Clinical trial NCT03019185
Conditions: Alport Syndrome
Keywords: Alport Syndrome Bardoxolone methyl CDDO-ME RTA 402
Sponsor: Biogen
Start date: 2017-03-02; Completion date: 2020-10-30
Enrollment: 187 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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 up to 30 patients. The Phase 3 portion of the trial will be double-blind, randomized, placebo-controlled and will enroll up to 180 patients.

Detailed description:
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 up to 30 patients. The Phase 3 portion of the trial will be double-blind, randomized, placebo-controlled and will enroll up to 180 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 baseline albumin to creatinine ratio (ACR). Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration.

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.

Arms: arm 1: Patients in the Phase 2 cohort will receive bardoxolone methyl throughout the study. 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. Adult patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if baseline ACR \>300 mg/g) unless contraindicated clinically and approved by the medical monitor. Patients under the age of 18 receiving bardoxolone methyl will start 5 mg every other day during the first week and begin once-daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing following the same aforementioned dose titration scheme based on baseline ACR at Weeks 2, 4, and 6. arm 2: 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. Adult patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if baseline ACR \>300 mg/g) unless contraindicated clinically and approved by the medical monitor. Patients under the age of 18 receiving bardoxolone methyl will start 5 mg every other day during the first week and begin once-daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing following the same aforementioned dose titration scheme based on baseline ACR at Weeks 2, 4, and 6. arm 3: Patients randomized to placebo will remain on placebo throughout the study, undergoing sham titration.
Interventions: intervention 1: Placebo Oral Capsule intervention 2: Bardoxolone Methyl
Intervention descriptions: intervention 1: Capsule containing an inert placebo intervention 2: Bardoxolone methyl dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status.

Protocol documents:
SAP_006.pdf: 
Statistical Analysis Plan
for 
Phase 2 Portion of 
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: 5.0 
Date: June 5, 2019 
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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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 3 of 37 
TABLE OF CONTENTS 
1. List of Abbreviations and Definitions of Terms ..................................................................................... 6 
2. Revision History and Relevant Documents ............................................................................................ 8 
3. Purpose of The Analysis Plan ............................................................................................................... 10 
4. Study Objectives and Endpoints ........................................................................................................... 10 
4.1. Objectives of Phase 2 ................................................................................................................. 10 
4.1.1. 
Primary Objective .......................................................................................................... 10 
4.1.2. 
Secondary Objectives .................................................................................................... 11 
4.1.3. 
Exploratory Objective .................................................................................................... 11 
4.2. Endpoints of Phase 2 .................................................................................................................. 11 
4.2.1. 
Efficacy Endpoints ........................................................................................................ 11 
4.2.2. 
Primary Efficacy Endpoint ............................................................................................ 11 
4.2.2.1. 
Secondary Efficacy Endpoint ........................................................................................ 11 
4.2.2.2. 
Exploratory Efficacy Endpoint ...................................................................................... 11 
4.2.3. 
Safety Endpoints ............................................................................................................ 11 
5. Study Design ........................................................................................................................................ 11 
5.1. Overall Study Design .................................................................................................................. 11 
5.2. Randomization and Dosing ........................................................................................................ 12 
5.3. Assessments ................................................................................................................................ 12 
5.3.1. 
Efficacy Measurement and Variable ............................................................................. 16 
5.3.2. 
Safety Measurements and Variables .............................................................................. 16 
5.3.3. 
Pharmacokinetics Measurements and Variables ........................................................... 16 
6. Sample Size and Power ........................................................................................................................ 16 
7. General Considerations ........................................................................................................................ 16 
7.1. Derived Variables ....................................................................................................................... 17 
7.1.1. 
Age ................................................................................................................................ 17 
7.1.2. 
Study Day ...................................................................................................................... 17 
7.1.3. 
Estimated Glomerular Filtration Rate ............................................................................ 17 
7.1.4. 
Urine Albumin and Urine Albumin to Creatinine Ratio ................................................ 18 
7.1.5. 
Electrocardiogram Fridericia Corrected QT Interval ..................................................... 18 
7.1.6. 
Log of The Minimum Angle of Resolution ................................................................... 18 
7.1.7. 
Natural log (ACR)/eGFR ............................................................................................... 18 
7.2. Baseline Values .......................................................................................................................... 18 
7.2.1. 
Estimated Glomerular Filtration Rate ............................................................................ 19 
7.2.2. 
Serum Creatinine ........................................................................................................... 19 
7.2.3. 
Vital Sign Assessments ................................................................................................. 19 
7.2.4. 
Natural log (ACR)/eGFR ............................................................................................... 19 
7.3. Analysis Windows ...................................................................................................................... 19 
7.4. Missing Data ............................................................................................................................... 20 
8. Analysis Sets ........................................................................................................................................ 21 
8.1. Safety Analysis Set ..................................................................................................................... 21 
8.2. ITT Analysis Set ......................................................................................................................... 21 
8.3. Per Protocol Analysis Sets .......................................................................................................... 21 
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Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 4 of 37 
8.4. Pharmacokinetics Analysis Set ................................................................................................... 21 
9. Study Population .................................................................................................................................. 21 
9.1. Patient Disposition ...................................................................................................................... 21 
9.2. Protocol Deviations .................................................................................................................... 22 
9.3. Demographics and Baseline Characteristics ............................................................................... 22 
9.4. Medical History .......................................................................................................................... 23 
9.4.1. 
Historical eGFR ............................................................................................................. 23 
9.4.1.1. 
Statistical Model ............................................................................................................ 24 
10. Study Drug and Other Medications ...................................................................................................... 25 
10.1. Prior and Concomitant Medications ........................................................................................... 25 
10.2. Prior and Concomitant Procedures and Surgeries ...................................................................... 25 
10.3. Duration of Study Treatment ...................................................................................................... 26 
11. Efficacy Analyses ................................................................................................................................. 26 
11.1. Primary Efficacy Objective ........................................................................................................ 26 
11.1.1. Statistical Hypothesis .................................................................................................... 27 
11.1.2. Statistical Model ............................................................................................................ 27 
11.1.3. Reporting Results .......................................................................................................... 27 
11.2. Additional Efficacy Analyses ..................................................................................................... 28 
11.2.1. Secondary Efficacy Objectives ...................................................................................... 28 
11.2.2. Exploratory Efficacy Objectives.................................................................................... 29 
11.2.3. Categorical Analyses of eGFR ...................................................................................... 29 
11.2.3.1. 
CKD Stage .................................................................................................................. 29 
11.2.3.2. 
Categorical Change in eGFR ...................................................................................... 30 
11.2.4. Patient Global Impression of Change ............................................................................ 30 
11.2.5. Clinical Global Impression-Improvement ..................................................................... 30 
11.2.6. (QG 6WDJH .LGQH\ 'LVHDVH H*)5 GHFOLQH  RU H*)5   .................................. 30 
11.2.6.1. 
)UHTXHQF\ RI (QG 6WDJH .LGQH\ 'LVHDVH H*)5 GHFOLQH  RU H*)5   ......... 31 
11.3. Sensitivity Analyses ................................................................................................................... 31 
11.4. Subgroups Analyses of Efficacy ................................................................................................. 32 
12. Safety Analyses .................................................................................................................................... 32 
12.1. Adverse Events and Serious Adverse Events ............................................................................. 32 
12.1.1. Treatment Emergent Adverse Events ............................................................................ 32 
12.1.2. Summary of Treatment-Emergent Adverse Events and Serious Adverse Events ......... 33 
12.2. Clinical Laboratory Evaluation ................................................................................................... 33 
12.3. Analyses of Continuous eGFR and ACR ................................................................................... 35 
12.3.1. Ratio of Natural log (ACR)/eGFR ................................................................................. 35 
12.3.2. Change from Baseline in ACR ...................................................................................... 35 
12.4. Vital Signs .................................................................................................................................. 36 
12.5. Body Weight ............................................................................................................................... 36 
12.6. 12-lead ECG ............................................................................................................................... 36 
12.7. Physical Examination ................................................................................................................. 36 
12.8. Visual Acuity .............................................................................................................................. 36 
12.9. Audiology Assessment ............................................................................................................... 37 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 5 of 37 
13. Pharmacokinetics Analysis ................................................................................................................... 37 
14. References ............................................................................................................................................ 37 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ................................................................................ 6 
Table 2: 
Schedule of Assessments ............................................................................................... 13 
Table 3: 
Analysis Visit Window .................................................................................................. 20 
Table 4:  
Comparison of eGFR Slope in CARDINAL vs. Historical eGFR Slope ...................... 24 
Table 5:  
Labels for Summary of Historical and On-Treatment Change in eGFR ....................... 24 
Table 6: 
Categorical Analysis of CKD Stage .............................................................................. 30 
Table 7: 
Pre-Specified Threshold Levels for Categorical Laboratory Summaries ...................... 34 
Table 8: 
Pre-Specified Upper Limit of Normal (ULN) Levels for Laboratory Parameters ......... 34 
Table 9: 
Pre-Specified Threshold Levels for ECG Parameters ................................................... 36 
 
 
 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 6 of 37 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and special terms are used in this statistical analysis plan. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term Explanation 
ACE 
angiotensin converting enzyme 
ACR 
albumin to creatinine ratio 
AE 
adverse event 
ALT 
alanine aminotransferase 
AR 
auto-regressive 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
ATC 
Anatomical/Therapeutic/Chemical 
AUC 
area under the plasma concentration curve 
BARD 
Bardoxolone methyl 
BCVA 
best corrected visual acuity 
BMI 
body mass index 
BNP 
B-type natriuretic peptide 
BP 
blood pressure 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CM 
concomitant medication 
Cmax 
maximum drug concentration in plasma 
CSR 
clinical study report 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
ESKD 
End stage kidney disease 
EOT 
end of treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration (US) 
GFR 
glomerular filtration rate 
Hgb 
hemoglobin 
ICH 
International Conference on Harmonization 
IGF-1 
insulin-like growth factor-1 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LLD 
lower limit of detection 
LS 
least squares 
MCH 
mean corpuscular hemoglobin 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 7 of 37 
Abbreviation or Specialist Term Explanation 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
pH 
potential of hydrogen 
PK 
pharmacokinetic 
PTA 
Pure tone audiometry 
PT 
preferred term 
QTc 
corrected QT interval 
RBC 
red blood cell 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCr 
serum creatinine 
SD 
standard deviation 
SOC 
system organ class 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
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 
WHO DD 
World Health Organization Drug Dictionary 
WOCBP 
women of child bearing potential 
 
 
 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 11 of 37 
x To assess the safety of bardoxolone methyl after 12 weeks of treatment. 
4.1.2. 
Secondary Objectives   
x To assess the safety and efficacy of bardoxolone methyl after 48 weeks of treatment. 
x To assess the safety and efficacy of bardoxolone methyl after 100 weeks of treatment.  
4.1.3. 
Exploratory Objective   
x To assess the safety and efficacy of bardoxolone methyl at Week 52 following a 4-
week drug treatment withdrawal period. 
4.2. 
Endpoints of Phase 2 
4.2.1. 
Efficacy Endpoints 
4.2.2. 
Primary Efficacy Endpoint 
x Change from baseline in eGFR at Week 12. 
4.2.2.1. 
Secondary Efficacy Endpoint 
x Change from baseline in eGFR at Week 48. 
4.2.2.2. 
Exploratory Efficacy Endpoint 
x Change from baseline in eGFR at Week 52 following a 4-week drug treatment 
withdrawal period. 
4.2.3. 
Safety Endpoints 
Frequency, intensity, and relationship of adverse events (AEs) and serious adverse events (SAEs) 
to study drug, and change from baseline in the following assessments: vital sign measurements, 
12-lead electrocardiograms (ECGs), clinical laboratory measurements, and weight. 
5. 
STUDY DESIGN 
5.1. 
Overall Study Design 
This is a multinational, multi-center, Phase 2/3 trial that will study the safety, tolerability, and 
efficacy of bardoxolone methyl in patients with Alport syndrome.  The Phase 2 portion of the 
trial will be open-label and enroll approximately 30 patients.  The Phase 2 primary efficacy 
endpoint will be analyzed after all patients in the Phase 2 cohort have completed their Week 12 
visit.  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. 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 12 of 37 
5.2. 
Randomization and Dosing 
The Phase 2 portion of the study will be open-label without randomization.  Patients will receive 
bardoxolone methyl throughout the study.  The maximum bardoxolone methyl dose in Phase 2 
cohort will be determined by baseline albumin-to-creatinine ratio (ACR).  Patients are stratified 
E\ EDVHOLQH $&5   ! WR  DQG  WR .  The diagram below shows dose 
titration and maintenance schedules according to the baseline (ACR category:  mg/g or 
>300 mg/g.  All patients will receive study drug from Study Day 1 to Week 48.  They will not 
receive study drug treatment during a 4-week withdrawal period (between Weeks 48 and 52).  
They will re-start study drug treatment at Week 52 at the same dose level that they received prior 
to the withdrawal period and will continue study drug treatment through Week 100.   
Schema for Phase 2 Portion of the Study 
Treatment of Bardoxolone Methyl in Patients with Alport Syndrome 
 
5.3. 
Assessments 
All patients in the study will follow the same visit and assessment schedule.  Table 2 lists the 
overall schedule of assessments for the study.  Following the first dose of study drug on Day 1, 
patients will be scheduled for assessment during treatment at Weeks 1, 2, 4, 6, 8, 12, 24, 36, 48, 
52, 64, 76, 88, 100, and 104, as well as by telephone contact on Days 3, 10, 21, 31, 38, and 45.  
Patients will also be scheduled for assessment at an in person follow-up visit at Week 104, four 
weeks after the end of treatment.   
 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 13 of 37 
Table 2: 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 
 
 
Xg 
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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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 14 of 37 
 
Assessment 
Wk 24  
Day 168±3 
Wk 36 
Day 
252±3 
Wk 48 
Day 336±3 
Wk 52 
Day 
364±3 
 
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±3 
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 
 
 
 
 
 
 
 
 
 
a Total Screening period should not exceed 6 months. 
b Screen B visit should be no more than 30 days prior to Day 1. 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 15 of 37 
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.   
 
$EEUHYLDWLRQV (&*  HOHFWURFDUGLRJUDP 3.  SKDUPDFRNLQHWLF :2&%3  ZRPHQ RI FKLOG-bearing potential 
 
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Reata Pharmaceuticals, Inc. 
 
