A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome
Phase: PHASE2
Conditions: Alport Syndrome
Sponsor: Biogen

Protocol 402-C-1603 
Reata Pharmaceuticals, Inc. 
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BARDOXOLONE METHYL (RTA 402) 
 
402-C-1603 
 
EUDRACT NUMBER: 2016-004395-22 
 
A PHASE 2/3 TRIAL OF THE EFFICACY AND SAFETY 
OF BARDOXOLONE METHYL IN PATIENTS WITH 
ALPORT SYNDROME 
 
VERSION 4.0 – 23 MAY 2019 
FRANCE, SPAIN, UNITED KINGDOM 
 
Protocol History 
Version 3.0 15 November 2018 
Version 2.0 23 May 2018 
Version 1.0 09 August 2017 
 
 
 
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 received and read the Investigator’s Brochure for bardoxolone methyl.  I have read the 
402-C-1603 clinical study protocol and agree to conduct the study as outlined.  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 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 402-C-1603 
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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 
 
 
 
 
 
 
 
Clinical Study 
Manager 
 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
 
SAE Reporting 
 
 
 
 
 
 

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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Product: 
Bardoxolone methyl 
Title of Study:  
A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome 
Study center(s): Up to 100 study centers 
Studied period: 3.5 years  
Estimated date first patient enrolled: December 2016 
Estimated date last patient completed: December 2020 
The end of the study is defined as the last visit of the 
last patient. 
Phase of development:  
2/3 
Objectives:   
For patients with Alport syndrome enrolled in this study, the objectives are as follows: 
Phase 2: 
Primary: 
• 
To assess the change from baseline in estimated glomerular filtration rate (eGFR) in 
bardoxolone methyl-treated patients after 12 weeks of treatment. 
• 
To assess the safety of bardoxolone methyl after 12 weeks of treatment. 
Secondary:  
• 
To assess the safety and efficacy of bardoxolone methyl after 48 weeks of treatment. 
• 
To assess the safety and efficacy of bardoxolone methyl after 100 weeks of treatment. 
Exploratory: 
• 
To assess the safety and efficacy of bardoxolone methyl at Week 52 following a 4-week drug 
treatment withdrawal period 
Phase 3: 
Year 1 Endpoints 
Primary: 
• 
To assess the change from baseline in estimated glomerular filtration rate (eGFR) in 
bardoxolone methyl-treated patients relative to placebo after 48 weeks of treatment. 
• 
To assess the safety of bardoxolone methyl relative to placebo after 48 weeks of treatment. 
Key Secondary: 
• 
To assess the change from baseline in eGFR in bardoxolone methyl-treated patients relative to 
placebo at Week 52 following a 4-week drug treatment withdrawal period. 
Exploratory: 
• 
To compare the percentage of bardoxolone methyl and placebo patients who experience an 
increase from baseline in eGFR of 30% or more after 48 weeks of treatment. 
• 
To compare the percentage of bardoxolone methyl and placebo patients who experience a 

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decrease from baseline in eGFR of 30% or more after 48 weeks of treatment. 
• 
To assess the distribution of changes from baseline in eGFR in bardoxolone methyl versus 
placebo patients after 48 weeks of treatment. 
• 
To assess the Patient Global Impression of Change (PGIC) scores in bardoxolone methyl-
treated patients relative to placebo after 48 weeks of treatment. 
• 
To assess the Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone methyl-
treated patients relative to placebo after 48 weeks of treatment. 
• 
To assess the percentage of bardoxolone methyl-treated patients relative to placebo with a 
kidney failure event defined as the composite endpoint by Week 52 consisting of: 
o 30% decline from baseline in eGFR;  
o eGFR < 15 mL/min/1.73 m2; 
o ESKD (initiation of maintenance dialysis or kidney transplant). 
 
Year 2 Endpoints: 
Primary: 
• 
To assess the change from baseline in estimated eGFR in bardoxolone methyl-treated patients 
relative to placebo after 100 weeks of treatment. 
• 
To assess the safety of bardoxolone methyl relative to placebo after 100 weeks of treatment. 
Secondary: 
• 
To assess the change from baseline in eGFR in bardoxolone methyl-treated patients relative to 
placebo at Week 104 following a 4-week drug treatment withdrawal period. 
Exploratory: 
• 
To compare the percentage of bardoxolone methyl and placebo patients who experience an 
increase from baseline in eGFR of 30% or more after 100 weeks of treatment. 
• 
To compare the percentage of bardoxolone methyl and placebo patients who experience a 
decrease from baseline in eGFR of 30% or more after 100 weeks of treatment. 
• 
To assess the distribution of changes from baseline in eGFR in bardoxolone methyl versus 
placebo patients after 100 weeks of treatment. 
• 
To assess the Patient Global Impression of Change (PGIC) scores in bardoxolone methyl-
treated patients relative to placebo after 100 weeks of treatment. 
• 
To assess the Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone methyl-
treated patients relative to placebo after 100 weeks of treatment. 
• 
To assess in bardoxolone methyl-treated patients relative to placebo the frequency and time-to-
first kidney failure event by Week 104 defined as the composite endpoint consisting of: 
o 30% decline from baseline in eGFR;  
o eGFR < 15 mL/min/1.73 m2; 
o ESKD (initiation of maintenance dialysis or kidney transplant). 
Methodology:  
This international, multi-center, Phase 2/3 trial will study the safety, tolerability, and efficacy of 
bardoxolone methyl in qualified patients with Alport syndrome.  The Phase 2 portion of the trial will be 
open-label and enroll approximately 30 patients.  The Phase 3 portion of the trial will be double-blind, 
randomized, and placebo-controlled and will enroll approximately 150 patients.   
Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study.  Patients in the 

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Phase 3 cohort will be randomized 1:1 to either bardoxolone methyl or placebo and randomization will 
be stratified by screening albumin to creatinine ratio (ACR).  Patients randomized to placebo will 
remain on placebo throughout the study, undergoing sham titration.   
The maximum bardoxolone methyl dose in the Phase 2 and Phase 3 cohorts will be determined by 
baseline proteinuria status.  Patients with macroalbuminuria (300 mg/g < ACR ≤ 3500 mg/g) at the 
Screen B visit will account for up to 50% of patients enrolled in the Phase 2 cohort and should not 
comprise more than approximately 40% of patients enrolled in the Phase 3 cohort.  Patients with 
baseline ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline 
ACR > 300 mg/g will be titrated to a maximum dose of 30 mg.  Patients 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 baseline ACR >300 mg/g) unless contraindicated clinically and 
approved by the medical monitor.  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.   
All patients in the study will follow the same visit and assessment schedule.  Following randomization 
on Day 1, patients will be scheduled to be assessed during treatment at Weeks 1, 2, 4, 6, 8, 12, 24, 36, 
48, 52, 64, 76, 88, 100, and 104 and by telephone contact on Days 3, 10, 21, 31, 38, and 45.  Patients 
will not receive study drug during a 4-week withdrawal period between Weeks 48 and 52.  They will 
re-start treatment at Week 52 at the same dose they received at Week 48 and will continue study drug 
treatment through Week 100.  Patients will also be scheduled to be assessed at an in-person follow-up 
visit at Week 104, four weeks after the end of treatment.   
The Phase 2 primary efficacy endpoint will be analyzed after all patients in the Phase 2 cohort have 
completed their Week 12 visit.  Enrollment of the Phase 3 cohort may begin after the last patient has 
enrolled in the Phase 2 cohort.  Available safety, tolerability, and efficacy data from the Phase 2 cohort 
will be evaluated by the DMC prior to opening enrollment in the Phase 3 cohort.  The Phase 2 
endpoints at Week 48 and Week 52 will be analyzed after all patients in the Phase 2 cohort have 
completed their Week 52 visit.  The Phase 3 Year 1 primary efficacy endpoint will be analyzed after all 
patients in the Phase 3 cohort have completed their Week 52 visit.  The Phase 3 Year 2 primary 
efficacy endpoint will be analyzed after all patients in the Phase 3 cohort have completed their Week 
104 visit. 
All enrolled patients are expected to remain on their blinded treatment assignment through Week 100, 
and to complete all scheduled assessments through Week 104.   
Number of patients (planned):  
Approximately 180 patients will be enrolled (approximately 30 patients in the Phase 2 cohort and 
approximately 150 patients in the Phase 3 cohort).   
Diagnosis and main criteria for inclusion: 
1. Male and female patients 18 ≤ age ≤ 70 upon study consent; 
2. Diagnosis of Alport syndrome by genetic testing (documented mutation in a gene associated 
with Alport syndrome, including COL4A3, COL4A4, or COL4A5) or histologic assessment 
using electron microscopy;   
3. Screening eGFR (average of Screen A and Screen B eGFR values) ≥ 30 and 
≤ 90 mL/min/1.73 m2.  The two eGFR values collected at Screen A and Screen B visits used to 
determine eligibility must have a percent difference ≤ 25%; 

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4. Albumin to creatinine ratio (ACR) ≤ 3500 mg/g at Screen B visit.  Up to 50% of patients in the 
Phase 2 cohort and approximately 40% of patients enrolled in the Phase 3 cohort can have 
ACR of 301 to 3500 mg/g.  Once enrollment of these patients is complete, the ACR inclusion 
criterion is ≤ 300 mg/g; 
5. Patients receiving an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II 
receptor blocker (ARB) should be receiving the maximally tolerated labeled daily dose 
(MTLDD), as defined in Section 9.1.7, for at least 6 weeks prior to the Screen A visit.  The 
dosage of ACE inhibitor and/or ARB should remain the same throughout the remainder of the 
study (i.e., no change in dosage or medication), and any potential changes should be discussed 
with the medical monitor.  Patients not currently taking an ACE inhibitor and/or ARB because 
they are not indicated or because of a medical contraindication may be eligible provided the 
patient has not taken an ACE inhibitor and/or ARB at least 8 weeks prior to the Screen A visit 
(these patients must be discussed with the medical monitor prior to enrollment); 
6. Adequate bone marrow reserve and organ function at the Screen A visit as follows: 
a. Hematologic: Absolute neutrophil count > 1.5 x 10
9/L, platelets > 100 x 10
9/L, 
hemoglobin (Hgb) ≥ 9 g/dL; 
b. Hepatic: Total bilirubin (TBL) ≤ 1.5X the upper limit of normal (ULN), alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5X ULN; 
7. Able to swallow capsules; 
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
study procedures; 
9. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study prior to initiation of any 
protocol-mandated procedures. 
Major exclusion criteria: 
1. Prior exposure to bardoxolone methyl; 
2. Ongoing chronic hemodialysis or peritoneal dialysis therapy;  
3. Renal transplant recipient; 
4. B-type natriuretic peptide (BNP) level > 200 pg/mL at Screen A visit; 
5. Uncontrolled diabetes (HbA1c > 11.0%) at Screen A visit; 
6. Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during 
Screening; 
7. Serum albumin < 3 g/dL at Screen A visit; 
8. History of clinically significant left-sided heart disease and/or clinically significant cardiac 
disease, including but not limited to any of the following: 
a. Clinically significant congenital or acquired valvular disease;  
b. Left ventricular ejection fraction < 40% (based on echocardiogram performed at 
Screen A visit or within 6 months prior to Day 1); 
c. Pericardial constriction (based on echocardiogram performed at Screen A visit or 
within 6 months prior to Day 1); 
d. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at 
Screen A visit or within 6 months prior to Day 1); 
e. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary 
intervention, coronary artery bypass graft surgery, or angina); 

