Changes 
from baseline in ACR are reported as the post-baseline/baseline ratios and are summarized by 
geometric means with 95% confidence intervals at each time point. Summaries of ACR will use 
the geometric mean instead of the arithmetic mean. Presentations will display ACR results in the 
original units (mg/g). Changes in ACR are calculated as the ratio of each visit to baseline. 
Additionally, ACR is summarized by baseline ACR quartile. Descriptive summaries at each visit 
include the geometric mean of ACR, SD as well as the geometric mean of percent change from 
baseline. Summaries of ACR exclude values within the Week 2 and Week 6 visit windows. 
8.4.1.2. 
Continuous eGFR 
Any eGFR values collected after starting dialysis or after receiving a kidney transplant are 
treated as missing. Missing values are not imputed as specified in Section 6.6.1. 
The change from baseline in eGFR is summarized by visit and treatment analysis group 
(Section 4.5). Summary statistics and change from baseline are presented by visit window 
(Section 6.5.4). Waterfall plots of eGFR change from baseline, labeled by treatment analysis 
group (Section 4.5) are generated at each visit window. Results are presented in tables and plots. 
8.4.1.3. 
Natural log (ACR)/eGFR 
Mean ratios of natural log (ACR)/eGFR (Section 6.5.8) are summarized at each time point for 
safety. The ratio of natural log (ACR)/eGFR by analysis visit is summarized by arithmetic means 
for safety. 
8.4.2. 
Categorical Summaries of Laboratory Results 
The number and percentage of patients by laboratory normality and abnormality categories at 
any time during the study (Normal, Low, High) are summarized by treatment analysis group 
(Section 4.5), laboratory category (hematology, chemistry, and urinalysis), and laboratory test. 
The worst abnormality values are defined as the maximum values while on study treatment (ie, 
up to < 14 days after last dose), except for magnesium and hemoglobin. The worst abnormal 
values for magnesium and hemoglobin are defined as the minimum values while on study 
treatment. 
An initial set of parameters of specific interest (ALT, AST, ACR) are summarized using shift 
tables, though additional parameters may be added as appropriate. Shift tables summarizing 
(1) baseline to end of treatment, and (2) baseline to worst on-treatment, (3) baseline to follow-up, 
and (4) worst on-treatment to follow-up are presented for lab parameters as appropriate. For 
ACR, summaries will present shifts from/to the categories in Section 6.5.7.1.  For ALT and AST, 
summaries will present shifts from/to the following categories: 


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• < 3× upper limit of normal (ULN) 
• ≥ 3× ULN to < 5× ULN 
• ≥ 5× ULN to < 10× ULN 
• ≥ 10× ULN to < 20× ULN 
• ≥ 20× ULN 
In addition, a summary table is provided by treatment analysis group (Section 4.5) for the 
number and percentage of patients meeting a following pre-specified threshold level at any time 
during the study: 
• ACR > 3500 mg/g 
• Magnesium < 1.3 mEq/L (0.65 mmol/L) 
• BNP > 200 pg/mL 
• N-terminal prohormone BNP > 1000 pg/mL 
8.4.2.1. 
Transaminases 
Evaluation of Drug-Induced Serious Hepatotoxicity plots are generated for ALT and AST versus 
TBL. 
The number and percentage of patients meeting the following thresholds, which are consistent 
with Food and Drug Administration guidance of Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation (July 2009 Drug Safety), are summarized by the maximum dosage received. 
Table 3: 
Pre-specified Threshold Levels for Transaminases 
Lab Parameter 
Threshold 
ALT, AST 
≥ 3 × ULN and < 5 × ULN 
≥ 5 × ULN and < 10 × ULN 
≥ 10 × ULN and < 20 × ULN 
≥ 20 × ULN 
≥ 5 × ULN for more than 2 weeks 
TBL 
≥ ULN and ≤ 1.5 × ULN 
> 1.5 × ULN and ≤ 2 × ULN 
> 2 × ULN 
ALT, AST, TBL 
ALT or AST > 3×ULN and TBL > 1.5×ULN 
ALT or AST > 3×ULN and TBL > 2×ULN 
ALP 
> 1.5 × ULN 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
TBL=total bilirubin; ULN=upper limit of normal. 
A summary table that includes frequencies and percentages of patients that meet any of the 
above criteria at any time during the study is provided. A listing of subjects with abnormal ALT, 
AST, or TBL will also be provided. 