Phase 2 Portion of 402-C-1603 
Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 16 of 37 
5.3.1. 
Efficacy Measurement and Variable 
Central laboratory reported eGFR values will be used to calculate change from baseline in eGFR, 
the primary efficacy endpoint for the study.  Baseline eGFR value will be calculated as described 
in Section 7.1.3 below.  
5.3.2. 
Safety Measurements and Variables 
Safety will be assessed by repeated clinical evaluation, including AEs, SAEs, vital signs, 
physical examinations, 12-lead ECGs, clinical laboratory tests (i.e., chemistry, B-type natriuretic 
peptide [BNP], N-Terminal Pro-Brain Natriuretic Peptide [NT-Pro BNP], Insulin-Like Growth 
Factor-1 [IGF-1], serum ketones, hematology, ACR, spot urinalysis, and urine microscopy), 
body weight, visual acuity assessments, audiology assessments, and concomitant medications. 
5.3.3. 
Pharmacokinetics Measurements and Variables 
Pharmacokinetic (PK) samples will be collected on Day 84±3 prior to study drug dosing (pre-
dose), and at post-dose hours 2 and 4.  The PK variables include bardoxolone methyl plasma 
concentration-time data, and estimated PK parameters. 
6. 
SAMPLE SIZE AND POWER 
:LWK  SDWLHQWV WKH 3KDVH  SRUWLRQ RI WKH VWXG\ ZLOO KDYH RYHU  SRZHU WR GHWHFW D FKDQJH
from baseline in eGFR relative to zero.  The power calculation assumes the following: 
x Two-sided type I error rate of 0.05 
x  RI WKH SDWLHQWV ZLOO QRW FRPSOHWH WKH IXOO FRXUVH RI VWXG\ WUHDWPHQW 
x A mean change from baseline in eGFR of 4.3 mL/min/1.73 m2  
x A standard deviation of change from baseline in eGFR of 8 mL/min/1.73 m2. 
The primary analysis of efficacy will use a mixed-model for repeated measures (MMRM), which 
is expected to be at least as powerful as the 2-sided t-test calculations used for the sample size 
estimation of Phase 2 portion of the study. 
7. 
GENERAL CONSIDERATIONS 
The analysis sets, as defined in Section 8, will be used for efficacy, safety, tolerability, and PK 
analyses.  Patient listings of all analysis data that support summary tables and/or figures will be 
provided along with relevant source data from the electronic case report forms (eCRFs).  
Measurements from patients excluded from the pre-defined analysis sets or extra measurements 
(such as unscheduled or repeat assessments) will not be included in summary tables unless 
specified otherwise, but will be included in the patient listings.  Missing data will not be 
imputed, unless otherwise specified.  In general, patient listings will be sorted by patient number 
and assessment date (time and parameter, as applicable).   
Unless otherwise specified, descriptive statistics for continuous variables will include the number 
of patients with data (N), mean, standard deviation (SD), median, minimum, and maximum.  The 
same number of decimal places as in the observed value will be presented when reporting 
minimum and maximum; 1 more decimal place than in the observed value will be presented 
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when reporting mean and median; and 2 more decimal places than in the observed value will be 
presented when reporting SD.  The natural log (ACR)/eGFR will be rounded 3 decimal places.  
Categorical/qualitative data will be presented using frequency counts and percentages.  All 
percentages will be rounded to 1 decimal place, unless otherwise specified.  Percentages equal to 
 ZLOO EH SUHVHQWHG DV  DQG no percentages will be presented for zero frequencies.  Where 
individual variable values are missing, categorical data will be summarized based on reduced 
denominators (i.e., only patients with available data will be included in the denominators).  For 
summaries of AEs and concomitant medications (CM), the percentages will be based on the 
number of patients who received study drug. 
Results of statistical analyses will be reported using summary tables, listings, and figures (TLFs).  
The ICH numbering convention will be used for all TLFs.  The following conventions will be 
followed: 
x Unless otherwise noted, all statistical testing will be two-sided and will be performed 
at the 0.05 significance level. 
x Tests will be declared statistically significant if the calculated p-value is 0.05. 
All analyses and summaries will be produced using SAS® version 9.3 (or higher). 
7.1. 
Derived Variables 
7.1.1. 
Age 
Age (years) will be calculated as the number of years between date of birth and date of informed 
consent, expressed as an integer. 
7.1.2. 
Study Day 
Study Day will follow the CDISC SDTM standard and is defined as follows: 
x assessment date – date of first study drug dosing + 1, where the assessment date is on 
or after the date of first study drug dosing;  
x assessment date – date of first study drug dosing, where the assessment date is before 
the date of first study drug dosing.   
7.1.3. 
Estimated Glomerular Filtration Rate 
Estimated glomerular filtration rate (eGFR) value will be calculated at the central laboratory and 
used in the data analyses.  The equation used to calculate eGFR for each patient will not change 
throughout the study, and will be based on the patient’s age on the date of consent.  For patients 
consented at age 18 years and older, the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation will be used: 
eGFR (mL/min/1.73 m2)   î PLQ6crț Į î PD[6crț -1.209 î Age î  
 >LI IHPDOH@ î  >LI EODFN@. 
For patients consented at age 12 to 17, the Bedside Schwartz equation will be used: 
eGFR (mL/min/1.73 m2   î +HLJKW LQ FP  Scr. 
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Where Scr is serum creatinine (mg/dL), ț is 0.7 for females or 0.9 for males, and Į is -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scrț and 1 and max indicates the 
maximum of Scrț and 1. 
Historical serum creatinine and eGFR values will be treated separately from data collected as 
part of the trial’s central lab assessments.  Historical eGFR values will be calculated from 
historical serum creatinine results. 
Missing eGFR values will not be imputed for the primary analysis of efficacy.  Values collected 
after the visit window of the date of last dose for patients who do not complete study treatment 
will not be included in the analysis. 
7.1.4. 
Urine Albumin and Urine Albumin to Creatinine Ratio 
Urine albumin to creatinine ratio (ACR) will be derived using the formula below:  
ACR  Urine Albumin (mg/dL) / Urine Creatinine (g/dL)  
The central laboratory uses an assay that has a lower limit of detection (LLD) and an upper limit 
of detection (ULD) for urine albumin.  Urine albumin results below LLD will be imputed with 
LLD/2 in mg/dL.  Urine albumin results above ULD will be imputed with the ULD value.  
Where imputation is necessary, the imputed urine albumin results will be used along with the 
urine creatinine result provided by the central laboratory for calculating ACR.     
7.1.5. 
Electrocardiogram Fridericia Corrected QT Interval 
Electrocardiogram intervals, including the Fridericia corrected QT interval (QTcF), will be 
assessed locally at each site.  In the event that QTcF interval is not provided, it will be calculated 
from QT and RR intervals using the following formula:  
ܳܶܿܨ=  ܳܶ/ξܴܴ
య
 
:KHUH 55    +HDUW 5DWH 
7.1.6. 
Log of The Minimum Angle of Resolution  
Best-corrected visual acuity (BCVA) assessments will be performed at time points specified in 
the scheduled assessments Table 2.  The Snellen chart values will be used to derive log of the 
minimum angle of resolution (logMAR) value as below: 
ORJ0$5  - log10 (Snellen) 
7.1.7. 
Natural log (ACR)/eGFR 
Natural log(ACR)/eGFR is defined as the ratio of the natural log of ACR (defined in 
Section 7.1.4) divided by eGFR (defined in Section 7.1.3).  Values collected after the analysis 
window of the date of last dose for patients who do not complete study treatment will not be 
included in the analysis.  The natural log (ACR)/eGFR will be rounded 3 decimal places. 
7.2. 
Baseline Values 
  Baseline values are defined as the last non-missing assessment prior to the first study drug 
dosing, unless otherwise specified below.  Assessments performed after the first dose of study 
drug will not be used in the baseline calculation. 
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7.2.1. 
Estimated Glomerular Filtration Rate 
The Screening eGFR value is the average of the last two eGFR measurements collected prior to 
Day 1, for example (Screen A eGFR + Screen B eGFR) / 2.  Unscheduled eGFR values collected 
prior to Day 1 will be used in the calculation of Screening eGFR if the unscheduled eGFR values 
are within the last two eGFR measurements collected prior to Day 1.  Baseline eGFR will be 
calculated as a weighted average of the Day 1 measurement and the Screening measurement as 
shown below:  
%DVHOLQH H*)5   î 'D\  H*)5   î 6FUHHQLQJ H*)5  
However, if no Day 1 eGFR value exists or Day 1 study drug administration occurred before 
Day 1 lab collection, then Baseline eGFR will equal Screening eGFR.  
7.2.2. 
Serum Creatinine 
The Screening SCr value is the average of the last two SCr measurements collected prior to Day 
1, for example (Screen A eGFR + Screen B eGFR) / 2.  Unscheduled SCr values collected prior 
to Day 1 will be used in the calculation of Screening SCr if the unscheduled SCr values are 
within the last two SCr measurements collected prior to Day 1.  Baseline SCr will be calculated 
as a weighted average of the Day 1 measurement and the Screening measurement as shown 
below:  
Baseline SCr   î 'D\  SCr   î 6FUHHQLQJ SCr  
However, if no Day 1 SCr value exists or Day 1 study drug administration occurred before Day 1 
lab collection, then Baseline SCr will equal Screening SCr. 
7.2.3. 
Vital Sign Assessments 
Baseline vital sign assessments is defined as the average value of measurements (from scheduled 
and unscheduled visits) collected up through Day 1, prior to first dose of study drug.    
7.2.4. 
Natural log (ACR)/eGFR 
Baseline of natural log(ACR)/eGFR is defined as the ratio of the natural log of baseline ACR (as 
defined as the last non-missing ACR assessment prior to the first dose of study drug) divided by 
baseline eGFR (defined in Section 7.2.1). 
7.3. 
Analysis Windows 
Because clinical visits may occur outside protocol specified windows, instead of relying solely 
on visit labels in the clinical database, analysis visits and their windows are defined using Study 
Day (See Section 7.1.2).  Analysis visit windows are presented in Table 3 by type of assessments 
and/or measurements.   
If more than one on-treatment assessment and/or measurement exists for a parameter within a 
visit window, the one that is closest to the protocol scheduled time point (or target Study Day) 
will be used for the purposes of data analysis and summary.  If more than one off-treatment 
assessment exists, the one closest to the target study day will be used for analysis and summary.   
 
 
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Table 3: 
Analysis Visit Window 
Protocol 
Scheduled 
Time Point 
Target 
Study Day 
Analysis Visit Windows 
All Other 
Assessments 
12-lead ECG 
Visual Acuity/ 
Audiology 
Screen A 
-60 
-180 to -31 
-180 to 1 
- 
Screen B 
-1 
-30 to -1 
- 
- 
Day 1 
1 
1 
- 
-30 to 1 
Week 1 
7 
2 to 10 
- 
- 
Week 2 
14 
11 to 21 
- 
- 
Week 4 
28 
22 to 35 
- 
- 
Week 6 
42 
36 to 49 
- 
- 
Week 8 
56 
50 to 70 
- 
- 
Week 12 
84 
71 to 126 
- 
- 
Week 24 
168 
127 to 210 
- 
- 
Week 36 
252 
211 to 294 
- 
- 
Week 48 
336 
295 to 350 
2 to 350 
2 to 490 
Week 52 
364 
351 to 406 
351 to 574 
- 
Week 64 
448 
407 to 490 
- 
- 
Week 76 
532 
491 to 574 
- 
- 
Week 88 
616 
575 to 658 
- 
- 
Week 100 
700 
659 to 714 
575 to 714 
> 491 
Week 104 
728 
> 714 
> 714 
- 
 
Note: Study Day is relative to the first date of study drug administration (Study Day 1).  Protocol 
Scheduled Time Point   Analysis Visit (AVISIT), after applying the analysis windows described 
above.  The Week 52 visit has the additional restriction that assessments must be collected 
during the off-treatment prior (i.e., after Week 48 dose and on or before Week 52 study drug 
dispense).  For patients who terminated treatment prior to Week 48, use Week 52 as follow-up 
visit, otherwise Week 104. 
If more than one measurement is equidistant to the target Study Day and on different collection 
date/time, the first measurement will be used for analysis and summary.  If more than one 
measurement is closest to the target Study Day and collected on the same date, the average of 
those measurements will be used for analysis and summary. 
7.4. 
Missing Data 
Missing data will not be imputed for primary analyses of efficacy variables, unless otherwise 
specified.  Lab parameters collected after the visit window of the date of last dose for patients 
who do not complete study treatment will not be included in the efficacy or safety analysis.  
Sensitivity analyses may be performed as appropriate to assess the effect of missing data. 
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8. 
ANALYSIS SETS 
8.1. 
Safety Analysis Set 
Safety analysis set is defined as all patients who received any amount of study drug.  The safety 
analysis set will be used for evaluation of safety variables. 
8.2. 
ITT Analysis Set 
The intent-to-treat analysis set is defined as all enrolled patients.  
8.3. 
Per Protocol Analysis Sets 
The one-year per protocol analysis set is defined as all enrolled patients who were dosing 
compliant through Week 48 as defined by: 
x No more than 21 consecutive missed doses total through Week 48; 
x Received study drug through Week 48; and 
x Had a Week 52 visit. 
The two-year per protocol analysis set is defined as all enrolled patients who were dosing 
compliant through Week 100 as defined by: 
x No more than 21 consecutive missed doses through Week 48 or from Week 52 to 
100; 
x Received study drug through Week 100; and 
x Had a Week 104 visit. 
The off-treatment analysis sets will be used for evaluation of efficacy off-treatment at Week 52 
and Week 104, respectively. 
8.4. 
Pharmacokinetics Analysis Set 
Pharmacokinetics analysis set is defined as all patients who received any amount of study drug 
and had at least one bardoxolone methyl plasma concentration measurement.  The PK analysis 
set will be used for evaluation of pharmacokinetics. 
9. 
STUDY POPULATION 
9.1. 
Patient Disposition 
Enrollment and disposition will be summarized.  A patient will be defined as enrolled if they 
sign the informed consent form.  The patient disposition summary will include the number of 
patients who:  
x enrolled in the study  
x are in the safety analysis set 
x are in the ITT analysis set 
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x are in the one-year per protocol analysis set 
x are in the two-year per protocol analysis set 
x are in the pharmacokinetics analysis set 
x completed the Week 12 treatment period 
x completed the Week 48 treatment period 
x completed the Week 52 treatment period 
x completed the Week 100 treatment period 
x completed the Week 104 treatment period 
x completed the study 
x prematurely discontinued from the study. 
The disposition summary will also include the primary reason for withdrawal from the study.  In 
addition, a summary of patient source will be provided. 
Patients who completed the study are defined as those who completed Week 104 visit.  A listing 
of disposition will be provided for all enrolled patients.   
9.2. 
Protocol Deviations 
Where available, protocol deviations will be listed by deviation category (e.g., eligibility criteria, 
out of window visit, serious adverse event (SAE) reporting, study procedures, treatment 
procedures).  All deviations, including major protocol deviations that could potentially affect the 
efficacy or safety conclusions of the study, will be identified prior to database lock.  Major 
protocol deviations will be listed in a data listing.   
9.3. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the safety analysis set.  
Demographic characteristics will include age, age group (t 18 RU  18), gender, race, and 
ethnicity.  Baseline ACR status is based on the baseline ACR value, not the stratification of a 
patient.  The baseline characteristics include:  
x Baseline weight; 
x Baseline height;  
x Body mass index (BMI);  
x Baseline values of eGFR; 
x Baseline serum creatinine; 
x Baseline ACR;  
x Baseline ACR status ($&5   PJJ  PJJ  $&5   PJJ $&5 ! 
mg/g);  
x Alport syndrome related information 
o Age at time of clinical diagnosis 
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o Mode of inheritance 
x Genotype 
o COL4A3 
o COL4A4 
o COL4A5 
o Unknown 
x Mutation type 
x Baseline Angiotensin converting enzyme (ACE)-inhibitor and Angiotensin II receptor 
blocker (ARB) use 
o Only ACEi treatment; 
o Only ARB treatment; 
o ACEi and ARB treatment; 
o No ACEi or ARB treatment and 
x Symptoms of Alport.  
  