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f. History of hospitalization for heart failure; 
g. Cardiac insufficiency, defined as New York Heart Association Class > 2; 
h. History of atrial fibrillation; 
i. 
History of unstable arrhythmias; 
9. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) 
> 160 mm Hg or sitting diastolic BP > 100 mm Hg at Screen A visit after a period of rest; 
10. Systolic BP < 90 mm Hg at Screen A visit after a period of rest; 
11. History of malignancy within 5 years prior to Screen A visit, with the exception of localized 
skin or cervical carcinomas; 
12. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior 
to randomization or anticipated need for immunosuppression during the study; 
13. Untreated or uncontrolled active bacterial, fungal, or viral infection; 
14. Participation in other interventional clinical studies within 30 days prior to Day 1; 
15. Unwilling to practice acceptable methods of birth control (both males who have partners of 
child-bearing potential and females of childbearing potential) during Screening, while taking 
study drug, and for at least 30 days after the last dose of study drug is ingested;  
16. Women who are pregnant or breastfeeding; 
17. Known hypersensitivity to any component of the study drug;  
18. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at 
risk by trial enrollment; 
19. 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. 
Investigational product, dosage, and mode of administration:  
Bardoxolone methyl will be administered orally at 5, 10, 20, or 30 mg.   
Duration of treatment:  
Bardoxolone methyl or placebo will be administered through Week 100. 
Reference therapy, dosage and mode of administration:  
Placebo will be administered orally through Week 100. 
Criteria for evaluation: 
Efficacy: eGFR, PGIC, and CGI-I  
Safety: Results of laboratory results (clinical chemistry, hematology, urinalysis), vital sign 
measurements, electrocardiogram (ECG) results, weight, adverse events (AEs), and serious adverse 
events (SAEs). 
Statistical methods: 
Sample size:  
Phase 2: 
With 30 patients, the Phase 2 portion of the study will have over 80% power to detect a change from 
baseline in eGFR relative to zero.  The power calculation, which was based on a 2-sided t-test, assumes 
the following: 
• 
Two-sided Type I error rate of 0.05 
• 
5% of the patients will not complete at least 12 weeks of study treatment  
• 
A change from baseline in eGFR of approximately 4.3 mL/min/1.73 m2  

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3.
TABLE OF CONTENTS AND LIST OF TABLES
TABLE OF CONTENTS 
1.
TITLE PAGE ................................................................................................................1 
2.
SYNOPSIS ...................................................................................................................5 
3.
TABLE OF CONTENTS AND LIST OF TABLES ..................................................11 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5.
INTRODUCTION ......................................................................................................21 
5.1. 
Clinical Experience with Bardoxolone Methyl ..........................................................23 
5.1.1. 
Efficacy .......................................................................................................................23 
5.1.2. 
Safety and Tolerability ...............................................................................................26 
5.1.2.1. 
Fluid Overload ............................................................................................................26 
5.1.2.2. 
Transaminase and Gamma-glutamyl Transpeptidase (GGT) Elevations ...................26 
5.1.2.3. 
Muscle Spasms ...........................................................................................................27 
5.1.2.4. 
Weight Loss ................................................................................................................27 
5.1.2.5. 
Hypomagnesaemia ......................................................................................................28 
5.1.2.6. 
Increases in Urinary Protein .......................................................................................28 
6.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................29 
6.1. 
Objectives ...................................................................................................................29 
6.1.1. 
Phase 2 ........................................................................................................................29 
6.1.1.1. 
Primary Objective .......................................................................................................29 
6.1.1.2. 
Secondary Objective ...................................................................................................29 
6.1.1.3. 
Exploratory Objective .................................................................................................29 
6.1.2. 
Phase 3 – Year 1 Objectives .......................................................................................29 
6.1.2.1. 
Primary Objectives .....................................................................................................29 
6.1.2.2. 
Key Secondary Objective ...........................................................................................29 
6.1.2.3. 
Exploratory Objectives ...............................................................................................29 
6.1.3. 
Phase 3 – Year 2 Objectives .......................................................................................30 
6.1.3.1. 
Primary Objectives .....................................................................................................30 
6.1.3.2. 
Secondary Objective ...................................................................................................30 
6.1.3.3. 
Exploratory Objectives ...............................................................................................30 
6.2. 
Endpoints ....................................................................................................................31 

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6.2.1. 
Phase 2 ........................................................................................................................31 
6.2.1.1. 
Primary Efficacy Endpoint .........................................................................................31 
6.2.1.2. 
Secondary Efficacy Endpoint .....................................................................................31 
6.2.1.3. 
Exploratory Efficacy Endpoint ...................................................................................31 
6.2.2. 
Phase 3 – Year 1 Endpoints ........................................................................................31 
6.2.2.1. 
Primary Efficacy Endpoint .........................................................................................31 
6.2.2.2. 
Key Secondary Efficacy Endpoint ..............................................................................31 
6.2.2.3. 
Exploratory Efficacy Endpoints .................................................................................31 
6.2.3. 
Phase 3 – Year 2 Endpoints ........................................................................................32 
6.2.3.1. 
Primary Efficacy Endpoint .........................................................................................32 
6.2.3.2. 
Secondary Efficacy Endpoint .....................................................................................32 
6.2.3.3. 
Exploratory Efficacy Endpoints .................................................................................32 
6.2.4. 
Safety Endpoints .........................................................................................................32 
7. 
INVESTIGATIONAL PLAN .....................................................................................33 
7.1. 
Overall Study Design ..................................................................................................33 
7.2. 
Number of Patients .....................................................................................................34 
7.3. 
Treatment Assignment and Rationale .........................................................................34 
7.3.1. 
Dose Escalation ..........................................................................................................34 
7.3.2. 
Dose De-Escalation and Re-Escalation ......................................................................34 
7.4. 
Criteria for Study Termination ...................................................................................35 
7.5. 
Schedule of Assessments ............................................................................................35 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................39 
8.1. 
Patient Inclusion Criteria ............................................................................................39 
8.2. 
Patient Exclusion Criteria ...........................................................................................40 
8.3. 
Screening Period .........................................................................................................41 
8.4. 
Patient Re-Screening ..................................................................................................41 
8.5. 
Patient Discontinuation and Termination ...................................................................41 
8.5.1. 
Patient Study Drug Discontinuation Criteria ..............................................................41 
8.5.2. 
Patient Study Termination Criteria .............................................................................42 
9. 
TREATMENT OF PATIENTS ..................................................................................43 
9.1. 
Select Management Guidelines ..................................................................................43 
9.1.1. 
Management of Fluid Status .......................................................................................43 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................44 

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9.1.3. 
Management of Muscle Spasms .................................................................................44 
9.1.4. 
Weight Loss ................................................................................................................44 
9.1.5. 
Hypomagnesaemia ......................................................................................................44 
9.1.6. 
Management of Urinary Protein .................................................................................44 
9.1.7. 
Management of Blood Pressure ..................................................................................45 
9.1.8. 
Nausea .........................................................................................................................45 
9.1.9. 
End Stage Kidney Disease ..........................................................................................45 
9.2. 
Description of Study Drug ..........................................................................................46 
9.3. 
Concomitant Medications ...........................................................................................47 
9.3.1. 
Excluded Medications ................................................................................................47 
9.3.2. 
Permitted Medications ................................................................................................47 
9.4. 
Treatment Compliance ................................................................................................48 
9.5. 
Randomization ............................................................................................................48 
9.6. 
Blinding ......................................................................................................................48 
9.6.1. 
Patient Unblinding ......................................................................................................48 
9.6.2. 
Unblinding for Regulatory Submission ......................................................................49 
9.6.3. 
Data Monitoring Committee .......................................................................................49 
9.7. 
Unscheduled Visits .....................................................................................................49 
9.8. 
Pregnancy ...................................................................................................................50 
9.8.1. 
Women of Childbearing Potential ..............................................................................50 
9.8.2. 
Methods of Birth Control............................................................................................50 
9.8.3. 
Suspected Pregnancy ..................................................................................................51 
9.9. 
Serious Toxicities .......................................................................................................51 
9.10. 
Study Procedures ........................................................................................................51 
9.10.1. 
Informed Consent .......................................................................................................52 
9.10.2. 
Inclusion/Exclusion ....................................................................................................52 
9.10.3. 
Demographics and Baseline Disease Characteristics .................................................52 
9.10.4. 
Prior and Current Concomitant Medications ..............................................................52 
9.10.5. 
Medical History ..........................................................................................................52 
9.10.6. 
Height .........................................................................................................................52 
9.10.7. 
Weight and Body Mass Index (BMI) .........................................................................52 
9.10.8. 
Electrocardiograms (ECG) .........................................................................................53 
9.10.9. 
Echocardiogram ..........................................................................................................53 

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9.10.10. 
Vital Sign Measurements ............................................................................................53 
9.10.11. 
Physical Examination .................................................................................................53 
9.10.12. 
Pregnancy Test ............................................................................................................53 
9.10.13. 
Study Drug Administration.........................................................................................53 
9.10.14. 
Study Drug Dispensation and Collection ...................................................................54 
9.10.15. 
Telephone Contact ......................................................................................................54 
9.10.16. 
Adverse Event Collection ...........................................................................................54 
9.10.17. 
Genetic Testing ...........................................................................................................54 
9.10.18. 
Clinical Chemistry ......................................................................................................54 
9.10.18.1. eGFR ...........................................................................................................................55 
9.10.19. 
N-Terminal Pro-Brain Natriuretic Peptide (NT-Pro BNP) and Brain 
Natriuretic Peptide (BNP) ...........................................................................................55 
9.10.20. 
Insulin-Like Growth Factor-1 (IGF-1) and Serum Ketones .......................................55 
9.10.21. 
Hemoglobin A1c .........................................................................................................55 
9.10.22. 
Hematology .................................................................................................................55 
9.10.23. 
Urinalysis and Microscopy .........................................................................................56 
9.10.24. 
Urine Collection for Albumin to Creatinine Ratio (ACR) .........................................56 
9.10.25. 
Visual Acuity ..............................................................................................................56 
9.10.26. 
Audiology Assessment ...............................................................................................56 
9.10.27. 
Patient Global Impression of Change .........................................................................56 
9.10.28. 
Clinical Global Impression-Improvement ..................................................................56 
9.10.29. 
Virus Serology ............................................................................................................56 
9.10.30. 
Pharmacokinetic (PK) Blood Samples .......................................................................57 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................58 
10.1. 
Study Drug ..................................................................................................................58 
10.2. 
Study Drug Packaging and Labeling ..........................................................................58 
10.3. 
Study Drug Storage .....................................................................................................58 
10.4. 
Study Drug Administration.........................................................................................58 
10.5. 
Study Drug Accountability .........................................................................................59 
10.6. 
Study Drug Handling and Disposal ............................................................................59 
11. 
SAFETY ASSESSMENTS ........................................................................................60 
11.1. 
Safety Parameters .......................................................................................................60 
11.2. 
Adverse and Serious Adverse Events .........................................................................60 