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8.4.2.2. 
Frequency of End Stage Kidney Disease, eGFR decline ≥ 30%, or eGFR < 15 
The kidney failure composite outcome is defined as reaching one of the following: 
• 30% decline from baseline in eGFR; or 
• eGFR < 15 mL/min/1.73 m2; or 
• ESKD (initiation of maintenance dialysis or kidney transplant). 
A ≥ 30% decline or eGFR < 15 is considered confirmed when the threshold is achieved at 
≥ 2 visits. Patients who achieved the threshold at their last visit, and did not have a second 
confirmatory visit, are considered confirmed. The analysis uses initiation of maintenance dialysis 
or kidney transplant as reported prior to the end of the follow-up window in the database by the 
investigator. Any initiation of maintenance dialysis or kidney transplant that occurs after the 
follow-up window will be listed separately. Patients with a decrease from baseline in eGFR of 
≥ 30% at the last on-treatment visit will be considered to have a ≥ 30% decrease from baseline 
eGFR. In the event a patient has both an increase from baseline in eGFR of ≥ 30% and a 
decrease from baseline in eGFR of ≥ 30%, only the decrease from baseline will be considered in 
composite endpoint analyses. 
The proportion of patients with ESKD (dialysis/transplant), eGFR decline ≥ 30%, or eGFR 
< 15 will be summarized, and the composite of all these criteria will be evaluated. The frequency 
analyses will be performed for all visits. No off-treatment eGFR values are included in the 
analysis. 
As a sensitivity analysis, the analyses are repeated for the frequency of patients with ESKD 
(dialysis/transplant), eGFR decline ≥ 30%, or eGFR < 15 with all-cause death added to the kidney 
failure composite. 
8.5. 
Vital Signs 
Vital signs assessments include systolic blood pressure (mmHg) and diastolic blood pressure 
(mmHg), body temperature (°C), heart rate (bpm), height (cm), weight (kg), and body mass 
index (kg/m2). Vital signs are summarized at baseline and at each time point (Section 6.5.4) 
along with the change from baseline by treatment analysis group (Section 4.5). Line graphs of 
change from baseline over time for blood pressure are plotted. 
All data are listed. 
8.5.1. 
Body Weight 
Body weight, as collected during each in-office visit in 402-C-1803, is summarized using 
descriptive statistics for observed results and change from baseline at each time point. In 
addition, number and percentage of patients experiencing a 5 pound (2.3 kilogram) or greater 
increase in weight are summarized by time point. Boxplots and line graphs of change from 
baseline over time for weight are plotted. 
8.6. 
Pregnancy 
A listing is provided for serum and urine pregnancy results of all on-study pregnancies. 


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9. 
PHARMACOKINETICS 
There are no pharmacokinetic samples collected in 402-C-1803. 


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10. 
COVID-19 IMPACT 
10.1. 
Operational Impact 
The COVID-19 pandemic has impacted the conduct of the study per protocol. The mitigation 
strategies are adopted to protect the health of participants in the 402-C-1803 study, while 
maintaining compliance with good clinical practice and minimizing the risk to trial integrity 
(Protocol Appendix 1). These measures apply to United States and rest of the world. An eCRF 
form is updated to collect data for COVID-19 impact. 
The number and percentage of patients impacted by COVID-19 are summarized by visit and 
treatment analysis group for the following categories: 
• Visit impact 
− Visit not done 
− Visit conducted out of window 
− One or more procedures could not be performed 
− Rollover delayed 
• Data collection methods 
− No change (occurred as expected per protocol) 
− Telephone visit 
− Video conference visit 
− Home health care visit 
− Local lab 
− Other 
• Drug dispensation methods 
− No change (office visit) 
− Investigational product dispense not scheduled (telephone visit) 
− Mailed to patient 
− Home health care provided 
− Dose not escalated 
− Dose de-escalated 
− Other 
The number and percentage of patients impacted by COVID-19 are summarized by treatment 
analysis group (Section 4.5) for the following categories: 
• Drug Interruption due to COVID-19 
− Tested positive for COVID-19 (yes, no, not tested) 


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− Primary reason for interruption (medical monitor/sponsor recommendation, site 
mandate, patient choice, insufficient investigational product supply, other) 
Patient narratives are provided for all patients who test positive for SARS-CoV-2, the causative 
agent of COVID-19. 
Early discontinuations of treatment or study due to COVID-19 are summarized and listed 
(specified in Section 7.1). 
All deviations due to the impacts of COVID-19 are identified and documented accordingly by 
the site and the sponsor. The failure to complete a protocol visit is not considered as a reason for 
study discontinuation and/or a major deviation. All COVID-19–related deviations will be 
identified in the protocol deviation listing (Section 7.3). 
10.2. 
Safety 
For continued patient safety oversight, patients should continue with protocol-specified visits. 
Where inadvisable for the patient to be seen for an in-person clinic visit or if a patient is 
unwillingly to come to the clinic, alternate visit completion methods should be considered, such 
as by phone, telemedicine, home health visits and/or local laboratory monitoring of safety labs. 
Patients affected by COVID-19 with visits not done, visits outside the window, one or more 
procedures not performed, and other impact to study assessments or procedures are listed. 
Patients with changes in safety data collection methods due to COVID-19 including telephone, 
video conference, home health, local lab, and other methods are listed. 
APPENDIX 1 
Programming Specifications 
Continuous data are listed corresponding to the precision measured or calculated. Measures of 
central tendency are presented using 1 more decimal place than the precision of the data. 
Summaries of variability are presented using 2 significant digits more than the precision of the 
underlying data. Minimum and maximum are presented using the precision of the data. 
All percentages are to be expressed as integers with 1 decimal place. The convention for 
rounding percentages is as follows: 
• Values greater than or equal to x.x5% are rounded up 
• Values between 0 and x.x5% are rounded down