All of the above information will be listed by patient, including family member information. 
9.4. 
Medical History 
Medical history will be mapped to preferred terms (PT) and system organ classes (SOC) using 
the Medical Dictionary for Regulatory Activities (MedDRA®) Dictionary (version 19.1).  
Medical history items will be summarized by MedDRA SOC and preferred term (PT) and patient 
listing will be provided.  Medical history will be summarized for each treatment group by 
MedDRA SOC and preferred term.  Patients may have more than one medical history term per 
MedDRA SOC and preferred term.  At each level of patient summarization, a patient is counted 
once if he/she reported one or more medical history events at that level.  Each summary will be 
ordered by descending order of incidence of MedDRA SOC and preferred term within each 
MedDRA SOC. 
9.4.1. 
Historical eGFR  
Up to 5 years of historical serum creatinine values will be collected for each patient as part of 
their medical history information.  Serum creatinine values will be converted to mg/dL and 
eGFR will be calculated according to the equations in Section 7.1.3 using the patient age at 
laboratory collection for adult patients, or patient height at Screening for pediatric patients.  
Historical serum creatinine values will have been analyzed at various local laboratories (i.e., not 
collected as part of central lab data).  Therefore, historical serum creatinine and eGFR values 
will be treated separately from data collected as part of the trial’s central lab assessments. 
 
 
 
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Table 4:  
Comparison of eGFR Slope in CARDINAL vs. Historical eGFR Slope 
Analysis Time Point 
Study Day Windows 
Historical  
1825 to 1 days prior to Screen A 
Baseline 
 Screen A to Day 1 
On Treatment 
Day 2 to Day 714, excluding eGFR measurements collected at Week 52 and 
Week 104 visits         
(Study Day 2 to 350 and 407 to 714) 
The eGFR values used in the analysis dataset for the baseline label will be the baseline eGFR 
values for each patient (defined in Section 7.2.1), not the individual Screen A, Screen B, and 
Day 1 eGFR values.  The year will be calculated as a continuous variable as Study Day / 365.25.  
HLVWRULFDO YDOXHV ZLOO KDYH D QHJDWLYH 6WXG\ 'D\ YDOXH FDOFXODWHG DV 6WXG\ 'D\  'DWH RI
Historical Lab Collection – Date of Day 1 Study Day.  Baseline eGFR values will have a 
continuous year value of zero.  Off-treatment eGFR values collected in CARDINAL (i.e., Week 
52 and Week 104) will not be included in the analysis.  The general linear model will be run 
according to the analysis dataset in Table 4 . 
A separate dataset will be generated for summary statistics of historical and on-treatment results, 
for patients with historical eGFR data entered.  The second date will separate the historical and 
on-treatment results by year to calculate summary statistics, but will not be used in the statistical 
model described in Section 9.4.1.1.  
Table 5:  
Labels for Summary of Historical and On-Treatment Change in eGFR 
Analysis Time Point 
Study Day Windows 
Historical Year 5 
1825 to 1461 days prior to Screen A 
Historical Year 4 
1460  to 1096 days prior to Screen A 
Historical Year 3 
1095  to 731 days prior to Screen A 
Historical Year 2 
730 to 366 days prior to Screen A 
Historical Year 1 
365 to 1 days prior to Screen A 
Baseline 
Screen A to Day 1 
Year 1 
Day 2 to Day 350 
Year 2 
Day 407 to Day 714 
 
The summary statistics will include the average GFR value by patient and analysis time point.  
For instance, if multiple values are listed in the year 1 results for a given patient, the average of 
those values will be used to calculate the summary statistics.  However, all eGFR values will be 
used in the statistical model described in Section 9.4.1.1. 
9.4.1.1. 
Statistical Model 
Only patients with at least one available historical eGFR value will be included in the analysis. 
The table summaries will report the historical change in eGFR vs. baseline (with no post-
baseline eGFR values from CARDINAL in the model), and the change in eGFR vs. baseline on 
bardoxolone methyl treatment for patients who have historical serum creatinine values reported.  
 
 
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The change in eGFR will be analyzed by an analysis of covariance, with baseline eGFR and 
natural log(Baseline ACR) as covariates: 
The LSMeanDiffCL will compare historical eGFR slopes and eGFR slope in CARDINAL along 
with appropriate confidence intervals, and the Diff results will provide the appropriate p-values.  
All historical eGFR data will be listed. 
Summary statistics of the datasets listed in Table 5 by analysis time point will also be 
summarized.  
10. 
STUDY DRUG AND OTHER MEDICATIONS 
10.1. 
Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms on eCRFs will be mapped to 
Anatomical/Therapeutic/Chemical (ATC) class and preferred names using the World Health 
Organization Drug Dictionary (WHO DD) Enhanced version, March 2016, B2 format. 
A prior medication is any medication that is taken and stopped prior to the first dose of study 
drug.  Medications are stopped on the date of first study drug administration are prior 
medications.  A concomitant medication is any medication taken at the time of first study 
treatment or a medication that was started after the start of study drug dosing.  Specifically, 
concomitant medications are medications 
x that are continued from screening and continued after the first study drug dosing, or 
x that have start dates or stop dates within the treatment period. 
Prior and concomitant medications will be summarized for each treatment group by WHO DD 
ATC class and preferred name.  These summaries will present the number and percentage of 
patients using each medication.  Patients may have more than one medication per ATC class and 
preferred name.  At each level of patient summarization, a patient is counted once if he/she 
reported one or more medications at that level.  Each summary will be ordered by descending 
order of incidence of ATC class and preferred name within each ATC class.  
In addition, patients who take excluded medications (defined in the Protocol Section 9.3.1) 
during the study will be listed. 
10.2. 
Prior and Concomitant Procedures and Surgeries 
Prior and concomitant procedures and surgeries will be listed. 
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10.3. 
Duration of Study Treatment  
Total number of doses received and total dose (mg) received will be calculated from study drug 
dispensation and return information.  Descriptive summaries for duration of study treatment will 
include the number of doses received, average daily dose (mg), study drug compliance, and 
duration (days) of exposure during the study treatment period.   
The duration of study treatment is defined as the number of days exposed to treatment, starting 
with the first dose of study drug through the last dose of study drug 
x DXUDWLRQ RI VWXG\ WUHDWPHQW  (last dose – first dose + 1).   
If all dispensed kits and bottles are returned, the total number of doses received will be 
calculated as follows:  
x 1XPEHU RI GRVHV UHFHLYHG  7otal number of doses dispensed – total number of doses 
returned.   
If a dispensed kit or bottle is not returned, the total number of doses received will be calculated 
as follows:  
x 1XPEHU RI GRVHV UHFHLYHG  total number of doses dispensed – total number of doses 
returned – total number of missed doses 
x 6WXG\ GUXJ FRPSOLDQFH     î WRWDO QXPEHU RI GRVHV UHFHLYHG  WRWDO QXPEHU RI
doses expected in each treatment period.   
Adult patients are expected to receive one dose daily, therefore 84, 336, and 700 doses are 
expected at Weeks 12, 48, and 100 respectively.  Pediatric SDWLHQWV LH DJH   DW WLPH RI
consent) are instructed to dose every other day during the first week, then start with daily dosing 
in Week 2.  Therefore, 81, 333, and 697 doses are expected at Weeks 12, 48, and 100, 
respectively, for pediatric patients. 
All study drug dispensation and accountability data will be listed. 
11. 
EFFICACY ANALYSES 
The primary analysis methods for each efficacy objective is described in the following 
subsections.  Additional sensitivity analyses may be performed as appropriate.  
11.1. 
Primary Efficacy Objective 
A mixed-model for repeated measures (MMRM) will be used to assess the primary efficacy 
objective, change from baseline eGFR at Week 12.  The ITT population will be used for analysis 
of the primary efficacy objective.  All scheduled eGFR values collected through the Week 12 
visit will contribute to the analysis.  Change from baseline in eGFR will be calculated for each 
scheduled visit after Day 1 through Week 12 visit (i.e., Weeks 1, 2, 4, 6, 8, and 12).  An 
inference test of LS mean versus zero will be performed at each time point.    
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11.1.1. 
Statistical Hypothesis 
For the primary efficacy objective, the null hypothesis is the Week 12 mean ȝ BARD) change 
from baseline in eGFR   mL/min/1.73 m2.  The alternative hypothesis is the Week 12 mean ȝ 
BARD) change from baseline in eGFR  0 mL/min/1.73 m2. 
11.1.2. 
Statistical Model 
The MMRM model will include the change from baseline in eGFR value as the dependent 
variable, protocol scheduled time point (analysis visit) 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).  The SAS pseudo-code is as follows: 
proc mixed data=efficacy method=reml; 
   class usubjid avisitn; 
   model chg=avisitn base_egfr lbase_acr; 
   repeated avisitn / subject=usubjid type=un rcorr; 
   lsmeans avisitn / diff cl alpha=0.05; 
run; 
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures will be as substitution in the following order.  Each subsequent 
covariance structure will be used only if all previous covariance structure(s) is (are) used and the 
model(s) did not converge. 
1. Toeplitz covariance structure (assuming measurements from samples taken closer 
together in time are more highly correlated than those from samples taken farther apart). 
2. First order of auto-regressive [AR(1)] covariance structure (assuming measurements from 
samples taken closer together in time are more highly correlated than those from samples 
taken farther apart). 
3. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a patient, regardless of how far apart in time when they were taken).  
11.1.3. 
Reporting Results 
The least squares (LS) mean, standard error (SE) of the LS mean, and two-VLGHG  confidence 
interval (CI) of the LS mean and p-value will be reported at each time point.  A formal test of 
mean change from baseline in eGFR   ZLOO EH FRQGXFWHG at Week 12.  The mean change from 
baseline in eGFR at all other time points will be considered exploratory, so tests at these time 
points will be performed with no adjustments for multiple comparisons.   
$ SORW RI WKH /6 PHDQV ZLWK  &,V RI FKDQJH IURP EDVHOLQH LQ eGFR value over time will be 
presented.   
Descriptive statistics for observed eGFR values and change from baseline in eGFR values will be 
provided by time point through the end of follow-up.  A plot of mean and standard error of eGFR 
values over time will be presented.   
All efficacy data will be listed. 
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11.2. 
Additional Efficacy Analyses 
Additional efficacy analyses conducted after database lock at Week 52 will not update efficacy 
tables results for visits at or before Week 52.  
11.2.1. 
Secondary Efficacy Objectives 
Additional analyses of on-treatment, continuous eGFR will be evaluated: 
x Change from baseline in eGFR at Week 48 
x Change from baseline in eGFR at Week 100 
Change from baseline in eGFR will be calculated for each scheduled, post-dose time point 
through the objective specified visit (i.e., Week 48 or Week 100).  The ITT population will be 
used for analysis of the secondary efficacy objectives.  An additional sensitivity analysis will be 
performed using the one-year and two-year per protocol analysis sets to assess the on-treatment 
effects of eGFR at Weeks 48 and 100, respectively.  Using the analysis methods described in 
below, the above efficacy endpoints will be evaluated in two separate MMRM models: 
(1) The first model includes all time points from Week 1 through Week 48;  
(2) The second model includes all on-treatment time points from Week 1 through Week 100 
(i.e., exclude the off-treatment assessments at Week 52).   
 
The estimation method for the model will be restricted maximum likelihood (REML).  The SAS 
pseudo-code is as follows: 
proc mixed data=efficacy method=reml; 
   class usubjid avisitn; 
   model chg=avisitn base_egfr lbase_acr “Baseline BMI>=30 Y/N”n; 
   repeated avisitn / subject=usubjid type=un rcorr; 
   lsmeans avisitn / diff cl alpha=0.05; 
run; 
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures will be as substitution in the following order.  Each subsequent 
covariance structure will be used only if all previous covariance structure(s) is (are) used and the 
model(s) did not converge. 
1. Toeplitz covariance structure (assuming measurements from samples taken closer 
together in time are more highly correlated than those from samples taken farther apart). 
2. First order of auto-regressive [AR(1)] covariance structure (assuming measurements from 
samples taken closer together in time are more highly correlated than those from samples 
taken farther apart). 
3. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a patient, regardless of how far apart in time when they were taken).  
Results will be reported as described in Section 11.1.3. 
 