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11.2.1. 
Definition of Adverse Events .....................................................................................60 
11.2.1.1. 
Adverse Event .............................................................................................................60 
11.2.1.2. 
Serious Adverse Event ................................................................................................60 
11.3. 
Eliciting Adverse Event Information ..........................................................................61 
11.4. 
Assessment of Causality .............................................................................................61 
11.5. 
Assessment of Severity ...............................................................................................62 
11.6. 
Recording Adverse Events .........................................................................................62 
11.7. 
Reporting Serious Adverse Events .............................................................................63 
12. 
STATISTICS ..............................................................................................................65 
12.1. 
Sample Size ................................................................................................................65 
12.2. 
Study Variables ...........................................................................................................66 
12.2.1. 
Pharmacokinetic Variables .........................................................................................66 
12.2.2. 
Efficacy Variables ......................................................................................................66 
12.2.3. 
Safety Variables ..........................................................................................................66 
12.3. 
Statistical Analyses .....................................................................................................66 
12.3.1. 
Primary Analysis of Efficacy ......................................................................................66 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................68 
13.1. 
Study Monitoring ........................................................................................................68 
13.2. 
Audits and Inspections ................................................................................................68 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................69 
14.1. 
Quality Assurance .......................................................................................................69 
14.2. 
Financial Disclosure ...................................................................................................69 
14.3. 
Sponsor Obligations....................................................................................................69 
14.4. 
Investigator Documentation ........................................................................................69 
14.5. 
Clinical Study Insurance .............................................................................................70 
14.6. 
Use of Information ......................................................................................................70 
15. 
ETHICS ......................................................................................................................71 
15.1. 
Institutional Review Board (IRB) or Ethics Committee (EC) Review .......................71 
15.2. 
Ethical Conduct of the Study ......................................................................................71 
15.3. 
Written Informed Consent ..........................................................................................71 
15.4. 
Confidentiality ............................................................................................................72 
15.5. 
Modification of the Protocol .......................................................................................72 
15.6. 
Protocol Deviations ....................................................................................................73 

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16. 
DATA HANDLING AND RECORDKEEPING .......................................................74 
16.1. 
Retention of Records ..................................................................................................74 
16.2. 
Case Report Forms .....................................................................................................74 
17. 
PUBLICATION POLICY ..........................................................................................75 
18. 
REFERENCES ...........................................................................................................76 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
Cross-Study Comparison of Increases in eGFR, Inulin Clearance, and 
Creatinine Clearance with Bardoxolone Methyl Treatment .......................................25 
Table 4: 
Schedule of Assessments ............................................................................................36 
Table 5: 
Bardoxolone Methyl Drug Product Information ........................................................46 
Table 6: 
Placebo Information ....................................................................................................47 
Table 7: 
SAE Reporting Contact Information ..........................................................................63 
 

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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 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations (US) 
CGI-I 
Clinical Global Impression - Improvement 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CrCl 
Creatinine clearance 
CRO 
Clinical research organization 
CV 
Cardiovascular 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ERA 
Endothelin receptor antagonist 
ESKD 
End stage kidney disease 
FDA 
Food and Drug Administration (US) 

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Abbreviation or Specialist Term 
Explanation 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transpeptidase 
HbA1c 
Hemoglobin A1c 
hCG-Qual 
Human chorionic gonadotropin-qualitative  
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
Hgb 
Hemoglobin 
ICH 
International Conference on Harmonization 
IGF-1 
Insulin-like growth factor-1 
IKKβ 
Inhibitor of nuclear factor kappa β kinase beta subunit 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
ITT 
Intent-to-treat 
KDIGO 
Kidney Disease: Improving Global Outcomes 
Keap1 
Kelch-like ECH associated protein-1 
Kf 
Ultrafiltration coefficient 
LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MMRM 
Mixed model repeated measures 
MRI 
Magnetic resonance imaging 
MTLDD 
Maximally tolerated labeled daily dose 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B-cells 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
PBO 
Placebo  
PGIC 
Patient Global Impression of Change 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic 

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Abbreviation or Specialist Term 
Explanation 
QTc 
Corrected QT interval 
RBC 
Red blood cell 
RNA 
Ribonucleic acid  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
T2D 
Type 2 diabetes  
TBL 
Total bilirubin 
Tmax 
Time when maximum drug concentration in plasma is achieved 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 

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5. 
INTRODUCTION 
Alport syndrome is a hereditary kidney disease caused by mutations in the COL4A3, COL4A4 
and COL4A5 genes, coding for the α3, α4, and α5 chains of type IV collagen.  Type IV collagen 
is a major constituent of basement membranes.  More than 500 different mutations have been 
described, mostly linked to X-chromosomal (XLAS, 85%) and autosomal recessive (ARAS, 
15%) inheritance.  The defective type IV collagen in Alport syndrome leads to typical splitting in 
the glomerular basement membrane (GBM), podocyte effacement, glomerulosclerosis with 
matrix deposition, as well as kidney fibrosis and end-stage renal failure early in life.  Although 
the genetic defect affects type IV collagen in the glomerular basement membrane, secondary 
events lead to tubulo-interstitial fibrosis (Krügel, 2013). 
For patients, Alport syndrome is a fateful diagnosis with important negative consequences 
regarding their life-expectancy and quality of life.  As Alport syndrome is a rare disease 
(prevalence of XLAS estimated 1:10,000 1:5,000 to 1:57,000; ARAS estimated to 1:50 000), it is 
often unnoticed despite family history for macrohematuria or chronic renal disease.  In Europe, 
untreated patients reach end-stage renal disease with a median age of 22 years (Gross, 2012).  In 
retrospective data from registries, therapeutic blockade of the renin-angiotensin-aldosterone-
system (RAAS) can significantly slow down the progression to end-stage renal failure depending 
on the stage of the disease (Gross, 2012).  Current treatment recommendations (Kashtan, 2013; 
Savige, 2013) recommend off-label therapy with RAAS-blockade in proteinuric Alport patients.  
However, despite RAAS-blockade, all Alport syndrome patients still progress to end-stage renal 
failure, increasing the massive unmet medical need for new nephroprotective therapies.  Children 
with Alport syndrome can usually be diagnosed in their first decade of life while being 
oligosymptomatic with hematuria and low-grade proteinuria.  Later, they develop severe 
proteinuria and progressive renal failure.  As a result, they face a ~1,000-fold increase risk of 
cardiovascular events, disabled growth, and infections, and life-expectancy of Alport syndrome 
patients is impaired by decades (Gross, 2012).  Therefore, there is an urgent unmet medical need 
for the development of new therapeutics that reduce the degree of fibrosis and inflammation, 
improve renal function, and delay end-stage renal disease for patients with Alport syndrome. 
Bardoxolone methyl and its analogs are oleanolic acid-derived synthetic triterpenoid compounds 
that potently induce the Nrf2-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 antioxidant and 
cytoprotective enzymes and related proteins (Lee, 2009; Dinkova-Kostova, 2005).  Bardoxolone 
methyl and its analogs are also potent inhibitors of the NF-κB inflammatory pathway through 
both direct (i.e., inhibition of IKKβ kinase activity) and indirect mechanisms (i.e., 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 

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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, 2010).  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.   
Like other chronic progressive renal diseases, declining glomerular filtration rate (GFR) and 
decreased kidney function in Alport syndrome is driven by proinflammatory processes and 
inflammation has been shown to be a pathogenic feature of Alport syndrome that correlates with 
declining renal function in patients (Jedlicka, 2010).  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).  All these 
components (NF-κB, inflammation, endothelial dysfunction, mesangial cells, fibrosis and 
hyperfiltration) have previously been demonstrated to contribute to pathogenesis of progressive 
loss of kidney function in Alport syndrome (Gross, 2014).  
Bardoxolone methyl has consistently improved parameters of renal function in multiple clinical 
studies in patients with chronic kidney disease (CKD), cancer, or pulmonary hypertension (PH), 
with significant increases in inulin clearance, creatinine clearance, and estimated 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, dynamic 
inflammation-mediated processes such 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 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 SAEs, and 
end-stage kidney disease (ESKD).  Thus, the collective data support that bardoxolone methyl 

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may have disease-modifying effects in the kidney (e.g., reversal of mesangial expansion and 
interstitial fibrosis) that are beneficial and not deleterious.   
In Alport patients, who have average eGFR declines of 4 mL/min/1.73 m2 per year 
(Rheault, 2016), the potential impact of a sustained eGFR increase with bardoxolone methyl 
treatment is profound and could provide a multi-year delay in disease progression to ESKD. 
5.1. 
Clinical Experience with Bardoxolone Methyl 
Approximately 1950 individuals have been exposed to bardoxolone methyl.  Sixteen studies 
have been completed (seven in patients with CKD who also had type 2 diabetes, four in non-
CKD indications, and five in healthy subjects) and two studies are ongoing in patients with PH.   
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 
2600 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 end-Stage kidney disease (ESKD; need 
for chronic dialysis, renal transplantation, or renal death) or cardiovascular (CV) 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 

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(−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 
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.   
Most recently, Reata’s Asian development partner, Kyowa Hakko Kirin, demonstrated that 
bardoxolone methyl treatment resulted in a significant improvement in GFR 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.  
 

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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)a 
CKD Studies 
402-C-0801  
(Stratum 1) 
2a/ 
US 
Multicenter, Open-
Label, Dose-
Ranging, 
Randomized 
Age >=18, 
Diabetic 
nephropathy 
60 
28 days 
6.7b 
(p<0.001) 
402-C-0801  
(Stratum 2) 
2b/ 
US 
Multicenter, Open-
Label, Dose-
Ranging, 
Randomized 
Age >=18, 
Diabetic 
nephropathy 
20 
56 days 
7.2b 
(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 
6.5b 
(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 
108 
16 weeks 
6.6 (inulin GFR) 
(p=0.008 vs PBO) 
Non-CKD Studies 
402-C-0501 
1/ 
US 
Open-label, Dose-
escalation 
Age >=18, 
Advanced Solid 
Tumors or 
Lymphoid 
Malignancies 
47 
Median:  
56 days 
18.2b 
(p<0.0001) 
402-C-0702 
1/2/ 
US 
Double-Blinded, 
Randomized 
Pancreatic 
Cancer 
34 
Median:  
56 days 
32.2b 
(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) 
54c 
16 weeks 
14.7 
(p<0.001 vs PBO) 
a 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. 
b 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. 
c Number of patients enrolled Cohorts 1 and 2. 

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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 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.  
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 or other signs of liver toxicity.  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 ULN.  The elevations resolved to levels less than the ULN in most all 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 

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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 GGT, a known Nrf2 target gene.  In clinical studies, low level 
GGT elevations during treatment were common, mild, and typically lasted longer than ALT/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 
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 
subjects 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. 

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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 
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 chronic kidney disease 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 absorption 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. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
The objectives are as follows: 
6.1.1. 
Phase 2  
6.1.1.1. 
Primary Objective   
• To assess the change from baseline in estimated glomerular filtration rate (eGFR) in 
bardoxolone methyl-treated patients after 12 weeks of treatment. 
• To assess the safety of bardoxolone methyl after 12 weeks of treatment. 
6.1.1.2. 
Secondary Objective   
• To assess the safety and efficacy of bardoxolone methyl after 48 weeks of treatment. 
• To assess the safety and efficacy of bardoxolone methyl after 100 weeks of treatment. 
6.1.1.3. 
Exploratory Objective   
• To assess the safety and efficacy of bardoxolone methyl at Week 52 following a 
4-week drug treatment withdrawal period 
6.1.2. 
Phase 3 – Year 1 Objectives 
6.1.2.1. 
Primary Objectives 
• To assess the change from baseline in estimated glomerular filtration rate (eGFR) in 
bardoxolone methyl-treated patients relative to placebo after 48 weeks of treatment. 
• To assess the safety of bardoxolone methyl relative to placebo after 48 weeks of 
treatment. 
6.1.2.2. 
Key Secondary Objective 
• To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at 
Week 52 following a 4-week drug treatment withdrawal period. 
6.1.2.3. 
Exploratory Objectives 
• To compare the percentage of bardoxolone methyl and placebo patients who 
experience an increase from baseline in eGFR of 30% or more after 48 weeks of 
treatment. 
• To compare the percentage of bardoxolone methyl and placebo patients who 
experience a decrease from baseline in eGFR of 30% or more after 48 weeks of 
treatment. 
• To assess the distribution of changes from baseline in eGFR in bardoxolone methyl 
versus placebo patients after 48 weeks of treatment. 