 
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11.2.2. 
Exploratory Efficacy Objectives 
Additional analyses of off-treatment, continuous eGFR will be evaluated: 
x Change from baseline in eGFR at Week 52 
x Change from baseline in eGFR at Week 104 
Change from baseline in eGFR will be calculated for each scheduled, post-dose time point 
through the objective specified visit (i.e., Week 52 or Week 104).  The per protocol analysis sets 
will be used to analyze the exploratory off-treatment efficacy objectives.  Using the analysis 
methods described in Section 11.1.2, the above efficacy endpoints will be evaluated in two 
separate MMRM models:   
(1) The first model includes all time points from Week 1 through Week 52.  The Week 52 
off-treatment analysis set will be used to assess efficacy at Week 52;  
(2) The second model includes all on-treatment time points from Week 1 through Week 100 
(i.e., exclude the off-treatment assessments at Week 52) in addition to the off-treatment 
values at Week 104.  The Week 104 off-treatment analysis set will be used to assess 
efficacy at Week 104. 
The estimation method for the model will be restricted maximum likelihood (REML).  The SAS 
pseudo-code is as follows: 
proc mixed data=efficacy method=reml; 
   class usubjid avisitn; 
   model chg=avisitn base_egfr lbase_acr “Baseline BMI>=30 Y/N”n; 
   repeated avisitn / subject=usubjid type=un rcorr; 
   lsmeans avisitn / diff cl alpha=0.05; 
run; 
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures will be as substitution in the following order.  Each subsequent 
covariance structure will be used only if all previous covariance structure(s) is (are) used and the 
model(s) did not converge. 
1. Toeplitz covariance structure (assuming measurements from samples taken closer 
together in time are more highly correlated than those from samples taken farther apart). 
2. First order of auto-regressive [AR(1)] covariance structure (assuming measurements from 
samples taken closer together in time are more highly correlated than those from samples 
taken farther apart). 
3. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a patient, regardless of how far apart in time when they were taken).  
Results will be reported as described in Section 11.1.3. 
11.2.3. 
Categorical Analyses of eGFR 
11.2.3.1. CKD Stage 
Shifts in CKD stage from baseline to Week 48 and baseline to Week 100 will be summarized 
using frequency counts and percentages based on the following definition of CKD stages: 
 
 
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Table 6: 
Categorical Analysis of CKD Stage 
CKD Stage 
eGFR (mL/min/1.73 m2) 
1 
  
2 
  WR   
3a 
  WR   
3b 
  WR   
4 
  WR   
5 
 
 
The eGFR values collected after the date of last dose for patients who do not complete study 
treatment will not be included in the analysis. 
11.2.3.2. Categorical Change in eGFR 
The percentage of patients with a confirmed increase LH RFFXUULQJ DW   YLVLWV from baseline 
RI  RU PRUH within 48 and 100 weeks of treatment will be summarized using frequency 
counts and percentages (excluding the Week 52 visit).  Similarly, the percentage of patients with 
a confirmed decrease LH RFFXUULQJ DW   YLVLWV IURP EDVHOLQH LQ H*)5 RI  RU PRUH within 
48 and 100 weeks of treatment will be summarized (excluding the Week 52 visit). 
11.2.4. 
Patient Global Impression of Change 
The Patient Global Impression of Change (PGIC) is a 7-point scale that asks the patient to assess 
how much the patient's illness has improved or worsened relative to a baseline state at the 
beginning of an intervention (Guy 1976).  The patient global impression of change is assessed by 
completing the following statement “since I began trial treatment, my overall status is: very 
much improved (1), much improved (2), minimally improved (3), no change (4), minimally 
worse (5), much worse (6), very much worse (7).”  PGIC will be summarized by response with 
frequency counts and percentages at each assessed visit: Weeks 24, 48, 52, 76, 100, and 104.  
11.2.5. 
Clinical Global Impression-Improvement  
The Clinical Global Impression-Improvement (CGI-I) is a 7-point scale that asks the clinician to 
assess how much the patient's illness has improved or worsened relative to a baseline state at the 
beginning of an intervention (Guy 1976).  The clinician global impression of change is assessed 
by completing the following statement “Compared to the patient’s condition at the start of the 
trial, this patient’s overall status is: very much improved (1), much improved (2), minimally 
improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7).”  CGI-
I will be summarized by response with frequency counts and percentages at each assessed visit: 
Weeks 24, 48, 52, 76, 100, and 104.  
11.2.6. 
End Stage Kidney 'LVHDVH H*)5 GHFOLQH  RU H*)5   
Time-to-event analyses for a composite renal endpoint consisting of time to end stage kidney 
disease (dialysis) H*)5 GHFOLQH  RU H*)5   will be performed.  Time-to-event 
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Page 31 of 37 
analyses will only be conducted after all patients have completed Week 104.  No off-treatment 
eGFR values will be included in the analysis. 
As a sensitivity analysis, the analyses will be repeated for the time to end stage kidney disease 
(dialysis) H*)5 GHFOLQH  RU H*)5  , or all-cause death.  Confirmation of each eGFR 
GHFOLQH HYHQW ZLOO EH EDVHG RQ   GHFOLQH IURP EDVHOLQH LQ H*)5 RU H*)5  P/PLQ
m2 occurring at 2 or more visits.  HazarGV UDWLRV DQG  &, ZLOO EH FRPSXWHG XVLQJ &R[
proportional hazards regression models:  
&DVHV LQ ZKLFK D SDWLHQW KDV DQ H*)5 YDOXH WKDW GHFOLQHG   RU IHOO EHORZ  P/PLQ
m2 at the last visit, but did not have a second confirmatory visit, will be considered events. 
Patients who do not experience one of these events will be censored using the following 
conventions: patients who died from any cause prior to the end of the study will be censored at 
the date of death for the sensitivity analysis where all-cause death is not included in the 
composite endpoint; patients who discontinued the study prematurely, withdrew consent, or were 
lost to follow-up prior to the end of the study will be censored at their last date of contact; 
patients who are alive and still being followed will be censored on the study termination (for 
early termination) or study completion date at Week 104.  
11.2.6.1. Frequency of End Stage Kidney Disease, eGFR GHFOLQH  RU H*)5   
The proportion of patients with HQG VWDJH NLGQH\ GLVHDVH GLDO\VLV H*)5 GHFOLQH  RU
H*)5   ZLOO EH SHUIRUPHG, and the composite of all of these criteria will be evaluated.  The 
frequency analyses will be performed after all patients have completed Week 104.  No off-
treatment eGFR values will be included in the analysis.  Rules for analysis of the composite renal 
endpoint consisting of time to all-cause death, end stage kidney disease (dialysis), eGFR decline 
 RU H*)5   will follow Section 11.2.6.  Statistical significance of the proportion of 
patients with a given event will be evaluated using Fisher’s exact test.   
As a sensitivity analysis, the analyses will be repeated for the frequency of patients with end 
VWDJH NLGQH\ GLVHDVH GLDO\VLV H*)5 GHFOLQH  RU H*)5   or all-cause death. 
11.3. 
Sensitivity Analyses 
The primary analysis method (MMRM) uses all available data, and assumes data are missing at 
random.  A tipping point analysis or other sensitivity analyses may be performed as appropriate 
for the Phase 2 portion of the study. 
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11.4. 
Subgroups Analyses of Efficacy 
The efficacy variables will be summarized using descriptive statisticV LQFOXGLQJ  &, IRU
change from baseline, will be reported for each subgroup of interest listed below: 
x Baseline ACR 300, ACR > 300 
x Baseline ACR    $&5   $&5 !   
x Baseline eGFR 60, >60 
x Male, Female 
x Genetic subtype (XLAS vs Non-XLAS) 
x $JH   $JH 18. 
x Baseline ACEi/ARB use (ACEi and/or ARB vs None) 
x %DVHOLQH %0,     
For the Phase 2 portion of the study, no statistical testing will be performed for subgroups. 
12. 
SAFETY ANALYSES 
Safety and tolerability are evaluated by AEs, SAEs, clinical laboratory test results, body weight, 
vital signs, 12-lead ECG findings, physical examination, visual acuity, and audiology 
assessment.  All analyses of the safety data will be performed using the safety analysis set and 
display descriptive statistics (described in Section 7). 
12.1. 
Adverse Events and Serious Adverse Events 
All adverse event verbatim terms on eCRFs will be mapped to preferred terms and system organ 
classes using the Medical Dictionary for Regulatory Activities (MedDRA®) Dictionary (version 
19.1).   
12.1.1. 
Treatment Emergent Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as any AEs, regardless of relationship to study 
drug, that have an onset or worsen in severity on or after the first dose of study drug and not 
more than 30 days after the date of the last dose of study drug.  If it cannot be determined 
whether the AE is treatment-emergent due to a partial onset date, then it will be counted as a 
TEAE.  Adverse events with incomplete start dates will be considered TEAEs, if: 
x Onset time is missing but the onset date is on Study Day 1. 
x Day and month are missing and the year is equal to or after the year of the first date 
of study drug dosing;  
x Day is missing and the year is after the year of the first date of study drug dosing;  
x Day is missing and the year is equal to the year of the first date of study drug dosing 
and the month is equal to or after the month of the first date of study drug dosing; or 
x Year is missing. 
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Related AEs are those with relationship to study drug reported as “possibly related”, “probably 
related”, or “definitely related”.  If severity (relationship) of an AE to study drug is not recorded, 
the severity (relationship) will be imputed as ‘severe’ (‘definitely related’). 
All reported AEs (including non-TEAEs), SAE, and deaths will be listed in separate patient 
listings. 
12.1.2. 
Summary of Treatment-Emergent Adverse Events and Serious Adverse Events 
All TEAE and SAE summary tables will include the number and percentages of patients 
reporting events.  A summary of TEAEs by severity, seriousness, and relation to study drug will 
be tabulated.  In addition, TEAEs and SAEs will be summarized by MedDRA system organ class 
and preferred term.  Patients can have more than one TEAE per system organ class and preferred 
term.  These summaries will include the following: 
x All TEAEs 
x TEAEs by worst severity 
x Related TEAEs 
x TEAEs leading to study drug interruption (if any) 
x TEAEs leading to study drug discontinuation (if any) 
x All treatment-emergent SAEs 
x Treatment-emergent SAEs by worst severity 
x Related treatment-emergent SAEs. 
Patients can have more than one TEAE (SAE) per system organ class and preferred term.  At 
each level of patient summarization, a patient is counted once if he/she reported one or more 
TEAE (SAE) at that level.  If a patient reported the same TEAE (SAE) on multiple occasions, 
the highest severity (severe > moderate > mild) or study drug relationship (related > probable > 
possible > unlikely > unrelated) recorded for the event will be summarized.  Each summary will 
be ordered by descending order of incidence of system organ class and preferred term within 
each system organ class.  
12.2. 
Clinical Laboratory Evaluation 
Clinical laboratory test (serum chemistry [including NT-Pro BNP, BNP, IGF-1 and serum 
ketones], hematology [including hematocrit, hemoglobin (Hgb), red blood cell (RBC) count, 
white blood cell (WBC) count, neutrophils, 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)], spot urine, and urinalysis of pH and specific gravity) results from the 
central laboratory, where available, will be summarized using descriptive statistics at each 
scheduled time point.  6XPPDULHV RI $&5 ZLOO XVH WKH JHRPHWULF PHDQ ZLWK  FRQILGHQFH
intervals instead of the arithmetic mean, and will display ACR results in units of mg/g. Changes 
from baseline in ACR will be reported as the post-baseline/baseline ratios and will be 
VXPPDUL]HG E\ JHRPHWULF PHDQV ZLWK  FRQILGHQFH LQWHUYDOV DW HDFK WLPH SRLQW 0HDQ UDWLRV
of natural log(ACR)/eGFR will also be summarized at each time point.  The ratio of natural 
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Statistical Analysis Plan v5 (Protocol v4) 
 
JUN 05, 2019 
 
Page 34 of 37 
log(ACR)/eGFR by analysis visit will be summarized by arithmetic means.  Laboratory 
assessments below the LLD will be imputed as LLD/2.  Laboratory assessments above the ULD 
will be imputed as the ULD.  Changes from baseline will also be summarized by time point.  
Box plot graphs and line graphs may be generated for selected laboratory tests, such as ACR, 
ALT, AST, BUN, uric acid, magnesium, and creatinine.  Line graphs will include mean ± SE 
over time for both the observed values and for the change from baseline values. 
Two additional summary tables will be provided that include the number and percentage of 
patients 1) meeting the following pre-specified threshold level at any time during the study 
(Table 7) and 2) ULN thresholds at any time during the study (Table 8).  
Table 7: Pre-Specified Threshold Levels for Categorical Laboratory Summaries 
Lab Parameter 
Pre-Specified Level 
ACR 
> 3500 mg/g 
Magnesium 
 1.3 mEq/L (0.65 mmol/L) 
BNP 
> 200 pg/mL 
ALT, AST 
> 3 î XSSHU OLPLW RI QRUPDO 8/1 
ALT, AST 
> 8 î 8/1 
ALT, AST 
> 5 î 8/1 IRU PRUH WKDQ  ZHHNV 
ALT, AST, TBL, INR > 3 î 8/N and (TBL > 2 î ULN or INR > 1.5) 
 
Table 8: 
Pre-Specified Upper Limit of Normal (ULN) Levels for Laboratory 
Parameters 
Lab Parameter 
 Sex 
Age 
ULN 
ALT 
Female 
All 
34 U/L 
Male 
All 
43 U/L 
AST 
Female 
  
40 U/L 
  
34 U/L 
Male 
  
40 U/L 
  
36 U/L 
TBL 
 
 
Central lab ULN 
INR 
 
 
1.5 
 
Urinalysis results (other than pH and specific gravity) of ketones, protein, blood, glucose, clarity, 
color, leukocytes, nitrite, bilirubin, and microscopic examinations (if indicated based on 
laboratory results), urine microscopic findings, and pregnancy test results will not be 
summarized.   
Laboratory results that are above or below normal limits will be flagged in the listings.   
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12.3. 
Analyses of Continuous eGFR and ACR 
Additional safety endpoints will be evaluated by rare chronic kidney disease cohort: 
x Change from baseline in eGFR at Week 16 following a 4-week drug treatment 
withdrawal period 
x Ratio of natural log (ACR)/eGFR by analysis visit, for visits at Baseline through 
Week 104.  The ratio of natural log(ACR)/eGFR by analysis visit will be summarized 
by arithmetic mean and standard deviation at each time point.  
x &KDQJH IURP EDVHOLQH LQ $&5 VXPPDUL]HG E\ EDVHOLQH $&5 FDWHJRU\ $&5  
ACR > 300) 
12.3.1. 
Ratio of Natural log (ACR)/eGFR 
The ratio of natural log(ACR)/eGFR will be analyzed through Week 104.  The ratio of natural 
log(ACR) / eGFR will be the natural log (ACR) and eGFR values collected closest to the target 
study day (Section 7.3) through the Week 104, and the baseline values are described in 
Section 7.2.4.  The change from baseline in natural log(ACR) / eGFR will be calculated for each 
time point through Week 104 visit.  Missing data will not be imputed.  The inference will be the 
test of LS mean at each time point.  The estimation method for the model will be restricted 
maximum likelihood (REML).  The SAS pseudo-code is as follows: 
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures will be as substitution in the following order.  Each subsequent 
covariance structure will be used only if all previous covariance structure(s) is (are) used and the 
model(s) did not converge. 
1. Toeplitz covariance structure (assuming measurements from samples taken closer 
together in time are more highly correlated than those from samples taken farther apart). 
2. First order of auto-regressive [AR(1)] covariance structure (assuming measurements from 
samples taken closer together in time are more highly correlated than those from samples 
taken farther apart). 
3. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a patient, regardless of how far apart in time when they were taken).  
12.3.2. 
Change from Baseline in ACR 
The change from baseline ACR will be summarized for all patients, as well as by baseline ACR 
category (ACR 300, ACR > 300).  6XPPDULHV RI $&5 ZLOO XVH WKH JHRPHWULF PHDQ ZLWK 
confidence intervals instead of the arithmetic mean, and will display ACR results in units of 
mg/g.  Changes from baseline in ACR will be reported as the post-baseline/baseline ratios and 
ZLOO EH VXPPDUL]HG E\ JHRPHWULF PHDQV ZLWK  FRQILGHQFH LQWHUYDOV DW HDFK WLPH SRLQW  
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JUN 05, 2019 
 
Page 36 of 37 
12.4. 
Vital Signs 
Descriptive statistics for blood pressure, heart rate, respiratory rate, and temperature including 
baseline values and change from baseline values, will be summarized by time point.  All vital 
signs parameters will be listed.   
12.5. 
Body Weight 
Descriptive statistics for body weight that are collected on the eCRF and change from baseline 
values will be will be summarized and listed by time point.  In addition, number and percentage 
of patients who experience a five-pound (2.3 kilogram) or greater increase in weight will be 
summarized by time point.  Boxplot and line graphs of change from baseline over time for 
weight will be plotted.  Weight change will also EH VXPPDUL]HG E\ EDVHOLQH %0, ! DQG 30 
kg/m2) DQG EDVHOLQH DJH ! DQG ). 
12.6. 
12-lead ECG 
Electrocardiogram (ECG) data, such as clinical interpretation of ECGs, ventricular rate and 
interval assessments of PR, QRS, QT, and QTcF, will be collected on the eCRF.  Descriptive 
statistics for observed values and change from baseline at each time point will be presented for 
these 12-lead ECG interval assessments.  In addition, number and percentage of patients with 
any abnormal values (i.e., above a pre-specified threshold) will be summarized by time point and 
overall while on study drug.  The pre-specified levels of ECG QTc thresholds are consistent with 
FDA guidance.   
Table 9: 
Pre-Specified Threshold Levels for ECG Parameters 
ECG Parameter 
Pre-Specified Level 
PR 
>200 msec 
QTcF 
>450, >480 or >500 msec, >30 or >60 msec increase from 
baseline 
Heart rate 
 ! EHDWVPLQ 
 
All ECG parameters will be listed.  Any results that exceed the above levels (provided in the 
above table) will be flagged in the listing. 
12.7. 
Physical Examination 
Abnormal clinically significant findings will be reported as Medical History or Adverse Events 
depending on date of onset.  Abnormal non-clinically significant findings from physical 
examinations will be listed.  
12.8. 
Visual Acuity 
Findings from visual acuity examinations will be listed.  Observed logMAR value and its 
associated change from baseline will be summarized descriptively by time point using 
descriptive statistics.  
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12.9. 
Audiology Assessment 
Findings from audiology assessments will be listed.  The average pure tone audiometry (PTA) 
values will be summarized by visit.  The number and percentage of patients with normal or 
impaired hearing in at least one ear will be summarized by time point.   
13. 
PHARMACOKINETICS ANALYSIS 
Blood samples for determination of plasma bardoxolone methyl and potential metabolite 
concentrations will be drawn as shown in Table 2.  The PK profile of bardoxolone methyl will be 
evaluated from plasma concentration data from individual patients.  The PK parameters, such as 
Cmax, Tmax, and AUC0-t will be determined by a third party vendor.  The bardoxolone methyl 
plasma concentration data, along with PK parameters, will be listed.  The PK parameters will be 
summarized descriptively. 
14. 
REFERENCES 
Guy, W. ECDEU Assessment Manual For Psychopharmacology, DHEW Publication No.  ADM 
76–338, US Government Printing Office, Washington, DC, USA, 1976).   
 
38

Prot_003.pdf: 
Protocol 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
Version 3.1 Germany – 15 November 2018 
1 
 
 
 
 
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 3.1 – 15 NOVEMBER 2018 
GERMANY 
Protocol History 
Version 2.1 – 23 May 2018 
Version 1.1 – 27 November 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. 




Protocol 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Version 3.1 Germany – 15 November 2018 
3 
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 
Reata Pharmaceuticals, Inc. 
Confidential 
Version 3.1 Germany – 15 November 2018 
4 
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 
 
 
 
 
 
 


Protocol 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Version 3.1 Germany – 15 November 2018 
5 
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: 
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. 
Secondary: 
 
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. 
 
To assess the change from baseline in eGFR in bardoxolone methyl-treated patients relative to 


Protocol 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Version 3.1 Germany – 15 November 2018 
6 
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 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. 
 
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 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 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 time-to-first kidney 
failure event defined as the composite endpoint consisting of: 
o 30% decline from baseline in eGFR;  
o eGFR < 15 mL/min/1.73 m2; 
o ESRD (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 
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.  Adult patients (≥ 18 years of age) 
receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg 


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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.  Patients under the age of 18 receiving 
bardoxolone methyl will start dosing at 5 mg every other day during the first week and begin once-
daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing 
following the same aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, and 6.  
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 primary efficacy endpoint will be analyzed after all 
patients in the Phase 3 cohort have completed their Week 52 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 12 ≤ 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


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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 (and assent form if 
necessary) indicating that the patient (or a legally acceptable representative) has been informed 
of all pertinent aspects of the study prior to initiation of any protocol-mandated procedures. 
Major exclusion criteria: 
1. 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 


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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  
 
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.  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 


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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 
 
Missing data for the Week 48 analysis will be imputed using Jump to Reference (J2R) multiple 
imputation (Ratitch, 2013) based on available data collected from patients discontinuing from 
study treatment but continuing in the study. 
 
 
Key secondary endpoint 
With 150 patients enrolled and at least 140 patients having available Week 52 data after completing 
48 weeks of treatment, 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 at Week 52 are based on available Week 52 data from the subset of patients who 
complete the 48-week treatment course. 
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 analysis of efficacy will use an unstructured 
covariance structure, which is expected to have approximately the same power as the analysis with 
compound symmetry used for study planning.  The method for maintaining strict control of the Type I 
error will be described in the statistical analysis plan. 
 
Schema for Study of Bardoxolone Methyl in Patients with Alport Syndrome 
Screening
Dose-Titration Period
W2
W1
W8
W12
ScrA
D1
D3
T
D10
T
W3
T
W4
Maintenance
W24
Placebo*
D31
T
W5
T
W6
W7
T
BARD (5 mg)*
BARD (20 mg)
W36
W48
W52
W/D
Off 
Study 
Drug
BARD (10 mg)
Cohort 2 primary efficacy analysis
O eGFR determination
T Telephone Contact
W64
W76
W88
W100
BARD (20 mg)
ScrB
Maintenance
Placebo
BARD (5 mg)*
BARD (20 mg)
BARD (10 mg)
BARD (30 mg)
BARD (30 mg)
Baseline ACR ≤ 300 mg/g
Baseline ACR > 300 mg/g
Cohort 1 primary efficacy analysis
W104
F/U
Off 
Study 
Drug
* Patients under the age of 18 will  receive study drug (BARD 
 
o) every other day during Week 1
R
Phase 3 Cohort
1 1 Randomization
  


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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.............................17 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Clinical Experience with Bardoxolone Methyl ..........................................................22 
5.1.1. 
Efficacy .......................................................................................................................22 
5.1.2. 
Safety and Tolerability ...............................................................................................25 
5.1.2.1. 
Fluid Overload ............................................................................................................25 
5.1.2.2. 
Transaminase and Gamma-glutamyl Transpeptidase (GGT) Elevations ...................25 
5.1.2.3. 
Muscle Spasms ...........................................................................................................26 
5.1.2.4. 
Weight Loss ................................................................................................................26 
5.1.2.5. 
Hypomagnesaemia ......................................................................................................27 
5.1.2.6. 
Increases in Urinary Protein .......................................................................................27 
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 ........................................................................................................................29 
6.1.2.1. 
Primary Objective .......................................................................................................29 
6.1.2.2. 
Key Secondary Objective ...........................................................................................29 
6.1.2.3. 
Secondary Objective ...................................................................................................29 
6.2. 
Endpoints ....................................................................................................................30 
6.2.1. 
Phase 2 ........................................................................................................................30 
6.2.1.1. 
Primary Efficacy Endpoint .........................................................................................30 
6.2.2. 
Phase 3 ........................................................................................................................31 
6.2.2.1. 
Primary Efficacy Endpoint .........................................................................................31 


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6.2.2.2. 
Key Secondary Efficacy Endpoint ..............................................................................31 
6.2.2.3. 
Secondary Efficacy Endpoints ....................................................................................31 
6.2.2.4. 
Exploratory Efficacy Endpoints .................................................................................31 
6.2.3. 
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 Discontinuation Criteria .................................................................................41 
8.5.2. 
Patient 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 
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 
9.2. 
Description of Study Drug ..........................................................................................45 
9.3. 
Concomitant Medications ...........................................................................................47 
9.3.1. 
Excluded Medications ................................................................................................47 


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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 
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 


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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 .........................................................................................................56 
9.10.22. 
Hematology .................................................................................................................56 
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 ..................................................................57 
9.10.29. 
Virus Serology ............................................................................................................57 
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 
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 


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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 
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 ...........................................................................17 
Table 3: 
Cross-Study Comparison of Increases in eGFR, Inulin Clearance, and 
Creatinine Clearance with Bardoxolone Methyl Treatment .......................................24 
Table 4: 
Schedule of Assessments ............................................................................................36 
Table 5: 
Bardoxolone Methyl Drug Product Information ........................................................45 
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 
ESRD 
End stage renal 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 
J2R 
Jump to reference 
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 


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Abbreviation or Specialist Term 
Explanation 
PK 
Pharmacokinetic 
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  and  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-1 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 renal disease (ESRD).  Thus, the collective data support that bardoxolone methyl may 


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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 ESRD. 
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 renal disease (ESRD; 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 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. 
5.1.3. 
Clinical Experience in Pediatric Patients 
Approximately 1950 adult individuals have been exposed to bardoxolone methyl in prior clinical 
trials.  In the Phase 2 portion of the present 402-C-1603 trial, 2 pediatric patients were enrolled 
(both 14 years of age).  Data from the 12-week primary efficacy and safety data for the Phase 2 
portion of this trial suggest that efficacy and safety in pediatric Alport patients may be similar to 
that observed in adult Alport patients.  Specifically, for the 2 pediatric Alport patients, an 
increase in eGFR of 26.1 mL/min/1.73m2 was observed, compared to 13.4 mL/min/1.73m2 in the 
total 30-patient cohort.  From a safety perspective, no SAEs were reported in the pediatric 
patients and only 1 of the pediatric patients reported any AEs during the first 12 weeks of the 
study.  The reported AEs for this patient included headache, fatigue, chest infection, sore throat, 
conjunctivitis, dry cough, and bronchial asthma, all of which were mild and considered by the 
investigator to be unrelated to study drug.  Systemic exposure to bardoxolone methyl, based on 


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Cmax and AUC, for the 2 pediatric Alport patients was near the median exposure observed in 
adult patients in the Phase 2 portion of the study.  Because the pharmacokinetics, safety, and 
efficacy of bardoxolone methyl have not been extensively characterized in pediatric patients, for 
the purpose of this study a dose adjustment is utilized for pediatric patients, as described in 
Section 7.3.  Based on available nonclinical and clinical data with bardoxolone methyl, there are 
no known safety risks that are specific to the pediatric population, and therefore patient 
discontinuation criteria for pediatric patients in this trial are the same as for adult patients, as 
described in Section 8.5. 


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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  
6.1.2.1. 
Primary Objective 
 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. 
Secondary Objective 
 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. 
 To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at 
Week 104 following a 4-week drug treatment withdrawal period. 


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6.1.2.4. 
Exploratory Objective 
 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. 
 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 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 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 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; 
 ESRD (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. 


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6.2.1.2. 
Secondary Efficacy Endpoint 
 Change from baseline in eGFR at Week 48. 
6.2.1.3. 
Exploratory Effiacy Endpoint 
 Change from baseline in eGFR at Week 52 following a 4-week drug treatment 
withdrawal period. 
6.2.2. 
Phase 3 
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. 
Secondary Efficacy Endpoints 
 The change from baseline in eGFR in bardoxolone methyl-treated patients relative to 
placebo at Week 100. 
 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. 
6.2.2.4. 
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. 
 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 48 weeks of treatment. 
 The Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone methyl-
treated patients relative to placebo after 48 weeks of treatment. 


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 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 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;  
 ESRD (initiation of maintenance dialysis or kidney transplant). 
6.2.3. 
Safety Endpoints 
 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.  Adult 
patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 
5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 
6 (only if baseline ACR >300 mg/g) unless contraindicated clinically and approved by the 
medical monitor. Patients under the age of 18 receiving bardoxolone methyl will start dosing at 
5 mg every other day during the first week and begin once-daily dosing with 5 mg during the 
second week of the study, and then continue with once-daily dosing following the same 
aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, and 6.  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 primary efficacy endpoint will 
be analyzed after all patients in the Phase 3 cohort have completed their Week 52 visit.   


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All enrolled patients are expected to remain on their blinded treatment assignment through 
Week 100, and to complete all scheduled assessments through Week 104. 
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.  Adult patients (>18 years of age) 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.  Patients 
under the age of 18 will receive 5 mg every other day during the first week and begin once-daily 
dosing with 5 mg during the second week of the study, and then continue with once-daily dosing 
following the same aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, 
and 6.  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, 


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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. 
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±3 
 
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±3 
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 
 
 
 
 
 
 
 
 
 
761


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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 12 ≤ 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 (and assent form 
if necessary) indicating that the patient (or a legally acceptable representative) has been 
informed of all pertinent aspects of the study prior to initiation of any 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 the study 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 or withdrawing a patient from the study.  The reason for a patient’s 
discontinuation from study drug or study termination will be recorded in the electronic case 
report form (eCRF).  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 Discontinuation Criteria 
Discontinuation refers to a patient’s stopping administration of study drug.  Reasons for study 
drug discontinuation may include the following: 
 Occurrence of an AE or change in medical status that leads the investigator to be 
concerned about the patient’s welfare; 
 Administrative reasons (e.g., inability to continue); 
 Sponsor termination of the study; 
 Voluntary withdrawal; 
 Females who become pregnant during the study; 
 Investigator unblinding. 
Patients should temporarily discontinue study drug and the medical monitor should be contacted 
to discuss if permanent study drug discontinuation is required if any of the following occur. 


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 ALT or AST > 8X ULN; 
 ALT or AST > 5X ULN for more than two weeks; 
 ALT or AST > 3X ULN and (total bilirubin > 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%). 
Patients who are discontinued from study drug should still continue in the study, complete all 
study visits, and undergo all scheduled study assessments, if possible.   
8.5.2. 
Patient Termination Criteria 
Termination refers to a patient’s stopping study drug and all study assessments and visits.  
Reasons for study termination include the following: 
 Loss to follow-up; 
 Death; 
 Withdrawal of consent; 
 ESRD (initiation of maintenance dialysis or kidney transplant). 
Every reasonable effort should be made to contact patients who do not return for a scheduled 
visit.  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.   
If a patient terminates from the study due to reaching ESRD (defined as the initiation of 
maintenance dialysis for 12 weeks or more or kidney transplant), the patient should complete an 
end-of-treatment visit and the investigator should record the ESRD event as an adverse event and 
document the date of dialysis initiation or kidney transplantation.  
 