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• To assess the Patient Global Impression of Change (PGIC) scores in bardoxolone 
methyl-treated patients relative to placebo after 48 weeks of treatment. 
• To assess the Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone 
methyl-treated patients relative to placebo after 48 weeks of treatment. 
• To assess the percentage of bardoxolone methyl-treated patients relative to placebo 
with a kidney failure event defined as the composite endpoint consisting of: 
− 30% decline from baseline in eGFR; 
− eGFR < 15 mL/min/1.73 m2; 
− ESKD (initiation of maintenance dialysis or kidney transplant). 
6.1.3. 
Phase 3 – Year 2 Objectives 
6.1.3.1. 
Primary Objectives 
• To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at 
Week 100. 
• To assess the safety of bardoxolone methyl relative to placebo after 100 weeks of 
treatment. 
6.1.3.2. 
Secondary Objective 
• To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at 
Week 104 following a 4-week drug treatment withdrawal period. 
6.1.3.3. 
Exploratory Objectives   
• To compare the percentage of bardoxolone methyl and placebo patients who 
experience an increase from baseline in eGFR of 30% or more after 100 weeks of 
treatment. 
• To compare the percentage of bardoxolone methyl and placebo patients who 
experience a decrease from baseline in eGFR of 30% or more after 100 weeks of 
treatment. 
• To assess the distribution of changes from baseline in eGFR in bardoxolone methyl 
versus placebo patients after 100 weeks of treatment. 
• To assess the Patient Global Impression of Change (PGIC) scores in bardoxolone 
methyl-treated patients relative to placebo after 100 weeks of treatment. 
• To assess the Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone 
methyl-treated patients relative to placebo after 100 weeks of treatment. 
• To assess in bardoxolone methyl-treated patients relative to placebo the frequency 
and time-to-first kidney failure event defined as the composite endpoint consisting of: 
− 30% decline from baseline in eGFR; 
− eGFR < 15 mL/min/1.73 m2; 

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− ESKD (initiation of maintenance dialysis or kidney transplant). 
6.2. 
Endpoints 
6.2.1. 
Phase 2 
6.2.1.1. 
Primary Efficacy Endpoint 
• Change from baseline in eGFR at Week 12. 
6.2.1.2. 
Secondary Efficacy Endpoint 
• Change from baseline in eGFR at Week 48. 
6.2.1.3. 
Exploratory Efficacy Endpoint 
• Change from baseline in eGFR at Week 52 following a 4-week drug treatment 
withdrawal period. 
6.2.2. 
Phase 3 – Year 1 Endpoints 
6.2.2.1. 
Primary Efficacy Endpoint 
• Change from baseline in eGFR relative to placebo at Week 48. 
6.2.2.2. 
Key Secondary Efficacy Endpoint 
• The change from baseline in eGFR in bardoxolone methyl-treated patients relative to 
placebo at Week 52 following a 4-week drug treatment withdrawal period. 
6.2.2.3. 
Exploratory Efficacy Endpoints 
• The percentage of bardoxolone methyl versus placebo patients with an increase from 
baseline in eGFR of 30% or more after 48 weeks of treatment. 
• The percentage of bardoxolone methyl versus placebo patients with a decrease from 
baseline in eGFR of 30% or more after 48 weeks of treatment. 
• The distribution of changes from baseline in eGFR in bardoxolone methyl versus 
placebo patients after 48 weeks of treatment. 
• To assess the percentage of bardoxolone methyl-treated patients relative to placebo 
with a kidney failure event defined as the composite endpoint consisting of: 
− 30% decline from baseline in eGFR; 
− eGFR < 15 mL/min/1.73 m2; 
− ESKD (initiation of maintenance dialysis or kidney transplant). 

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6.2.3. 
Phase 3 – Year 2 Endpoints 
6.2.3.1. 
Primary Efficacy Endpoint 
• The change from baseline in eGFR in bardoxolone methyl-treated patients relative to 
placebo at Week 100. 
6.2.3.2. 
Secondary Efficacy Endpoint 
• The change from baseline in eGFR in bardoxolone methyl-treated patients relative to 
placebo at Week 104 following a 4-week drug treatment withdrawal period. 
6.2.3.3. 
Exploratory Efficacy Endpoints 
• The percentage of bardoxolone methyl versus placebo patients with an increase from 
baseline in eGFR of 30% or more after 100 weeks of treatment. 
• The percentage of bardoxolone methyl versus placebo patients with a decrease from 
baseline in eGFR of 30% or more after 100 weeks of treatment. 
• The distribution of changes from baseline in eGFR in bardoxolone methyl versus 
placebo patients after 100 weeks of treatment. 
• The Patient Global Impression of Change (PGIC) scores in bardoxolone methyl-
treated patients relative to placebo after 100 weeks of treatment. 
• The Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone methyl-
treated patients relative to placebo after 100 weeks of treatment. 
• To assess in bardoxolone methyl-treated patients relative to placebo the frequency 
and time-to-first kidney failure outcome event defined as the composite endpoint 
consisting of: 
− 30% decline in eGFR; 
− eGFR < 15 mL/min/1.73 m2;  
− ESKD (initiation of maintenance dialysis or kidney transplant). 
6.2.4. 
Safety Endpoints 
The following safety endpoints will be assessed at the time of the year 1 efficacy analysis, and 
again at the time of the year 2 efficacy analysis.   
• Frequency, intensity, and relationship to study drug of AEs and SAEs, and change 
from baseline in the following assessments: vital sign measurements, 12-lead ECGs, 
clinical laboratory measurements, and weight. 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This international, multi-center, Phase 2/3 trial will study the safety, tolerability, and efficacy of 
bardoxolone methyl in qualified patients with Alport syndrome.  The Phase 2 portion of the trial 
will be open-label and enroll approximately 30 patients.  The Phase 3 portion of the trial will be 
double-blind, randomized, placebo-controlled and will enroll approximately 150 patients.   
Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study.  Patients in 
the Phase 3 cohort will be randomized 1:1 to either bardoxolone methyl or placebo and 
randomization will be stratified by screening albumin to creatinine ratio (ACR).  Patients 
randomized to placebo will remain on placebo throughout the study, undergoing sham titration.   
The maximum bardoxolone methyl dose in the Phase 2 and Phase 3 cohorts will be determined 
by baseline proteinuria status.  Patients with macroalbuminuria (300 mg/g < ACR ≤ 3500 mg/g) 
at the Screen B visit will account for up to 50% of patients enrolled in the Phase 2 cohort and 
should not comprise more than approximately 40% of patients enrolled in the Phase 3 cohort.  
Patients with baseline ACR ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and 
patients with baseline ACR > 300 mg/g will be titrated to a maximum dose of 30 mg.  Patients 
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 baseline 
ACR >300 mg/g) unless contraindicated clinically and approved by the medical monitor.  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.  Please 
refer to Section 7.3.1 for additional details on dose escalation and dose de-escalation.   
All patients in the study will follow the same visit and assessment schedule.  Following 
randomization on Day 1, patients will be scheduled to be assessed during treatment at Weeks 1, 
2, 4, 6, 8, 12, 24, 36, 48, 52, 64, 76, 88, 100, and 104 and by telephone contact on Days 3, 10, 21, 
31, 38, and 45.  Patients will not receive study drug during a 4-week withdrawal period between 
Weeks 48 and 52.  They will re-start treatment at Week 52 at the same dose they received at 
Week 48 and will continue study drug treatment through Week 100.  Patients will also be 
scheduled to be assessed at an in-person follow-up visit at Week 104, four weeks after the end of 
treatment.   
The Phase 2 primary efficacy endpoint will be analyzed after all patients in the Phase 2 cohort 
have completed their Week 12 visit.  Enrollment of the Phase 3 cohort may begin after the last 
patient has enrolled in the Phase 2 cohort.  Available safety, tolerability, and efficacy data from 
the Phase 2 cohort will be evaluated by the DMC prior to opening enrollment in the Phase 3 
cohort.  The Phase 2 endpoints at Week 48 and Week 52 will be analyzed after all patients in the 
Phase 2 cohort have completed their Week 52 visit.  The Phase 3 Year 1 primary efficacy 
endpoint will be analyzed after all patients in the Phase 3 cohort have completed their Week 52 
visit.  The Phase 3 Year 2 primary efficacy endpoint will be analyzed after all patients in the 
Phase 3 cohort have completed their Week 104 visit. 
All enrolled patients are expected to remain on their blinded treatment assignment through 
Week 100, and to complete all scheduled assessments through Week 104. 

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7.2. 
Number of Patients 
Approximately 180 patients will be enrolled (approximately 30 patients in the Phase 2 cohort and 
approximately 150 patients in the Phase 3 cohort).  
7.3. 
Treatment Assignment and Rationale 
Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study.  Patients in 
the Phase 3 cohort will be randomized 1:1 to either bardoxolone methyl or placebo.  
Randomization for the Phase 3 portion of the study will be performed using an interactive web 
response system (IWRS).  Patients randomized to placebo in the Phase 3 cohort will remain on 
placebo throughout the study but will follow sham titration to maintain the blind.   
A dose-titration regimen is being utilized to allow for individual dose optimization based on 
tolerability and based on the anticipated maximally efficacious dose of bardoxolone methyl, 
which may vary based on a patient’s proteinuria status at baseline.  Based on results from prior 
trials in patients with type 2 diabetes and CKD, Reata has concluded that higher bardoxolone 
methyl doses may be required to have an optimal effect on eGFR following drug withdrawal in 
patients with macroalbuminuria.  Specifically, eGFR improvements in patients with normo- or 
micro-albuminuria were observed with a 20 mg bardoxolone methyl dose and the effects were 
retained following a 1-month withdrawal.  In patients with macroalbuminuria, a 30-mg dose was 
required to produce a response that was similar to the patients with microalbuminuria treated at 
20 mg.  Consequently, the study includes dose titration up to a maximum dose of 20 mg for 
patients with ACR ≤ 300 mg/g and a maximum dose of 30 mg for patients with 
ACR > 300 mg/g, as described below.  From a safety perspective, the 30 mg dose may be 
associated with an increased incidence of nausea; however, the nausea experienced in previous 
trials is generally mild, transient, and clinically manageable. 
7.3.1. 
Dose Escalation  
Patients randomized to placebo in the Phase 3 cohort will remain on placebo throughout the 
study, undergoing sham titration.  Patients in Phase 2 or Phase 3 cohorts 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 baseline ACR >300 mg/g) unless 
contraindicated clinically and approved by the medical monitor.  The dosing objective is to 
titrate patients to the maximum dose determined by baseline ACR, and maintain the maximum 
dose after initial dose-titration.  The investigator should discuss any reason for not dose-
escalating at Weeks 2 and 4 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 (e.g., 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 dose and must be documented.  After dose de-
escalation, patients should return for an unscheduled office visit within 4 weeks (± 3 days) to 
collect clinical chemistry and to perform the assessments detailed in Section 9.7. 

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Once 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 after dose escalation and an unscheduled office visit 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 9.7.  
7.4. 
Criteria for Study Termination 
Although the Sponsor intends to complete the study, 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. 
7.5. 
Schedule of Assessments 
Table 4 lists the overall schedule of assessments for the study. 