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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 retenetion 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.   
9.2. 
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  


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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-TNF 
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 
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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 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. 
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 discontinue 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; 
 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, 
diaphragm [always use with spermicidal jelly/cream]).  Double-barrier method is not 
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 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. 
For pediatric patients, informed consent will be obtained from the parent(s) or legal guardian in 
accordance with regional laws or regulations.  In addition, dependent upon the patient’s age and 
IRBs, IEC, and/or local requirements, assent of the patient may also need to be obtained.  
Pediatric patients may be asked to personally sign and date either a separately designed, written 
assent form, or the written informed consent. 
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 


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within the Informed Consent Form to help ensure consistent weight collection throughout the 
study.  
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 under the age of 18 should self-administer one capsule from each bottle included in the 
study drug kit orally every other day for the first week after randomization, and begin dosing 
once a day on Day 7 through the end of the study, as indicated in Table 4.  Adult patients (≥ 18 
years of age) 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 


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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. 
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, 


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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. 
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 equation used to calculate eGFR for each patient throughout the study will be based on the 
patient’s age on the date of consent.  For patients consented at age 18 years and older, the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation will be used to 
calculate eGFR for each patient throughout the study: 
eGFR (mL/min/1.73 m2) = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age ×  
1.018 [if female] × 1.159 [if black] 
For patients consented at age 12 to 17, the Bedside Schwartz equation will be used: 
eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Scr  
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scr/κ or 1 and max indicates the 
maximum of Scr/κ or 1. 
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.   


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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, 
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.   


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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. 
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 30 days (+/- 3 days) following administration of the final dose of study medication, 
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. 
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.  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 
 Missing data for the Week 48 analysis will be imputed using Jump to Reference (J2R) 
multiple imputation (Ratitch, 2013) based on available data collected from patients 
discontinuing from study treatment but continuing in the study. 
Key secondary endpoint  
With 150 patients enrolled  and at least 140 patients having available Week 52 data after 
completing 48 weeks of treatment, 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 at Week 52 are based on available Week 52 data from the subset of patients 
who complete the 48-week treatment course 


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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 analysis of efficacy will use an 
unstructured covariance structure, which is expected to have approximately the same power as 
the analysis with compound symmetry used for study planning.  The method 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 


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with an unstructured covariance structure.  The estimation method for the model will be 
restricted maximum likelihood (REML).  
For analysis of the Phase 3 primary endpoint at Week 48, missing data in the ITT population will 
be imputed using Jump to Reference (J2R) multiple imputation (Ratitch, 2013) based on 
available data collected from patients discontinuing from study treatment but continuing in the 
study.  Appropriate sensitivity analyses will be performed.  The 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 key 
secondary endpoint will be based on available Week 52 data from the subset of patients who 
complete the 48-week treatment course.   


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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(R1): 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(R1) 
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, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
 Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
are accurate and current; 


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14.5. 
•
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.
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 (and assent form if necessary) 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(R1) [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, (or assent form if necessary), in compliance with 
Title 21 of US CFR Part 50, will be obtained from each patient before the patient enters the 
study.  For sites outside of the United States, the signed consent will be obtained in accord with 
local regulations, ICH E6 (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 (or assent as required) to participate in the study by signing the 
informed consent form(or assent form, if necessary). 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.  For pediatric patients, 
informed consent will be obtained from the parent(s) or legal guardian in accordance with 
regional laws or regulations.  In addition, dependent upon the patient’s age and IRBs, IEC, 
and/or local legal requirements, assent of the patient may also need to be obtained.  Pediatric 
patients may be asked to personally sign and date either a separately designed, written assent 
form, or the written informed consent. 
Informed consent and assent, if necessary, 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 (and assent, if necessary) 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 and/or 
assent form as necessary (signed copy to be provided per applicable law) to the patient and/or 
legal guardian.  The original form will be maintained in the patient’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/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 


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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 
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. 
REFERENCES 
Aminzadeh MA, Reisman SA, Vaziri ND, et al. The synthetic triterpenoid RTA dh404 (CDDO-
dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney 
disease.  Redox Biol 2013;1:527-31. 
de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 
chronic kidney disease.  N Engl J Med 2013;369:2492-503. 
Ding Y, Stidham RD, Bumeister R, et al. The synthetic triterpenoid, RTA 405, increases the 
glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial 
cells.  Kidney Int 2013;83:845-54. 
Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci USA 2005;102:4584-9. 
Ferguson DA, Wigley WC, Heiss E. Bardoxolone methyl (BARD) improves markers of 
endothelial function in cultured cells.  Poster American Society of Nephrology (ASN) 2010. 
Gross O, Licht C, Anders HJ, et al. Early angiotensin converting enzyme inhibition in Alport 
syndrome delays renal failure and improves life expectancy.  Kidney Int 2012;81:494-501. 
Gross O, Perin L, Deltas C. Alport syndrome from bench to bedside: the potential of current 
treatment beyond RAAS-blockade and the horizon of future therapies. Nephrol Dial Transplant 
2014; Suppl 4:iv124-30. 
Jedlicka J, Soleiman A, Draganovici D, et al. Interstitial inflammation in Alport syndrome.  
Human Pathology 2010;41:582-93. 
Jiang T, Tian F, Zheng H, et al. Nrf2 suppresses lupus nephritis through inhibition of oxidative 
injury and the NF-kB-mediated inflammatory response.  Kidney Int 2014;85:333-43. 
Kashtan CE, Ding J, Gregory M, et al. Clinical practice guidelines for the treatment of Alport 
syndrome: a statement of the Alport Syndrome Research Collaborative.  
Ped Nephrol 2013;28:5-11. 
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 
Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney 
Disease. Kidney Int Suppl  2012;2:337–414. 
Krügel J, Rubel D, Gross O: Alport Syndrome – Recent insights in basic and clinical research. 
Nature Reviews Nephrology  2013;9:170-8. 
Lee D-F, Kuo H-P, Liu M, et al. KEAP1 E3 ligase-mediated downregulation of NF-kB signaling 
by targeting IKKß.  Molecular Cell 2009;36:131-40. 
Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmune inflammation, enhanced 
lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the 
antioxidant-activated transcription factor Nrf2.  Am J Pathol 2006;168:1960-74. 
Osburn WO & Kensler TW. Nrf2 signaling: An adaptive response pathway for protection against 
environmental toxic insults.  Mutat Res 2008;669:31-9. 


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Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with 
type 2 diabetes.  N Engl J Med 2011;365:327-36. 
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models.  Pharm Stat 2013;12:337-47. 
Rheault M, Gross O, Appel G, et al. Change in glomerular filtration rate and renal biomarkers in 
patients with chronic kidney disease due to Alport syndrome: interim results from the ATHENA 
study, a prospectively designed natural history study.  Nephrol Dial Transplant 2016;31:i126. 
Rojas-Rivera J, Ortiz A, Egido J. Antioxidants in kidney diseases: The impact of bardoxolone 
methyl.  Int J Nephrol 2012;2012:1-11. 
Saha P, Reddy V, Konopleva M, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-
oic-acid methyl ester has potent antidiabetic effects in diet-induced diabetic mice and 
Lepr(db/db) mice.  J Biol Chem 2010;285:40581-92. 
Savige J, Gregory M, Gross O, et al. Expert Guidelines for the management of Alport syndrome 
and TBMN. J Am Soc Nephrol 2013;24:364-75. 
Tanaka Y, Aleksunes LM, Goedken MJ, et al. Coordinated induction of Nrf2 target genes 
protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity.  Toxicol Appl Pharmacol 
2008;231:364-73. 
Wu QQ, Wang Y, Senitko M, et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and 
increases expression of protective genes Nrf2, PPARgamma, and HO-1.  Am J Physiol Renal 
Physiol 2011;300:F1180-F1192. 
Yoh K, Itoh K, Enomoto A, et al. Nrf2-deficient female mice develop lupus-like autoimmune 
nephritis.  Kidney Int 2001;60:1343-53. 
Zoja C, Corna D, Locatelli M, et al. Targeting Keap1-Nrf2 Pathway Ameliorates Renal 
Inflammation and Fibrosis in Mice with Protein-Overload Proteinuria.  Poster American Society 
of Nephrology Meeting 2010. 

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1  
 
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 
ADDENDUM 1 DATED 21 APRIL 2020  
TO  
PROTOCOL VERSION 4.0 – 23 MAY 2019 
FRANCE, SPAIN, UNITED KINGDOM 
 
 
 
 
 
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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3  
INVESTIGATOR’S AGREEMENT 
I have received and read the addendum to the protocol v4 dated 23 May aimed at managing the 
study during the COVID-19 emergency and agree to conduct the study according the mitigation 
measures put in place. I agree to maintain the confidentiality of all information received or 
developed in connection with this addendum.  
Printed Name of Investigator 
Signature of Investigator 
Date 




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3.
JUSTIFICATION FOR THE ADDENDUM
Since the OMS declared the COVID-19 pandemic, various challenges exist which result in 
restrictions of visits to healthcare facilities, increased demands on the health services and 
changes to trial staff availability and resources. Participants may also be required to self-isolate, 
which introduces difficulties for Investigators to maintain medical oversight. These challenges 
could have an impact on the conduct of trials and data integrity, such as the completion of trial 
assessments, completion of trial visits, continued patient safety oversight and the provision of 
Investigational Medicinal Products (IMPs). 
As a sponsor, Reata Pharmaceuticals is committed to ensuring the safety of trial participants, 
maintaining compliance with good clinical practice (GCP), and minimizing risks to trial 
integrity. 
To face this evolving situation, Reata Pharmaceuticals has put in place some pragmatic actions to 
address the challenges of conducting research, and in ensuring the rights, safety and wellbeing of 
participants. 
This addendum outlines Reata Pharmaceuticals’ strategies to be implemented during the 
COVID-19 pandemic, to maintain ongoing safety reporting, access to study drug, continuity of 
patient care, and oversight of clinical site performance and quality. 
This document is being presented in an effort to make available information regarding the 
mitigation strategies that have been implemented for the CARDINAL study as a result of 
COVID-19.  Of course, since the nature and scope of this outbreak is rapidly evolving, Reata 
continues to monitor the situation and adjust its response as appropriate. 
The main activities this addendum addresses are: 
•
ongoing safety monitoring of the trial participants
•
continuity of IMP supply for patients
•
preservation of trial integrity through the collection of critical data












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5.
CHANGES IN OTHER STUDY-RELATED DOCUMENTS
5.1. 
Informed Consent 
An ICF letter has been created and provided to the EC for approval in participating countries. 
Approval of the revised consent form will allow sites to obtain verbal permission from the study 
patient to share their contact information with the home health services company and conduct of 
the study visit.  After verbal agreement is obtained, written permission can be obtained at the 
next on-site study visit. 


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6.
APPENDICES
List of memos provided to the study sites: 
1. Initial COVID-19 Guidance dated 10 March 2020
2. IP shipping instructions dated 17 March 2020
3. Lab Kit Shipping Instructions dated 19 March 2020

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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 2.0 – 23 MAY 2018 
EUROPEAN UNION 
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 


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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: June 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: 
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. 
Secondary: 
 
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. 
 
To assess the change from baseline in eGFR in bardoxolone methyl-treated patients relative to 


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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 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. 
 
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 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 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. 
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 
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 33% 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.  Adult patients (≥ 18 years of age) receiving bardoxolone 
methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at 
Week 4, and then to 30 mg at Week 6 (only if baseline ACR >300 mg/g) unless contraindicated 
clinically and approved by the medical monitor.  Patients under the age of 18 receiving bardoxolone 
methyl will start dosing at 5 mg every other day during the first week and begin once-daily dosing with 
5 mg during the second week of the study, and then continue with once-daily dosing following the 
same aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, and 6.  Dose de-
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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 primary efficacy endpoint will be analyzed after all 
patients in the Phase 3 cohort have completed their Week 52 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 12 ≤ age ≤ 60 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; 
5. Receiving an angiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin II receptor 
blocker (ARB) at 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 taking an ACE inhibitor and/or ARB because of a medical 
contraindication may be eligible if they have discontinued treatment 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; 


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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 (and assent form if 
necessary) indicating that the patient (or a legally acceptable representative) has been informed 
of all pertinent aspects of the study prior to initiation of any protocol-mandated procedures. 
Major exclusion criteria: 
1. 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; 
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; 


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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  
 
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.  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 
 
Missing data for the Week 48 analysis will be imputed using Jump to Reference (J2R) multiple 
imputation (Ratitch, 2013) based on available data collected from patients discontinuing from 
study treatment but continuing in the study. 
 


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Key secondary endpoint 
With 150 patients enrolled and at least 140 patients having available Week 52 data after completing 
48 weeks of treatment, 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 at Week 52 are based on available Week 52 data from the subset of patients who 
complete the 48-week treatment course. 
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 analysis of efficacy will use an unstructured 
covariance structure, which is expected to have approximately the same power as the analysis with 
compound symmetry used for study planning.  The method for maintaining strict control of the Type I 
error will be described in the statistical analysis plan. 
 
Schema for Study of Bardoxolone Methyl in Patients with Alport Syndrome 
Screening
Dose-Titration Period
W2
W1
W8
W12
ScrA
D1
D3
T
D10
T
W3
T
W4
Maintenance
W24
Placebo*
D31
T
W5
T
W6
W7
T
BARD (5 mg)*
BARD (20 mg)
W/D
 
 
BARD (10 mg)
Cohort 2 primary efficacy analysis
O eGFR determination
T Telephone Contact
 
 
ScrB
Maintenance
BARD (5 mg)*
BARD (20 mg)
BARD (10 mg)
BARD (30 mg)
 
 
Baseline ACR ≤ 300 mg/g
Baseline ACR > 300 mg/g
Cohort 1 primary efficacy analysis
F/U
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
R
Phase 3 Cohort
1 1 Randomization
  


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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.............................17 
5.
INTRODUCTION ......................................................................................................20 
5.1. 
Clinical Experience with Bardoxolone Methyl ..........................................................22 
5.1.1. 
Efficacy .......................................................................................................................22 
5.1.2. 
Safety and Tolerability ...............................................................................................25 
5.1.2.1. 
Fluid Overload ............................................................................................................25 
5.1.2.2. 
Transaminase and Gamma-glutamyl Transpeptidase (GGT) Elevations ...................25 
5.1.2.3. 
Muscle Spasms ...........................................................................................................26 
5.1.2.4. 
Weight Loss ................................................................................................................26 
5.1.2.5. 
Hypomagnesaemia ......................................................................................................27 
5.1.2.6. 
Increases in Urinary Protein .......................................................................................27 
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 ........................................................................................................................29 
6.1.2.1. 
Primary Objective .......................................................................................................29 
6.1.2.2. 
Key Secondary Objective ...........................................................................................29 
6.1.2.3. 
Secondary Objective ...................................................................................................29 
6.2. 
Endpoints ....................................................................................................................30 
6.2.1. 
Phase 2 ........................................................................................................................30 
6.2.1.1. 
Primary Efficacy Endpoint .........................................................................................30 
6.2.2. 
Phase 3 ........................................................................................................................30 
6.2.2.1. 
Primary Efficacy Endpoint .........................................................................................30 


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6.2.2.2. 
Key Secondary Efficacy Endpoint ..............................................................................30 
6.2.2.3. 
Secondary Efficacy Endpoints ....................................................................................30 
6.2.2.4. 
Exploratory Efficacy Endpoints .................................................................................30 
6.2.3. 
Safety Endpoints .........................................................................................................31 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Overall Study Design ..................................................................................................32 
7.2. 
Number of Patients .....................................................................................................33 
7.3. 
Treatment Assignment and Rationale .........................................................................33 
7.3.1. 
Dose Escalation ..........................................................................................................33 
7.3.2. 
Dose De-Escalation and Re-Escalation ......................................................................33 
7.4. 
Criteria for Study Termination ...................................................................................34 
7.5. 
Schedule of Assessments ............................................................................................34 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................38 
8.1. 
Patient Inclusion Criteria ............................................................................................38 
8.2. 
Patient Exclusion Criteria ...........................................................................................38 
8.3. 
Screening Period .........................................................................................................40 
8.4. 
Patient Re-Screening ..................................................................................................40 
8.5. 
Patient Discontinuation and Termination ...................................................................40 
8.5.1. 
Patient Discontinuation Criteria .................................................................................40 
8.5.2. 
Patient Termination Criteria .......................................................................................41 
9. 
TREATMENT OF PATIENTS ..................................................................................42 
9.1. 
Select Management Guidelines ..................................................................................42 
9.1.1. 
Management of Fluid Status .......................................................................................42 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................43 
9.1.3. 
Management of Muscle Spasms .................................................................................43 
9.1.4. 
Weight Loss ................................................................................................................43 
9.1.5. 
Hypomagnesaemia ......................................................................................................43 
9.1.6. 
Management of Urinary Protein .................................................................................43 
9.1.7. 
Management of Blood Pressure ..................................................................................44 
9.1.8. 
Nausea .........................................................................................................................44 
9.2. 
Description of Study Drug ..........................................................................................44 
9.3. 
Concomitant Medications ...........................................................................................45 
9.3.1. 
Excluded Medications ................................................................................................45 


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9.3.2. 
Permitted Medications ................................................................................................45 
9.4. 
Treatment Compliance ................................................................................................46 
9.5. 
Randomization ............................................................................................................46 
9.6. 
Blinding ......................................................................................................................46 
9.6.1. 
Patient Unblinding ......................................................................................................46 
9.6.2. 
Unblinding for Regulatory Submission ......................................................................47 
9.6.3. 
Data Monitoring Committee .......................................................................................47 
9.7. 
Unscheduled Visits .....................................................................................................47 
9.8. 
Pregnancy ...................................................................................................................48 
9.8.1. 
Women of Childbearing Potential ..............................................................................48 
9.8.2. 
Methods of Birth Control............................................................................................48 
9.8.3. 
Suspected Pregnancy ..................................................................................................49 
9.9. 
Serious Toxicities .......................................................................................................49 
9.10. 
Study Procedures ........................................................................................................49 
9.10.1. 
Informed Consent .......................................................................................................50 
9.10.2. 
Inclusion/Exclusion ....................................................................................................50 
9.10.3. 
Demographics and Baseline Disease Characteristics .................................................50 
9.10.4. 
Prior and Current Concomitant Medications ..............................................................50 
9.10.5. 
Medical History ..........................................................................................................50 
9.10.6. 
Height .........................................................................................................................50 
9.10.7. 
Weight and Body Mass Index (BMI) .........................................................................50 
9.10.8. 
Electrocardiograms (ECG) .........................................................................................51 
9.10.9. 
Echocardiogram ..........................................................................................................51 
9.10.10. 
Vital Sign Measurements ............................................................................................51 
9.10.11. 
Physical Examination .................................................................................................51 
9.10.12. 
Pregnancy Test ............................................................................................................51 
9.10.13. 
Study Drug Administration.........................................................................................51 
9.10.14. 
Study Drug Dispensation and Collection ...................................................................52 
9.10.15. 
Telephone Contact ......................................................................................................52 
9.10.16. 
Adverse Event Collection ...........................................................................................52 
9.10.17. 
Genetic Testing ...........................................................................................................52 
9.10.18. 
Clinical Chemistry ......................................................................................................52 
9.10.18.1. eGFR ...........................................................................................................................53 


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9.10.19. 
N-Terminal Pro-Brain Natriuretic Peptide (NT-Pro BNP) and Brain 
Natriuretic Peptide (BNP) ...........................................................................................53 
9.10.20. 
Insulin-Like Growth Factor-1 (IGF-1) and Serum Ketones .......................................53 
9.10.21. 
Hemoglobin A1c .........................................................................................................54 
9.10.22. 
Hematology .................................................................................................................54 
9.10.23. 
Urinalysis and Microscopy .........................................................................................54 
9.10.24. 
Urine Collection for Albumin to Creatinine Ratio (ACR) .........................................54 
9.10.25. 
Visual Acuity ..............................................................................................................54 
9.10.26. 
Audiology Assessment ...............................................................................................54 
9.10.27. 
Patient Global Impression of Change .........................................................................54 
9.10.28. 
Clinical Global Impression-Improvement ..................................................................55 
9.10.29. 
Virus Serology ............................................................................................................55 
9.10.30. 
Pharmacokinetic (PK) Blood Samples .......................................................................55 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................56 
10.1. 
Study Drug ..................................................................................................................56 
10.2. 
Study Drug Packaging and Labeling ..........................................................................56 
10.3. 
Study Drug Storage .....................................................................................................56 
10.4. 
Study Drug Administration.........................................................................................56 
10.5. 
Study Drug Accountability .........................................................................................57 
10.6. 
Study Drug Handling and Disposal ............................................................................57 
11. 
SAFETY ASSESSMENTS ........................................................................................58 
11.1. 
Safety Parameters .......................................................................................................58 
11.2. 
Adverse and Serious Adverse Events .........................................................................58 
11.2.1. 
Definition of Adverse Events .....................................................................................58 
11.2.1.1. 
Adverse Event .............................................................................................................58 
11.2.1.2. 
Serious Adverse Event ................................................................................................58 
11.3. 
Eliciting Adverse Event Information ..........................................................................59 
11.4. 
Assessment of Causality .............................................................................................59 
11.5. 
Assessment of Severity ...............................................................................................60 
11.6. 
Recording Adverse Events .........................................................................................60 
11.7. 
Reporting Serious Adverse Events .............................................................................61 
12. 
STATISTICS ..............................................................................................................63 
12.1. 
Sample Size ................................................................................................................63 


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12.2. 
Study Variables ...........................................................................................................64 
12.2.1. 
Pharmacokinetic Variables .........................................................................................64 
12.2.2. 
Efficacy Variables ......................................................................................................64 
12.2.3. 
Safety Variables ..........................................................................................................64 
12.3. 
Statistical Analyses .....................................................................................................64 
12.3.1. 
Primary Analysis of Efficacy ......................................................................................64 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................66 
13.1. 
Study Monitoring ........................................................................................................66 
13.2. 
Audits and Inspections ................................................................................................66 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................67 
14.1. 
Quality Assurance .......................................................................................................67 
14.2. 
Financial Disclosure ...................................................................................................67 
14.3. 
Sponsor Obligations....................................................................................................67 
14.4. 
Investigator Documentation ........................................................................................67 
14.5. 
Clinical Study Insurance .............................................................................................68 
14.6. 
Use of Information ......................................................................................................68 
15. 
ETHICS ......................................................................................................................69 
15.1. 
Institutional Review Board (IRB) or Ethics Committee (EC) Review .......................69 
15.2. 
Ethical Conduct of the Study ......................................................................................69 
15.3. 
Written Informed Consent ..........................................................................................69 
15.4. 
Confidentiality ............................................................................................................70 
15.5. 
Modification of the Protocol .......................................................................................70 
15.6. 
Protocol Deviations ....................................................................................................71 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................72 
16.1. 
Retention of Records ..................................................................................................72 
16.2. 
Case Report Forms .....................................................................................................72 
17. 
PUBLICATION POLICY ..........................................................................................73 
18. 
REFERENCES ...........................................................................................................74 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................17 
Table 3: 
Cross-Study Comparison of Increases in eGFR, Inulin Clearance, and 
Creatinine Clearance with Bardoxolone Methyl Treatment .......................................24 
Table 4: 
Schedule of Assessments ............................................................................................35 
Table 5: 
Bardoxolone Methyl Drug Product Information ........................................................44 
Table 6: 
Placebo Information ....................................................................................................45 
Table 7: 
SAE Reporting Contact Information ..........................................................................61 
 


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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 
ESRD 
End stage renal 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 
J2R 
Jump to reference 
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 


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Abbreviation or Specialist Term 
Explanation 
PK 
Pharmacokinetic 
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  and  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-1 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, and 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 renal disease (ESRD).  Thus, the collective data support that bardoxolone methyl may 


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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 ESRD. 
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 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 renal disease (ESRD; 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 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. 
5.1.3. 
Clinical Experience in Pediatric Patients 
Approximately 1950 adult individuals have been exposed to bardoxolone methyl in prior clinical 
trials.  In the Phase 2 portion of the present 402-C-1603 trial, 2 pediatric patients were enrolled 
(both 14 years of age).  Data from the 12-week primary efficacy and safety data for the Phase 2 
portion of this trial suggest that efficacy and safety in pediatric Alport patients may be similar to 
that observed in adult Alport patients.  Specifically, for the 2 pediatric Alport patients, an 
increase in eGFR of 26.1 mL/min/1.73m2 was observed, compared to 13.4 mL/min/1.73m2 in the 
total 30-patient cohort.  From a safety perspective, no SAEs were reported in the pediatric 
patients and only 1 of the pediatric patients reported any AEs during the first 12 weeks of the 
study.  The reported AEs for this patient included headache, fatigue, chest infection, sore throat, 
conjunctivitis, dry cough, and bronchial asthma, all of which were mild and considered by the 
investigator to be unrelated to study drug.  Systemic exposure to bardoxolone methyl, based on 


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Cmax and AUC, for the 2 pediatric Alport patients was near the median exposure observed in 
adult patients in the Phase 2 portion of the study.  Because the pharmacokinetics, safety, and 
efficacy of bardoxolone methyl have not been extensively characterized in pediatric patients, for 
the purpose of this study a dose adjustment is utilized for pediatric patients, as described in 
Section 7.3.  Based on available nonclinical and clinical data with bardoxolone methyl, there 
are no known safety risks that are specific to the pediatric population, and therefore patient 
discontinuation criteria for pediatric patients in this trial are the same as for adult patients, as 
described in Section 8.5. 


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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  
6.1.2.1. 
Primary Objective 
 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. 
Secondary Objective 
 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. 
 To assess the change from baseline in eGFR in bardoxolone methyl-treated patients at 
Week 104 following a 4-week drug treatment withdrawal period. 
 


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6.2. 
Endpoints 
6.2.1. 
Phase 2 
6.2.1.1. 
Primary Efficacy Endpoint 
 Change from baseline in eGFR at Week 12. 
6.2.2. 
Phase 3 
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. 
Secondary Efficacy Endpoints 
 The change from baseline in eGFR in bardoxolone methyl-treated patients relative to 
placebo at Week 100. 
 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. 
6.2.2.4. 
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. 
 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 48 weeks of treatment. 
 The Clinical Global Impression-Improvement (CGI-I) scores in bardoxolone methyl-
treated patients relative to placebo after 48 weeks of treatment. 


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 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. 
6.2.3. 
Safety Endpoints 
 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 33% 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.  Adult patients 
(≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 5 mg and 
will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if 
baseline ACR >300 mg/g) unless contraindicated clinically and approved by the medical 
monitor. Patients under the age of 18 receiving bardoxolone methyl will start dosing at 5 mg 
every other day during the first week and begin once-daily dosing with 5 mg during the second 
week of the study, and then continue with once-daily dosing following the same aforementioned 
dose-titration scheme based on baseline ACR at Weeks 2, 4, and 6.  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 primary efficacy endpoint will 
be analyzed after all patients in the Phase 3 cohort have completed their Week 52 visit.   


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All enrolled patients are expected to remain on their blinded treatment assignment through 
Week 100, and to complete all scheduled assessments through Week 104. 
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.  Adult patients (>18 years of age) 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.  Patients 
under the age of 18 will receive 5 mg every other day during the first week and begin once-daily 
dosing with 5 mg during the second week of the study, and then continue with once-daily dosing 
following the same aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, 
and 6.  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, 


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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. 
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±3 
 
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±3 
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 12 ≤ age ≤ 60 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;
5. Receiving an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin II
receptor blocker (ARB) at 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 taking an ACE inhibitor and/or ARB because of a
medical contraindication may be eligible if they have discontinued treatment 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 (and assent form
if necessary) indicating that the patient (or a legally acceptable representative) has been
informed of all pertinent aspects of the study prior to initiation of any patient-mandated
procedures.
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;


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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;
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;


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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 must 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 the study 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 or withdrawing a patient from the study.  The reason for a patient’s 
discontinuation from study drug or study termination will be recorded in the electronic case 
report form (eCRF).  
8.5.1. 
Patient Discontinuation Criteria 
Discontinuation refers to a patient’s stopping administration of study drug.  Reasons for study 
drug discontinuation may include the following: 
 Occurrence of an AE or change in medical status that leads the investigator to be 
concerned about the patient’s welfare; 
 Administrative reasons (e.g., inability to continue); 
 Sponsor termination of the study; 
 Voluntary withdrawal; 
 Females who become pregnant during the study; 
 Investigator unblinding. 
Patients must discontinue study drug if any of the following occur. 
 ALT or AST > 8X ULN; 
 ALT or AST > 5X ULN for more than two weeks; 
 ALT or AST > 3X ULN and (total bilirubin > 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%). 


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Patients who are discontinued from study drug should still continue in the study, complete all 
study visits, and undergo all scheduled study assessments, if possible.   
8.5.2. 
Patient Termination Criteria 
Termination refers to a patient’s stopping study drug and all study assessments and visits.  
Reasons for study termination include the following: 
 Loss to follow-up 
 Death 
 Withdrawal of consent 
Every reasonable effort should be made to contact patients who do not return for a scheduled 
visit.  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 that 
experience a BNP > 100 pg/mL that represents a doubling (or more) of BNP levels from Day 1 
should be instructed to stop taking their study medication immediately and return to the clinic 
within 1 week (± 3 days) for an unscheduled physical examination and laboratory assessment by 
the investigator. 
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 will be instructed to stop taking their study 
medication immediately and return to the clinic for an unscheduled physical examination and 
laboratory assessment by the investigator.   
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 
symptoms of acute volume overload, investigators will be expected to report if changes to a 
patient’s diuretic regimen have been required to manage edema. 


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9.1.2. 
Management of Elevated 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 during an unscheduled 
visit 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. 
Discontinue study drug administration permanently 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 
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.  