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Table 4: Schedule of Assessments  
Assessment 
Screen 
Aa 
Screen 
Bb 
Day 1c 
Wk 1 
(Phone) 
Day 3±2 
Wk 1 
 Day 7±3 
Wk 2 
(Phone) 
Day 10±2 
Wk 2 
Day 
14±3 
Wk 3 
(Phone) 
 Day 21±2 
Wk 4 
Day 
28±3 
Wk 4 
(Phone) 
Day 31±2  
Wk 5 
(Phone) 
Day 38±2 
Wk 6 
Day 
42±3 
Wk 7 
(Phone) 
Day 45±2 
Wk 8 
Day 
56±3 
Wk 12 
Day 84±3 
Informed consent 
X 
Inclusion/ exclusion 
X 
Xd 
Demographics and baseline disease 
characteristics 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
Height 
X 
X 
X 
X 
X 
X 
X 
X 
Weight in clinic  
X 
X 
X 
X 
X 
X 
X 
X 
Weight at home 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense weight diary 
X 
X 
X 
X 
X 
X 
Collect/review weight diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
Echocardiograme 
X 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test for WOCBPf 
X 
X 
X 
X 
X 
X 
Study drug administration 
---------------------------------------------X----------------------------------------- 
Dispense study drug 
X 
X 
X 
X 
X 
X 
Collect study drug 
X 
X 
X 
X 
X 
Telephone contact 
X 
X 
X 
X 
X 
X 
Adverse event collection 
X
g
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic testingh 
X 
Clinical chemistry (incl. eGFR)  
X 
X 
X 
X 
X 
X 
X 
X 
X 
BNP and NT-proBNP 
X 
X 
X 
X 
X 
X 
X 
X 
IGF-1 and serum ketones 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin A1c 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Urinalysis and microscopy 
X 
X 
X 
X 
X 
X 
X 
Urine collection for ACRi 
X 
X 
X 
X 
Visual acuity 
X 
Audiology assessment 
X 
PGIC 
CGI-I 
Virus serology 
X 
PK samplesj 
X 

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Assessment 
Wk 24 
Day 168±3 
Wk 36 
Day 252±3 
Wk 48 
Day 336±3 
Wk 52 
Day 364 (-6) 
Wk 64 
Day 448±5 
Wk 76 
Day 532±5 
Wk 88 
Day616±5 
Wk 100 or  
End of Treatmentk 
Day 700±3 
Wk 104 or  
Follow-upk 
Day 728 (-6) 
Informed consent 
Inclusion/ exclusion 
Demographics and baseline disease 
characteristics 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
Height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight in clinic  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight at home 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense weight diary 
X 
X 
X 
X 
X 
X 
X 
Collect/review weight diary 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
Echocardiograme 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test for WOCBPf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
-----------X---------- 
---------------------------------------------X----------------------------------------- 
Dispense study drug 
X 
X 
X 
X 
X 
X 
Collect study drug 
X 
X 
X 
X 
X 
X 
X 
Telephone contact 
Adverse event collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic testingh 
Clinical chemistry (incl. eGFR) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BNP and NT-proBNP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IGF-1 and serum ketones 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin A1c 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis and microscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for ACRi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual acuity 
X 
X 
Audiology assessment 
X 
X 
PGIC 
X 
X 
X 
X 
X 
X 
CGI-I 
X 
X 
X 
X 
X 
X 
Virus serology 
PK samplesj 

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a Total Screening period should not exceed 6 months.
b Screen B visit should be no more than 30 days prior to Day 1.
c Day 1 is the day of administration of the first dose.  On Day 1, all procedures should be performed before study drug administration. 
d Screening eligibility procedures do not need to be repeated on Day 1; however, a review of any changes in eligibility criteria should be evaluated prior to Day 1 procedures, and a 
urine pregnancy test should be performed for WOCBP.
e An echocardiogram performed at the Screen A visit or within 6 months prior to Day 1 may be used to determine eligibility. 
f A serum pregnancy test will be performed at the Screen A visit for WOCBP or 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 regulatory authorities or IRBs/ECs.  
g  AE assessments on Day 1 should be performed following study drug administration.
h Patients with definitive diagnosis of Alport syndrome from previous genetic testing will not have genetic testing performed as part of the study but must provide documentation 
of genetic diagnosis for eligibility.
i Albumin to creatinine ratio will be measured by first morning void spot urine collection.  Appropriate containers for the collection will be provided to the patient at the visit prior 
to collection.
j Patients must be instructed to not take their study drug prior to coming to the clinic for visits when PK samples will be collected.  Patients must administer the study drug dose in 
the clinic on PK sample collection visits after the 0-hour PK blood sample is collected.  Patients will have blood samples for PK analysis drawn just prior to (0 hour) and after 
(2 and 4 hours) dose administration.  
k Patients who terminate from the study prior to the Week 100 study visit should be brought back to the clinic as soon as possible for early termination assessments (i.e., end-of- 
treatment visit) as well as a follow-up visit 4 weeks later.  
Abbreviations: ECG = electrocardiogram, PK = pharmacokinetic, WOCBP = women of child-bearing potential 

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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Diagnosis and main criteria for inclusion:  
1. Male and female patients 18 ≤ age ≤ 70 upon study consent; 
2. Diagnosis of Alport syndrome by genetic testing (documented mutation in a gene 
associated with Alport syndrome, including COL4A3, COL4A4, or COL4A5) or 
histologic assessment using electron microscopy; 
3. Screening eGFR (average of Screen A and Screen B eGFR values) ≥ 30 and 
≤ 90 mL/min/1.73 m2.  The two eGFR values collected at Screen A and Screen B visits 
used to determine eligibility must have a percent difference ≤ 25%; 
4. Albumin to creatinine ratio (ACR) ≤ 3500 mg/g at Screen B visit.  Up to 50% of patients 
in the Phase 2 cohort and approximately 40% of patients enrolled in the Phase 3 cohort 
can have ACR of 301 to 3500 mg/g.  Once enrollment of these patients is complete, the 
ACR inclusion criterion is ≤ 300 mg/g; 
5. Patients receiving an angiotensin-converting enzyme (ACE) inhibitor and/or an 
angiotensin II receptor blocker (ARB) should be receiving the maximally tolerated 
labeled daily dose (MTLDD), as defined in Section 9.1.7, for at least 6 weeks prior to the 
Screen A visit.  The dosage of ACE inhibitor and/or ARB should remain the same 
throughout the remainder of the study (i.e., no change in dosage or medication), and any 
potential changes should be discussed with the medical monitor.  Patients not currently 
taking an ACE inhibitor and/or ARB because they are not indicated or because of a 
medical contraindication may be eligible provided the patient has not taken an ACE 
inhibitor and/or ARB at least 8 weeks prior to the Screen A visit (these patients must be 
discussed with the medical monitor prior to enrollment); 
6. Adequate bone marrow reserve and organ function at the Screen A visit as follows: 
a. Hematologic: Absolute neutrophil count > 1.5 x 10
9/L, platelets > 100 x 10
9/L, 
hemoglobin (Hgb) ≥ 9 g/dL; 
b. Hepatic: Total bilirubin (TBL) ≤ 1.5X the upper limit of normal (ULN), alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5X ULN; 
7. Able to swallow capsules; 
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures; 
9. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study prior to initiation of any 
patient-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. Prior exposure to bardoxolone methyl; 
2. Ongoing chronic hemodialysis or peritoneal dialysis therapy; 
3. Renal transplant recipient; 
4. B-type natriuretic peptide (BNP) level >200 pg/mL at Screen A visit; 
5. Uncontrolled diabetes (HbA1c >11.0%) at Screen A visit; 
6. Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during 
Screening; 
7. Serum albumin < 3 g/dL at Screen A visit; 
8. History of clinically significant left-sided heart disease and/or clinically significant 
cardiac disease, including but not limited to any of the following: 
a. Clinically significant congenital or acquired valvular disease;  
b. Left ventricular ejection fraction < 40% (based on echocardiogram performed at 
Screen A visit or within 6 months prior to Day 1); 
c. Pericardial constriction (based on echocardiogram performed at Screen A visit or 
within 6 months prior to Day 1); 
d. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at 
Screen A visit or within 6 months prior to Day 1); 
e. Symptomatic coronary disease (prior myocardial infarction, percutaneous 
coronary intervention, coronary artery bypass graft surgery, or angina); 
f. History of hospitalization for heart failure; 
g. Cardiac insufficiency, defined as New York Heart Association Class >2; 
h. History of atrial fibrillation; 
i. History of unstable arrhythmias; 
9. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) 
> 160 mm Hg or sitting diastolic BP > 100 mm Hg at Screen A visit after a period of rest; 
10. Systolic BP < 90 mm Hg at Screen A visit after a period of rest; 
11. History of malignancy within 5 years prior to Screen A visit, with the exception of 
localized skin or cervical carcinomas; 
12. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks 
prior to randomization or anticipated need for immunosuppression during the study.  
Refer to Section 9.3.1 for additional details; 
13. Untreated or uncontrolled active bacterial, fungal, or viral infection; 
14. Participation in other investigational clinical studies within 30 days prior to Day 1; 

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15. Unwilling to practice acceptable methods of birth control (both males who have partners 
of childbearing potential and females of childbearing potential) during Screening, while 
taking study drug, and for at least 30 days after the last dose of study drug is ingested;  
16. Women who are pregnant or breastfeeding; 
17. Known hypersensitivity to any component of the study drug;  
18. Any abnormal laboratory level that, in the opinion of the investigator, would put the 
patient at risk by trial enrollment; 
19. 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. 
8.3. 
Screening Period 
The screening period should not exceed 6 months.  The Screen B visit should be no more than 
30 days prior to Day 1. 
8.4. 
Patient Re-Screening 
Patients may repeat the Screening procedures to qualify for the study with approval from the 
medical monitor. 
8.5. 
Patient Discontinuation and Termination 
Patients have the right to discontinue study drug or withdraw from study follow-up at any time 
for any reason, without prejudice to their medical care.  Furthermore, the investigator may 
discontinue a patient from study drug.  Consultation with the medical monitor should occur prior 
to study drug discontinuation.  The reason for a patient’s discontinuation from study drug or 
study termination will be recorded in the electronic case report form (eCRF).  Any patient that 
discontinues study drug for 14 consecutive days or more must have approval from the medical 
monitor prior to resuming treatment with study drug.  
8.5.1. 
Patient Study Drug Discontinuation Criteria 
Study drug discontinuation refers to a patient’s stopping administration of study drug.  Reasons 
for study drug discontinuation may include the following: 
 
• ADVERSE EVENT; 
• DEATH; 
• LOST TO FOLLOW-UP; 
• PHYSICIAN DECISION; 
• PREGNANCY; 
• PROTOCOL SPECIFIED CRITERION MET; 
• WITHDRAWAL BY SUBJECT 

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To minimize missing data, patients who are permanently discontinued from study drug should 
still continue with study, follow-up, completing all study visits, and undergo all scheduled study 
assessments through Week 104, if possible.   
For patients who permanently discontinue study drug and are no longer willing to return for all 
scheduled study visits, a number of follow-up options are available including: 
• Reduced in-person visit schedule; 
• Telephone contact only; 
• Non-direct follow-up of patient information including obtaining additional information 
from the patient’s medical records (e.g., ESKD or death). 
These reduced follow-up options should be discussed with any patient considering study 
termination.  Any discussions about reduced follow-up options must be documented in the 
patient’s source file and discussed with the study manager. 
8.5.2. 
Patient Study Termination Criteria 
Study termination refers to a patient’s stopping study follow-up, which includes study 
assessments, visits, and all contact with the site regarding the trial.  Reasons for study 
termination include the following: 
• LOST TO FOLLOW-UP 
• DEATH 
• WITHDRAWAL OF CONSENT BY SUBJECT 
Every reasonable effort should be made to contact patients who do not return for a scheduled 
visit.  Follow-up options described in Section 8.5.1 should be discussed with patients who no 
longer wish to return for all scheduled in-person visits.  Patients should not be considered lost to 
follow-up until the scheduled Week 104 visit date. 
The term “withdrawal of consent” should be used only when the patient no longer wishes to 
participate in the trial and no longer authorizes investigators to make efforts to continue to obtain 
their outcome data.  The investigator should inquire about the reason for withdrawal, request the 
patient return all unused investigational product, request the patient return for end-of-treatment 
and follow-up visits (if applicable), and follow-up with the patient regarding any unresolved 
AEs.   
 

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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.  These procedures include exclusion of patients with any severe 
renal disease, defined as an eGFR value of < 30 mL/min/1.73 m2.  To exclude patients with 
significant cardiac dysfunction, the study will exclude patients with a history of left-sided heart 
disease.  Patients who have evidence of volume overload at baseline, defined as BNP level of 
> 200 pg/mL, will also be excluded.   
Laboratory data will also be used to monitor fluid status after randomization.  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 (see Section 9.10.15 for description 
of telephone contact).  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 randomization, 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.  Patients who experience a five-pound (2.3 kilogram) or greater increase in weight 
since their Day 1 weight during the first 8 weeks should have an unscheduled telephone contact 
immediately.  If fluid retention is suspected, the patient should 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 
discontinuation and re-initiation.  Patients may not restart their study medication until the 
investigator has completed and documented an assessment of fluid overload.  
Patients who experience a five-pound (2.3 kilogram) or greater increase in weight after the 
Week 8 study visit will be instructed to return to the clinic for an unscheduled physical 
examination and laboratory assessment by the investigator.  Study medication should not be 
discontinued 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 

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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. 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) 
Nearly all instances of elevated transaminases due to bardoxolone methyl treatment are expected 
to be asymptomatic.  Check transaminase levels (as well as TBL, GGT, alkaline phosphatase 
(ALP), and International Normalized Ratio (INR)) within 48 to 72 hours if the following occurs: 
• ALT or AST levels > 5X ULN. 
Repeat testing every 72 to 96 hours until transaminase levels are below 5X the ULN for at least 
one week or until the patient withdraws consent.  Testing for patients not located near the 
investigator (such that it is not practical to return to the site at the required intervals) may be 
performed at a local lab and sent to the investigator for review, by approval from medical 
monitor.   
Discontinue study drug administration temporarily and contact the medical monitor to discuss if 
permanent study drug discontinuation is required if any of the following occurs: 
• ALT or AST > 8X ULN; 
• ALT or AST > 5X ULN for more than 2 weeks; 
• ALT or AST > 3X ULN and (TBL > 2X ULN or 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%).  
The hepatobiliary tree must be visualized (e.g., ultrasound, magnetic resonance imaging [MRI]) 
and assessed if a patient discontinues taking study drug secondary to elevated transaminase 
levels.  Additional tests/studies may be warranted depending on the clinical presentation. 
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.  If vitamin D 
levels are low, supplementation may be warranted.  Muscle relaxants may also help relieve 
symptoms. 
9.1.4. 
Weight Loss 
Ongoing assessments 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.   
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 

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albumin to creatinine ratios increase by more than 100% and exceed 1000 mg/g for proteinuria 
associated with nephrotic syndrome.  Other concurrent signs of nephrotic syndrome include 
serum albumin levels below 3.5 g/dL, peripheral edema, increased blood pressure, increased 
BNP, or other signs of fluid retention.  If nephrotic syndrome is suspected, the medical monitor 
should be consulted to discuss appropriate measures, which may include dose adjustment, 
temporary study drug discontinuation, and/or administration of loop diuretics.  
9.1.7. 
Management of Blood Pressure  
Investigators should attempt to maintain the blood pressure within the range recommended by 
the Kidney Disease Blood Pressure Working Group (KDIGO): ≤ 140 mm Hg systolic and 
≤ 90 mm Hg diastolic for patients with UACR < 30 mg/g, and ≤ 130 mm Hg systolic and 
≤ 80 mmHg diastolic for patients with UACR > 30 mg/g (KDIGO, 2012).   
Patients being treated with an ACE inhibitor and/or 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 adverse effects (e.g., hypotension, hyperkalemia), based on the 
investigator's assessment.  If the patient is currently receiving one drug (ACE inhibitor or ARB) 
below the maximum labeled dose, the drug should be titrated to the MTLDD based on the 
assessment of tolerability by the investigator at least 6 weeks prior to the Screen A visit.  
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 end stage kidney disease (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 
(i.e., clinical chemistry (incl. eGFR), hematology, vital sign assessments (incl. weight), BNP 
and 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 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 discontinued.  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 

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drug with medical monitor approval.  After completing acute dialysis, such patients should 
continue to undergo frequent follow-up (i.e., at least once every 4 weeks (± 2 weeks)) while 
eGFR ≤ 15.0 mL/min/1.73 m2.  Study drug may be re-started 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. 
Following permanent study drug discontinuation due to confirmation of maintenance dialysis 
or receipt of kidney transplant, patients should continue to be followed only for vital status 
and SAEs by phone or in person according to the planned contact schedule in Section 7.5 
through their scheduled Week 104 visit date.  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.   
9.2. 
Description of Study Drug 
Bardoxolone methyl (RTA 402) drug product information is shown in Table 5.  Information 
about the placebo is shown in Table 6. 
Table 5: 
Bardoxolone Methyl Drug Product Information 
Description 
Bardoxolone methyl capsule (5 mg, 
15 mg) 
Ingredients 
Bardoxolone methyl 
Methacrylic Acid – Ethyl Acrylate 
Copolymer 
Type A  
Silicified Microcrystalline Cellulose 
Hydroxypropyl Methylcellulose  
Lactose Monohydrate 
Sodium Lauryl Sulfate 
Colloidal Silicon Dioxide 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide 
 
Route of Administration 
Oral 

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Table 6: 
Placebo Information 
Description 
Placebo for bardoxolone methyl capsule 
(size #4 and size #1) 
Ingredients 
Silicified Microcrystalline Cellulose  
Lactose monohydrate 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide 
 
Route of Administration 
Oral 
9.3. 
Concomitant Medications 
9.3.1. 
Excluded Medications 
Patients taking these medications or treatments will be ineligible for enrollment: 
• Any other investigational drug or device as part of an interventional study; 
• Chronic (> 2 weeks) immunosuppressive therapy, or need for corticosteroids, 
including therapies such as glucocorticoids, oncologic preparations, and anti-TNFα 
agents [e.g., infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol 
(Cimzia®), etanercept (Enbrel®)].  Glucocorticoid intra-articular injections, inhaled 
products, topical preparations, and nasal preparations are allowed. 
Patients who take excluded medications during the study should not discontinue study drug 
solely on this basis.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study. 
9.3.2. 
Permitted Medications 
Allowed concomitant medications include the following: 
• Antibiotics; 
• Daily multivitamins or recommended daily supplements; 
• Other medications intended to manage concurrent diseases, as authorized by the 
treating physician; 
• Oral, implantable, or injectable contraceptives. 
Patients taking medication chronically, including ACE inhibitors and ARBs, 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 and discussed 
with the Medical Monitor.   

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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.  The study drug must not be 
used for reasons other than that described in the protocol. 
9.5. 
Randomization 
All patients enrolled in the Phase 2 portion will be assigned to bardoxolone methyl.  An IWRS 
will be utilized to randomize Phase 3 patients 1:1 to bardoxolone methyl or placebo.  
Randomization will be stratified by screening albumin to creatinine ratio (ACR) using the 
following categories:  (1) ACR ≤ 300 mg/g; (2) 300 mg/g < ACR ≤ 1000, (3) ACR > 1000 mg/g. 
9.6. 
Blinding 
The Phase 2 portion of the study is open-label.  For the double-blind Phase 3 portion of the 
study, all patients, investigators, site personnel, laboratories, and central readers with direct 
involvement in the conduct of the study or their designees will be blinded to treatment 
assignments.  To prevent potential bias, appropriate measures will be taken to ensure the blind is 
maintained for the patients and personnel mentioned previously.  To maintain the blind, 
investigators will distribute blinded study drug treatment kits to patients as directed by the IWRS 
system.  Investigators and patients will not be blinded to dose level, but will be blinded to 
treatment assignment (i.e., bardoxolone methyl vs. placebo).  
An IWRS will manage treatment assignments and dose-titration.  The only people with direct 
access to treatment assignments in the Phase 3 portion of the study will be those individuals who 
develop and maintain the randomization code, the Data Monitoring Committee (DMC) and the 
statistical group reporting to the DMC.   
9.6.1. 
Patient Unblinding 
Although bardoxolone methyl has no known antidote, under rare circumstances unblinding may 
be considered medically necessary. 
The investigator is encouraged to contact the medical monitor to discuss situations in which he 
or she believes that the blind should be broken, but the investigator has the right to break the 
blind (e.g., in the event of a serious or life-threatening medical situation).  If unblinding is 
required, the investigator will utilize the IWRS to perform the unblinding.  If a study drug 
assignment is unblinded, the investigator must describe the event that required unblinding in the 
patient’s source documents.  
Patients must permanently discontinue taking study drug if their treatment assignment has been 
unblinded to the investigator (or designee).  Such patients must undergo the same study drug 
discontinuation procedures as those patients who discontinue taking study drug for other reasons. 
Following permanent study drug discontinuation due to patient unblinded, patients should 
continue with study follow-up through their scheduled Week 104 visit date for vital status only. 
Patient treatment assignments must not be unblinded in the case of an AE or SAE, except as 
described above. 

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9.6.2. 
Unblinding for Regulatory Submission 
In situations where regulation requires unblinding and reporting of a particular serious AE, the 
appropriate bodies (e.g., ECs, IRBs, regulatory agencies) must be provided with unblinded 
information according to the applicable regulatory requirement.  This information must not be 
conveyed to any investigator, site personnel or patient; therefore, this type of unblinding does not 
necessitate that the patient discontinues taking study drug.  In cases when unblinded information 
must be conveyed to local health authorities, personnel without direct involvement in the conduct 
of the study must be responsible for unblinding the patient’s treatment using the IWRS and 
conveying the necessary information. 
9.6.3. 
Data Monitoring Committee 
An independent DMC will review unblinded safety data throughout the study and make 
recommendations as appropriate.  The DMC will begin data reviews approximately 3 months 
after the first patient is enrolled and continue quarterly reviews through the last dose of the last 
patient enrolled.  The DMC will also evaluate available safety, tolerability, and efficacy data 
from the Phase 2 cohort prior to opening enrollment in the Phase 3 cohort.   
The DMC will consist of external experts supported by an independent statistical group which 
will prepare unblinded analyses for the DMC and will have no role in the statistical analysis plan 
(SAP) after the study has started enrolling patients.  A separate, blinded statistical group (i.e., not 
associated with the DMC) will be responsible for producing and finalizing the SAP and 
executing final data analysis of the study.   
The DMC will be governed by a charter that will describe the following: 
• Roles and responsibilities of the DMC members and the independent statistical group 
• Meeting format and frequency 
• Communication channels between the DMC, the independent statistical group, the 
Sponsor, and the blinded study statisticians 
• Voting process and requirements (e.g., requirement of consensus for issuance of a 
termination recommendation) 
• Provisions governing conflict of interest and confidentiality  
Briefly, the DMC will review the progress of the study and the accumulating unblinded data 
while the study is ongoing.  The DMC will make recommendations to Sponsor representatives 
following each meeting.  The DMC may recommend that the study continue as is, be modified to 
protect patient safety, or be terminated.  However, investigators, not the DMC, will make intra-
patient dose-escalation decisions.   
9.7. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
• Assessment of weight gain per Section 9.1.1;  
• Management of an AE or SAE; 

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• Performance of additional laboratory tests for clinically abnormal laboratory test 
values or to confirm a possible pregnancy; 
• Dose re-escalation; 
• Dose de-escalation; 
• eGFR ≤15.0 mL/min/1.73 m2 per Section 9.1.9; 
• Any time the investigator feels that it is clinically appropriate for patient safety. 
At a minimum, unscheduled visits should include collection of AEs, clinical chemistry, 
hematology, concomitant medications and vital signs, as well as collection/review of weight 
diary.  Additional conversations may be necessary with the medical monitor following an 
unscheduled visit to assess patient safety. 
9.8. 
Pregnancy 
9.8.1. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) are those who are not surgically sterile (no history 
of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy) do not have 
fallopian inserts with confirmed blockage, have not had reproductive potential terminated by 
radiation, and are not postmenopausal for at least 1 year. 
9.8.2. 
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 (e.g., 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; 
• Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
90 days prior to start of study drug administration; 
• Use of an intrauterine device; 
• Abstain from sexual intercourse completely.  Complete abstinence from sexual 
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 after the final dose of study 
medication is taken, males who have female partners of childbearing potential must practice one 
of the following methods of birth control: 
• Have had a vasectomy (at least 6 months earlier); 
• Use double barrier contraception method, defined as male use of a condom and 
female use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, 

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diaphragm [always use with spermicidal jelly/cream]).  Double-barrier method is not 
allowed for patients at participating sites in Germany; 
• Partner use of an intrauterine device; 
• Partner use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) for 
at least 90 days prior to start of study drug administration; 
• Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
9.8.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).  Male patients must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a 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 patient must permanently discontinue taking study drug.  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 consenting), 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. 
9.9. 
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.  
9.10. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 4.  All Day 1 procedures, except AE assessments, should be completed prior to 
administration of first dose of study drug. 

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9.10.1. 
Informed Consent 
Written informed consent (see Section 15.3) must be obtained from the patient before any 
study-related procedures are performed, and again if there is a change in the study procedures 
that would affect the patient’s willingness to participate. 
9.10.2. 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Table 4.  Patients must meet all 
of 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 randomizing the 
patient on Day 1. 
9.10.3. 
Demographics and Baseline Disease Characteristics 
Demographic data including sex, age, race, and ethnicity, will be collected as indicated in  
Table 4.  Baseline disease characteristics will be collected as indicated in Table 4.   
9.10.4. 
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.  Concomitant medications will be reviewed as indicated in  
Table 4 and all changes will be recorded. 
9.10.5. 
Medical History 
A complete medical history (e.g., per patient report) that includes all medical history within the 
past 5 years must be collected.  Medical history will be recorded as indicated in Table 4.   
9.10.6. 
Height 
Height should be measured without footwear or prosthetics as indicated in Table 4. 
9.10.7. 
Weight and Body Mass Index (BMI) 
Weight must be measured as indicated in Table 4.  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 
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 during 
the first 8 weeks per the criteria outlined in Section 9.1.1.  Patients will be provided instructions 
within the Informed Consent Form to help ensure consistent weight collection throughout the 
study.  

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9.10.8. 
Electrocardiograms (ECG) 
A 12-lead ECG will be recorded as indicated in Table 4 after the patient has rested for at least 
10 minutes in a supine position.  The heart rate from the ECG machine should not be used as part 
of the vital sign measurements. 
9.10.9. 
Echocardiogram 
An echocardiogram will be recorded as indicated in Table 4 to determine patient eligibility. 
9.10.10. 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), respiration rate, 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 (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 4.  
9.10.11. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner as indicated in Table 4 and as documented within the table 
footnotes.  The examination must include the following organ or body system assessments: head, 
eyes, ears, nose, throat, musculoskeletal, cardiovascular, lymphatic, respiratory, abdomen, skin, 
extremities, and neurological.  Assessments of any specific signs or symptoms reported by the 
patient must also be performed and documented along with any other findings of note.  Clinically 
significant findings at Screening must be recorded as medical history.  Following the 
examination at Screening, new or changed physical examination findings meeting the definition 
of an adverse event must be reported as an adverse event.  If possible, the same individual should 
perform each physical examination on a patient during the study. 
9.10.12. 
Pregnancy Test 
WOCBP (see Section 9.8) will complete a pregnancy test as indicated in Table 4, 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 9.8.3 for a description of procedures to be followed in case 
of pregnancy. 
9.10.13. 
Study Drug Administration 
Patients should self-administer one capsule from each bottle included in the study drug kit orally 
once a day beginning on Day 1 through the end of the study, as indicated in  
Table 4.  Each dose of study drug should be administered at approximately the same time each 
day, preferably in the morning.  On days when PK samples are collected, patients must not self-
administer study drug.  Study staff will administer study drug at the clinic following collection of 
the first PK sample.   
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. 

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9.10.14. 
Study Drug Dispensation and Collection 
Study drug will be dispensed to the patient and collected from the patient as indicated in Table 4.  
The patient will be dispensed one treatment kit at Day 1, Week 2, Week 4, Week 6 (only if 
baseline ACR >300 mg/g) and Week 8.  Three treatment kits will be dispensed at Week 12, 
Week 24, Week 36, Week 52, Week 64, Week 76, and Week 88, but 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. 
9.10.15. 
Telephone Contact 
Patients will be contacted by telephone as indicated in Table 4.  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. 
9.10.16. 
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 4.  Patients must be instructed to volunteer any 
information regarding AEs on or after the first dose of study drug or query the patients with an 
open question regarding any AEs they may be experiencing (e.g., “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. 
9.10.17. 
Genetic Testing 
Genetic testing will be performed at the Screen A Visit to confirm eligibility.  Patients with 
definitive diagnosis of Alport syndrome from previous genetic testing will not have genetic 
testing performed as part of the study but must provide documentation of genetic diagnosis for 
eligibility.  Patients without definitive genetic diagnosis of Alport must provide documentation of 
histopathological diagnosis, as assessed by electron microscopy, for eligibility. 
Detailed instructions on collection, storage and shipment of the blood sample required for 
genetic testing will be provided in a separate laboratory manual provided to the investigator. 
9.10.18. 
Clinical Chemistry 
Samples will be collected for the following clinical chemistry analyses as indicated in Table 4: 
ferritin, creatine kinase (CK), BUN, enzymatic creatinine, eGFR, TBL, direct bilirubin, ALT, 
AST, ALP, sodium, potassium, calcium, phosphorus, uric acid, total protein, glucose, albumin, 
lactate dehydrogenase (LDH), magnesium, chloride, bicarbonate, and GGT.  Women of child-
bearing potential will require a serum pregnancy test (hCG-Qual) at the Screen A visit or at any 
point in time if a pregnancy is suspected. 

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9.10.18.1. eGFR 
The eGFR value will be calculated by a central laboratory and provided to the investigator by a 
facsimile report.  The eGFR values collected at Screen A and Screen B visits will be averaged to 
determine eligibility.  The two eGFR values used to determine eligibility must have a percent 
difference ≤ 25%, as determined by the following calculation:   
Percent Difference = |X-Y| / ((X+Y)/2) 
X=1st eGFR value (Screen A) 
Y=2nd eGFR value (Screen B) 
|X-Y|=absolute value of the difference between the two eGFR values 
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation will be used: 
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] 
  
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. 
9.10.19. 
N-Terminal Pro-Brain Natriuretic Peptide (NT-Pro BNP) and Brain Natriuretic 
Peptide (BNP)  
Samples will be collected for NT-Pro BNP and BNP as indicated in Table 4.  As recent exercise 
may affect BNP and NT-Pro BNP levels, patients should be allowed to rest for 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, e.g., sitting or semi-
recumbent. 
Detailed instructions on collection, storage and shipment of the sample will be provided in a 
separate laboratory manual provided to the investigator.   
9.10.20. 
Insulin-Like Growth Factor-1 (IGF-1) and Serum Ketones 
Samples will be collected for IGF-1 and serum ketones as indicated in Table 4.  Detailed 
instructions on collection, storage and shipment of the samples will be provided in a separate 
laboratory manual provided to the investigator.   
9.10.21. 
Hemoglobin A1c 
Samples will be collected for hemoglobin A1c as indicated in Table 4.  Detailed instructions on 
collection, storage, and shipment of the samples will be provided in a separate laboratory manual 
provided to the investigator.   
9.10.22. 
Hematology 
Samples will be collected for the following hematology assessments as indicated in Table 4: 
hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count, neutrophils, 

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bands (if detected), lymphocytes, monocytes, basophils (if detected), eosinophils (if detected), 
absolute platelet count, mean corpuscular hemoglobin (MCH), mean corpuscular volume 
(MCV), and mean corpuscular hemoglobin concentration (MCHC). 
9.10.23. 
Urinalysis and Microscopy 
Samples will be collected for the following urinalysis and microscopy assessments as indicated 
in Table 4: specific gravity, ketones, pH, protein, blood, glucose, clarity, color, leukocytes, 
nitrite, bilirubin, and a microscopic examination (if indicated based on laboratory results). 
9.10.24. 
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 4.  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 after 5 AM.  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. 
9.10.25. 
Visual Acuity  
Visual acuity will be performed as indicated in Table 4.  Detailed instructions for visual acuity 
assessment will be provided in a separate laboratory manual provided to the investigator.   
9.10.26. 
Audiology Assessment  
Audiology assessments will be performed as indicated in Table 4.  Detailed instructions for 
audiology assessments will be provided in a separate laboratory manual provided to the 
investigator.   
9.10.27. 
Patient Global Impression of Change  
Patient Global Impression of Change (PGIC) assessments will be performed as indicated in 
Table 4.  Detailed instructions will be provided in a separate laboratory manual provided to the 
investigator.   
9.10.28. 
Clinical Global Impression-Improvement  
Clinical Global Impression-Improvement (CGI-I) assessments will be performed as indicated in 
Table 4.  Detailed instructions will be provided in a separate laboratory manual provided to the 
investigator.   
9.10.29. 
Virus Serology 
Blood samples will be collected for testing for hepatitis B and hepatitis C as indicated in Table 4.  
If the initial hepatitis C result is positive, then the patient will need to return for an unscheduled 
hepatitis C virus ribonucleic acid (HCV RNA) assessment to determine if the virus is present at 
the current time.  If the results of this test are negative, the patient may continue in the Screening 
process. 

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9.10.30. 
Pharmacokinetic (PK) Blood Samples 
Blood samples for determination of plasma bardoxolone methyl and potential metabolite 
concentrations will be drawn as indicated in Table 4.  Patients must be instructed to not take their 
study drug prior to coming to the clinic for visits when PK samples will be collected.  Patients 
will be asked by site personnel to provide the time of their last two administrations of study drug 
prior to the blood samples being collected.  Blood sample collection instructions should be 
referenced in the laboratory manual.  Patients must administer the study drug dose in the clinic 
on PK sample collection visits after the 0-hour PK blood sample is collected.  Patients will have 
blood samples for PK analysis drawn just prior to (0 hour) and after (2 and 4 hours) dose 
administration.   
The date and time of collection of all PK blood samples should be recorded; however, any 
deviations from the protocol-specified sampling times will not be considered protocol deviations.  
Sample time deviations will be summarized in the study report.  Dates in the case report form 
should be recorded in an unambiguous format (e.g., DD MMM YYYY) and time should be 
recorded to the nearest minute (e.g., HH:MM using the 24-hour clock).  Blood samples not 
drawn should be recorded as such. 

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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 5 mg and 15 mg, will be used in this study. 
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied in tamper-evident kits containing two 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 capsules of 5 mg or 15 mg strength bardoxolone methyl 
or the matching placebo capsules.  Each bottle will also contain a desiccant insert that must not 
be ingested.  Labeling on each kit bottle will contain at minimum the following information: 
• Medication ID number; 
• Protocol 402-C-1603; 
• Caution Statement: New Drug – Limited by Federal Law to Investigational Use.  
Keep out of sight and reach of children; 
• Control or lot number; 
• Store at 20° – 25°C (68° – 77°F), short term excursions allowed to 15° – 30°C (59° – 
86°F); 
• Reata Pharmaceuticals, Inc., Irving, TX. 
A double-panel label will be presented on the treatment kit carton containing this and other 
information as well.  Additionally, labeling, in the relevant local languages for investigational 
medicinal product (IMP) for use and distribution in the EU shall adhere to current Eudralex, 
Volume 4 Annex 13 guidance and requirements.   
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 20° - 25°C (68° - 77°F), with short term excursions allowed to 15° – 
30°C (59° – 86°F).   
10.4. 
Study Drug Administration 
Please refer to Section 9.10.13 for details on study drug administration.  Clear instructions will 
be provided to the patient regarding the number and type of capsules to be ingested at each study 
drug administration time point listed in Table 4.  Patients must be instructed to continue taking 
study drug once daily up through their Week 48 visit and from Week 52 to Week 100 unless: 
(1) the patient has been otherwise instructed by the investigator or (2) the patient has been 
formally discontinued from study treatment.    

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10.5. 
Study Drug Accountability 
The investigator, or designee, will maintain a record of all study drug received, dispensed, and 
returned to the Sponsors’ designee.  No study drug shall be destroyed by the clinical site unless 
directed in writing to do so by the Sponsor’s quality assurance department.  Study drug bottles 
and any unused capsules should be returned to the study staff for eventual disposition by the 
Sponsor.  The number of capsules returned at each visit will be recorded for each bottle in the 
kit. 
10.6. 
Study Drug Handling and Disposal 
At the conclusion of the study or in an instance of planned study drug replacement, the Sponsor 
or its designee will direct the site regarding the final disposition of study drug. 

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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, ECG results, AEs, SAEs, weight, and laboratory 
test results (clinical chemistry, hematology, urinalysis and microscopy).  
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 condition that has 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 time of 
administration of the first dose at the Day 1 visit until the final visit indicated in Table 4) must be 
reported, regardless of their relationship to study drug or their clinical significance. 
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 inpatient 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.  
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. 

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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 4, as appropriate).  Certain pregnancy outcomes will require submission as an 
SAE (see Section 9.8). 
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 4, 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.  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 ECG 
abnormalities, or from other documents that are relevant to patient safety. 
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 

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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 (e.g., concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
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 medical history.  After the first dose, documentation of AEs shall continue 
until the last study follow-up visit, regardless of the relationship of the AE to study drug.  
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.  
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents, but when documenting the AE, only the total duration and 
greatest severity should be recorded in the eCRF.  AEs characterized as intermittent require 
documentation of onset and duration. 
All drug-related (possibly, probably, or definitely related, see Section 11.4) AEs and abnormal 
laboratory test results reported or observed during the study must be followed to resolution 
(either return to baseline or within normal limits).  All other AEs will be followed through the 
final visit indicated in Table 4, as appropriate. 
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 (e.g., “worsening of…”).  Any improvement in condition should be 
documented per Section 9.10.11. 
Each AE should be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs.  If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an 

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AE(s).  Changes in laboratory test values or ECG parameters are only considered AEs if they are 
judged to be clinically significant (i.e., 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 or ECG findings are the result of pathology for which there is an 
overall diagnosis (e.g., 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 (e.g., elective periodontal 
surgery).  However, if a pre-planned procedure is performed early (e.g., 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 the completed SAE form to 
 (fax numbers listed in Table 7) 
within 24 hours of awareness. 
Table 7: 
SAE Reporting Contact Information 
 
 
 
 
 
 
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 (e.g., subject discharge summary or autopsy reports), should be faxed 
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 

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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 institutional review 
board (IRB) or Ethics Committee (EC), as appropriate.  
Principal investigators are responsible for informing their IRB/EC of any SAEs at their site.  
SAE correspondence with regulatory authorities or IRBs/ECs 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 
Phase 2: 
With 30 patients, the Phase 2 portion of the study will have over 80% power to detect a change 
from baseline in eGFR relative to zero.  The power calculation, which was based on a 2-sided 
t-test, assumes the following: 
• Two-sided Type I error rate of 0.05 
• 5% of the patients will not complete the full course of study treatment 
• A change from baseline in eGFR of approximately 4.3 mL/min/1.73 m2  
• Standard deviation of change from baseline in eGFR of 8 mL/min/1.73 m2  
Phase 3: 
Primary endpoint  
With 150 patients enrolled (75 in each group), the study will have approximately 80% power to 
detect a difference between the two treatment groups in change from baseline in eGFR of 
3.1 mL/min/1.73 m2 at Week 48 for the primary endpoint (i.e., Week 48 in Year 1 or Week 100 
in Year 2).  The power calculation, which was based on mixed-model repeated measures 
(MMRM) analysis, assumes the following: 
• 9 repeated measurements (Weeks 1, 2, 4, 6, 8, 12, 24, 36, and 48) having compound 
symmetry covariance structure 
• The correlation between observations on the same subject is 0.7 
• Two-sided Type I error rate of 0.05 
• Standard deviation of change from baseline in eGFR of 8 mL/min/1.73 m2  
• Analyses at Week 48 are based on the intent-to-treat (ITT) population 
Key secondary endpoint  
With 150 patients enrolled and at least 140 patients having available key secondary data (i.e., 
Week 52 in Year 1 or Week 104 in Year 2) the study will have a minimum detectable difference 
between the two treatment groups in change from baseline in eGFR of approximately 
2.2 mL/min/1.73 m2 at Week 52.  The power calculation was based on the same analysis method 
and assumptions as the primary endpoint, with the following exceptions: 
• With the addition of Week 52 the model has 10 repeated measurements (Weeks 1, 2, 
4, 6, 8, 12, 24, 36, 48, and 52)  
• Analyses of the key secondary endpoint are based on the ITT population 
Since the Phase 2 and Phase 3 cohorts are independent sets of patients, the Phase 2 analysis will 
not impact the type I error rate for the Phase 3 analysis.  The Phase 3 primary analysis of efficacy 
will use an unstructured covariance structure, which is expected to have approximately the same 

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power as the analysis with compound symmetry used for study planning.  The methods for 
handling missing data, and for maintaining strict control of the Type I error will be described in 
the statistical analysis plan. 
12.2. 
Study Variables 
12.2.1. 
Pharmacokinetic Variables 
The pharmacokinetic variables include bardoxolone methyl plasma concentration-time data and 
estimated pharmacokinetic parameters. 
12.2.2. 
Efficacy Variables 
Change from baseline in eGFR will be used to determine the primary, secondary, and 
exploratory efficacy endpoints.  Baseline ACR and eGFR values will be calculated using 
averages of measurements collected up through Day 1, prior to first dose of study drug.  The 
SAP will provide details of these calculations. 
12.2.3. 
Safety Variables 
The safety variables include results of laboratory test results (clinical chemistry, hematology, 
urinalysis and microscopy), vital sign measurements, ECG results, weight, AEs, and SAEs. 
12.3. 
Statistical Analyses 
A SAP detailing the analyses will be developed prior to database lock.  All statistical analyses 
and data summaries will be performed using SAS® (Version 9.1 or higher) or other validated 
software.  The SAP will serve as the final arbiter of all statistical analyses.  Data will be 
summarized overall 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 Efficacy 
The ITT population, which includes all patients randomized within each cohort, will be used as 
the population for assessment of the primary efficacy endpoint.  Mixed-model repeated measures 
(MMRM) analyses will be used to analyze the Phase 2 and Phase 3 primary and key secondary 
efficacy endpoints.  For the Phase 2 portion of the study, eGFR values for all scheduled visits 
collected through the Week 12 visit will contribute to the primary analysis.  For the Phase 3 
portion of the study, eGFR values for all scheduled visits collected through the Week 48 visit 
will contribute to the primary analysis.  The dependent variable will be change from baseline in 
eGFR.  The model will include change from baseline in eGFR as the dependent variable, 
protocol-scheduled nominal time point as a fixed effect, patient as a random effect, and the 
baseline eGFR and log-transformed baseline ACR as continuous covariates.  Within-patient 
correlations will be modeled using an unstructured covariance structure.  Time ordering is a 
repeated measure within patients.  It is assumed that errors for different patients are independent 
with an unstructured covariance structure.  The estimation method for the model will be 
restricted maximum likelihood (REML).  

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The Year 1 primary analyses of efficacy using an unstructured covariance structure is expected 
to have approximately the same power as the analysis with compound symmetry used for study 
planning.  The analysis of the Phase 3 Year 1 key secondary endpoint will be based on available 
Week 52 data from the subset of patients who complete the 48-week treatment course.   
Analysis methods for Year 2 endpoints will be similar to analysis of Year 1 endpoints.  Analysis 
of the Year 2 endpoints is independent of the Year 1 analysis of efficacy. 

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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 Conference on Harmonisation (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. 
13.2. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/EC 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 Food and Drug Administration (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/IMP 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/EC approval of the protocol; 
• The IRB- or EC-approved informed consent, 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 form), fully executed, and 
all updates on a new fully executed Form FDA 1572 (or equivalent Statement of 
Investigator form); 
• Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572 (or equivalent Statement of Investigator form).  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; 

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•
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 
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 Ethics Committee (EC) Review
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB/EC before study start.  Each investigator must provide the Sponsor or 
its designee a signed and dated statement that the protocol and informed consent have been 
approved by the IRB/EC 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/EC chairperson or designee must sign all IRB/EC approvals and must identify the 
IRB/EC 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/EC, 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 (e.g., 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 International 
Conference on Harmonization (ICH) for Guidance for Industry on Good Clinical Practice (GCP) 
ICH E6(R2) [http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ 
Efficacy/E6/E6_R1_Guideline.pdf] and the principles of the Declaration of Helsinki 
[http://www.wma.net/en/30publications/10policies/b3/].  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, 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 (R1), 
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/EC submission.  Once reviewed, the consent will be submitted by the 
principal investigator to his or her IRB/EC 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 consent form. 

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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 to participate in the study by signing the informed consent form. 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.   
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of 
the procedures described in the protocol).  The process of obtaining informed consent must be 
documented in the patient source documents. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/EC, and a copy of the approved version and the notice 
of approval must be provided to the Sponsor’s designated monitor after IRB/EC approval. 
The principal investigator or designee will provide a copy of the informed consent form (signed 
copy to be provided per applicable law) to the patient.  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/EC. 
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 
On the basis of the Phase 2 primary efficacy analyses, the Sponsor may reduce the Phase 3 
sample size and/or change the percentage of patients with macroalbuminuria (ACR > 300 mg/g) 
eligible to enroll in the study.  These changes will be documented in a note-to-file to the 
investigators/IRBs/ECs (as appropriate) and will not require a protocol amendment.  Any other 
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 
investigator, the IRB/EC, 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/EC. 
The investigator is responsible for informing the IRB/EC of all problems involving risks to 
patients according to national legislation.  In case of urgent safety measures, the Sponsor will 

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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/EC 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 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 the protocol will be 
reported to the Regulatory Authority, as required.  Any potential protocol waiver must be 
discussed with the medical monitor.  Protocol waivers are not allowed for sites in the United 
Kingdom. 
If there is an immediate hazard to a patient the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/EC approval.  The Sponsor and IRB/EC must be 
notified of the 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.  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 Electronic Data Capture system (EDC) 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. 
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