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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 should 
receive the maximally tolerated labeled daily dose (MTLDD) of an ACE inhibitor and/or ARB, 
which is 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.   
9.2. 
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-TNF 
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 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. 
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 discontinue 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; 
 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, 
diaphragm [always use with spermicidal jelly/cream]).  Double-barrier method is not 
allowed for patients at participating sites in Germany; 


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 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. 
For pediatric patients, informed consent will be obtained from the parent(s) or legal guardian in 
accordance with regional laws or regulations.  In addition, dependent upon the patient’s age and 
IRBs, IEC, and/or local requirements, assent of the patient may also need to be obtained.  
Pediatric patients may be asked to personally sign and date either a separately designed, written 
assent form, or the written informed consent. 
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 


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within the Informed Consent Form to help ensure consistent weight collection throughout the 
study.  
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 under the age of 18 should self-administer one capsule from each bottle included in the 
study drug kit orally every other day for the first week after randomization, and begin dosing 
once a day on Day 7 through the end of the study, as indicated in Table 4.  Adult patients (≥ 18 
years of age) 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 


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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. 
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 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 must be brought into the clinic and 
evaluated by the investigator as soon as possible, 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-


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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. 
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 equation used to calculate eGFR for each patient throughout the study will be based on the 
patient’s age on the date of consent.  For patients consented at age 18 years and older, the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation will be used to 
calculate eGFR for each patient throughout the study: 
eGFR (mL/min/1.73 m2) = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age ×  
1.018 [if female] × 1.159 [if black] 
For patients consented at age 12 to 17, the Bedside Schwartz equation will be used: 
eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Scr  
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scr/κ or 1 and max indicates the 
maximum of Scr/κ or 1. 
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.   


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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, 
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.   


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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. 
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 30 days (+/- 3 days) following administration of the final dose of study medication, 
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 AEs which are commonly observed in this patient population will not be 
reported to regulatory authorities as individual expedited reports, except in unusual 
circumstances. 
 Hypotension 
 Hyperkalemia 
 Fatigue 
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.  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 
 Missing data for the Week 48 analysis will be imputed using Jump to Reference (J2R) 
multiple imputation (Ratitch, 2013) based on available data collected from patients 
discontinuing from study treatment but continuing in the study. 
Key secondary endpoint  
With 150 patients enrolled  and at least 140 patients having available Week 52 data after 
completing 48 weeks of treatment, 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 at Week 52 are based on available Week 52 data from the subset of patients 
who complete the 48-week treatment course 


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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 analysis of efficacy will use an 
unstructured covariance structure, which is expected to have approximately the same power as 
the analysis with compound symmetry used for study planning.  The method 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 


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with an unstructured covariance structure.  The estimation method for the model will be 
restricted maximum likelihood (REML).  
For analysis of the Phase 3 primary endpoint at Week 48, missing data in the ITT population will 
be imputed using Jump to Reference (J2R) multiple imputation (Ratitch, 2013) based on 
available data collected from patients discontinuing from study treatment but continuing in the 
study.  Appropriate sensitivity analyses will be performed.  The 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 key 
secondary endpoint will be based on available Week 52 data from the subset of patients who 
complete the 48-week treatment course.   


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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(R1): 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(R1) 
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, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
 Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
are accurate and current; 


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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 (and assent form if necessary) 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(R1) [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, (or assent form if necessary), in compliance with 
Title 21 of US CFR Part 50, will be obtained from each patient before the patient enters the 
study.  For sites outside of the United States, the signed consent will be obtained in accord with 
local regulations, ICH E6 (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 (or assent as required) to participate in the study by signing the 
informed consent form(or assent form, if necessary). 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.  For pediatric patients, 
informed consent will be obtained from the parent(s) or legal guardian in accordance with 
regional laws or regulations.  In addition, dependent upon the patient’s age and IRBs, IEC, 
and/or local legal requirements, assent of the patient may also need to be obtained.  Pediatric 
patients may be asked to personally sign and date either a separately designed, written assent 
form, or the written informed consent. 
Informed consent and assent, if necessary, 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 (and assent, if necessary) 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 and/or 
assent form as necessary (signed copy to be provided per applicable law) to the patient and/or 
legal guardian.  The original form will be maintained in the patient’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/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 


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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 
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. 
REFERENCES 
Aminzadeh MA, Reisman SA, Vaziri ND, et al. The synthetic triterpenoid RTA dh404 (CDDO-
dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney 
disease.  Redox Biol 2013;1:527-31. 
de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 
chronic kidney disease.  N Engl J Med 2013;369:2492-503. 
Ding Y, Stidham RD, Bumeister R, et al. The synthetic triterpenoid, RTA 405, increases the 
glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial 
cells.  Kidney Int 2013;83:845-54. 
Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci USA 2005;102:4584-9. 
Ferguson DA, Wigley WC, Heiss E. Bardoxolone methyl (BARD) improves markers of 
endothelial function in cultured cells.  Poster American Society of Nephrology (ASN) 2010. 
Gross O, Licht C, Anders HJ, et al. Early angiotensin converting enzyme inhibition in Alport 
syndrome delays renal failure and improves life expectancy.  Kidney Int 2012;81:494-501. 
Gross O, Perin L, Deltas C. Alport syndrome from bench to bedside: the potential of current 
treatment beyond RAAS-blockade and the horizon of future therapies. Nephrol Dial Transplant 
2014; Suppl 4:iv124-30. 
Jedlicka J, Soleiman A, Draganovici D, et al. Interstitial inflammation in Alport syndrome.  
Human Pathology 2010;41:582-93. 
Jiang T, Tian F, Zheng H, et al. Nrf2 suppresses lupus nephritis through inhibition of oxidative 
injury and the NF-kB-mediated inflammatory response.  Kidney Int 2014;85:333-43. 
Kashtan CE, Ding J, Gregory M, et al. Clinical practice guidelines for the treatment of Alport 
syndrome: a statement of the Alport Syndrome Research Collaborative.  
Ped Nephrol 2013;28:5-11. 
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 
Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney 
Disease. Kidney Int Suppl  2012;2:337–414. 
Krügel J, Rubel D, Gross O: Alport Syndrome – Recent insights in basic and clinical research. 
Nature Reviews Nephrology  2013;9:170-8. 
Lee D-F, Kuo H-P, Liu M, et al. KEAP1 E3 ligase-mediated downregulation of NF-kB signaling 
by targeting IKKß.  Molecular Cell 2009;36:131-40. 
Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmune inflammation, enhanced 
lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the 
antioxidant-activated transcription factor Nrf2.  Am J Pathol 2006;168:1960-74. 
Osburn WO & Kensler TW. Nrf2 signaling: An adaptive response pathway for protection against 
environmental toxic insults.  Mutat Res 2008;669:31-9. 


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Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with 
type 2 diabetes.  N Engl J Med 2011;365:327-36. 
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models.  Pharm Stat 2013;12:337-47. 
Rheault M, Gross O, Appel G, et al. Change in glomerular filtration rate and renal biomarkers in 
patients with chronic kidney disease due to Alport syndrome: interim results from the ATHENA 
study, a prospectively designed natural history study.  Nephrol Dial Transplant 2016;31:i126. 
Rojas-Rivera J, Ortiz A, Egido J. Antioxidants in kidney diseases: The impact of bardoxolone 
methyl.  Int J Nephrol 2012;2012:1-11. 
Saha P, Reddy V, Konopleva M, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-
oic-acid methyl ester has potent antidiabetic effects in diet-induced diabetic mice and 
Lepr(db/db) mice.  J Biol Chem 2010;285:40581-92. 
Savige J, Gregory M, Gross O, et al. Expert Guidelines for the management of Alport syndrome 
and TBMN. J Am Soc Nephrol 2013;24:364-75. 
Tanaka Y, Aleksunes LM, Goedken MJ, et al. Coordinated induction of Nrf2 target genes 
protects against iron nitrilotriacetate (FeNTA)-induced nephrotoxicity.  Toxicol Appl Pharmacol 
2008;231:364-73. 
Wu QQ, Wang Y, Senitko M, et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and 
increases expression of protective genes Nrf2, PPARgamma, and HO-1.  Am J Physiol Renal 
Physiol 2011;300:F1180-F1192. 
Yoh K, Itoh K, Enomoto A, et al. Nrf2-deficient female mice develop lupus-like autoimmune 
nephritis.  Kidney Int 2001;60:1343-53. 
Zoja C, Corna D, Locatelli M, et al. Targeting Keap1-Nrf2 Pathway Ameliorates Renal 
Inflammation and Fibrosis in Mice with Protein-Overload Proteinuria.  Poster American Society 
of Nephrology Meeting 2010. 

Prot_004.pdf: 
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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 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
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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 
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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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nephritis.  Kidney Int 2001;60:1343-53. 
Zoja C, Corna D, Locatelli M, et al. Targeting Keap1-Nrf2 Pathway Ameliorates Renal 
Inflammation and Fibrosis in Mice with Protein-Overload Proteinuria.  Poster American Society 
of Nephrology Meeting 2010. 

Prot_001.pdf: 
Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
1 
 
 
 
 
 
 
 
 
 
 
 
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 
 
 
US/AUS ADDENDUM 1.0 
DATED 05 JUNE 2020 
TO 
PROTOCOL VERSION 4.0 – 22 APR 2019 
 
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. 
 




Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
3 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the addendum to the protocol v4 dated 22 Apr 2019 aimed at managing 
the study during the COVID-19 emergency and agree to conduct the study according the 
mitigation measures put in place. I agree to maintain the confidentiality of all information 
received or developed in connection with this addendum. 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
Date 
 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
4 
2.
TABLE OF CONTENTS
1.
TITLE PAGE ................................................................................................................1 
2.
TABLE OF CONTENTS .............................................................................................4 
3.
JUSTIFICATION FOR THE ADDENDUM ...............................................................5 
4.
CHANGES TO THE CURRENT APPROVED PROTOCOL ....................................6 
5.
CHANGES IN OTHER STUDY-RELATED DOCUMENTS ..................................11 
5.1. 
Informed Consent .......................................................................................................11 
6.
APPENDICES ............................................................................................................12 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
5 
 
 
3. 
JUSTIFICATION FOR THE ADDENDUM 
Since the WHO declared the COVID-19 pandemic, various challenges exist which result in 
restrictions of visits to healthcare facilities, increased demands on the health services and 
changes to trial staff availability and resources. Study participants may also be required to 
self-isolate, which introduces difficulties for Investigators to maintain medical oversight.  
These challenges could have an impact on the conduct of trials and data integrity, such as the 
completion of trial assessments, completion of trial visits, continued patient safety oversight and 
the provision of Investigational Products (IPs). 
As a sponsor, Reata Pharmaceuticals is committed to ensuring the safety of trial participants, 
maintaining compliance with good clinical practice (GCP), and minimizing risks to trial 
integrity. 
To face this evolving situation, Reata Pharmaceuticals has put in place some pragmatic actions to 
address the challenges of conducting research, while ensuring the rights, safety and wellbeing of 
participants. 
This addendum outlines Reata Pharmaceuticals’ strategies to be implemented during the 
COVID-19 pandemic, to maintain ongoing safety reporting, access to study drug, continuity of 
patient care, and oversight of clinical site performance and quality. 
This document is being presented in an effort to make available information regarding the 
mitigation strategies that have been implemented for the CARDINAL study as a result of 
COVID-19.  Since the nature and scope of this outbreak is rapidly evolving, Reata continues to 
monitor the situation and adjust its response as appropriate. 
The main activities this addendum addresses are: 
• ongoing safety monitoring of the trial participants 
• continuity of IP supply for subjects 
• preservation of trial integrity through the collection of critical data 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
6 
 
 
4. 
CHANGES TO THE CURRENT APPROVED PROTOCOL 
THE FOLLOWING CHANGES ARE IMPLEMENTED DURING THE COVID-19 
PANDEMIC. AS THE IMPACTS OF COVID RESOLVE, THE CURRENTLY APPROVED 
VERSION OF THE PROTOCOL WILL BE FULLY REIMPLEMENTED FOR STUDY 
CONDUCT.  AS SUCH, THESE CHANGES ARE PRESENTED AS AN ADDENDUM TO BE 
FOLLOWED, AS NEEDED, AND DURING THIS GIVEN PERIOD ONLY. 
 
VERSION NUMBER 
VERSION DATE 
CURRENT APPROVED 
PROTOCOL: 
4.0 
22 Apr 2019 
CHANGES TO THE CURRENT APPROVED PROTOCOL 
1. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
7. INVESTIGATIONAL PLAN page 34 
OLD TEXT: 
No changes 
NEW TEXT: 
Added subparagraph 7.6. Home Health Provider Use 
Due to the COVID-19 outbreak and the resulting restrictive measures put 
in place by the different national and regional governments that, in many 
cases, resulted in travel restrictions, limited availability of site access and 
personnel, and local limitation on the movement of delegated individuals, 
the use of  home health services has been implemented to assist with the 
collection of study required visits and laboratory assessments while also 
guaranteeing the rights, safety and wellbeing of participants and of the trial 
sites’ staff. The use of a company specialized in home health services 
ensures the ongoing safety monitoring of trial participants and maintaining 
trial integrity through the collection of critical data, in accordance with 
FDA and local guidelines about the COVID-19 pandemic management.  
For each hired home health nurse/professional, the site will be provided 
with the following documentation: signed and dated CV, current Nursing 
Licensure, GCP training certificate, and protocol training certificate.  The 
home health nurse/professional will also be included in the Delegation of 
Activities log of the site. 
The tasks delegated to the home health nurse/professional at the patient’s 
home will be: collection of vital signs and weight measurements, 
collection of information about adverse events and concomitant 
medications, collection of laboratory samples (blood and urine), supply 
urine pregnancy test for self-reading, drug accountability, and diary 
collection. The laboratory samples are collected using the laboratory kit 
provided by the centralized laboratory, normally used for the study visit 
conduct, and are processed and shipped according to the laboratory manual 
of the study. All costs relevant to these additional services will be covered 
by Reata Pharmaceuticals. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the sponsor to ensure safety of subjects 
and trial’s integrity during the COVID outbreak. 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
7 
 
 
2. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
8.5 Patient Discontinuation and Termination page 42 
OLD TEXT: 
No changes 
NEW TEXT: 
Added sub-paragraph 8.5.3 SARS-COV-2 Testing and 
Investigational Product Use 
If a patient tests positive for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, the 
investigational product (IP) RTA-402 (bardoxolone methyl) must be 
temporarily discontinued until the patient no longer presents an active 
infection, as assessed by the Investigator and/or the patient’s 
physician(s).  The Sponsor must be notified immediately for 
additional guidance.  
When the investigator deems that the patient can safely return to the 
site for an in-person visit, the investigator should conduct an 
unscheduled visit and perform a full clinical assessment with labs: 
• 
Safety labs  
o Clinical chemistry (including eGFR) 
o BNP and NT-proBNP 
o Hematology 
o Urinalysis and microscopy / Urine collection for ACR 
o Urine pregnancy test for WOCBP  
• 
Vital signs  
• 
Weight  
• 
Adverse event assessment  
• 
Prior and concomitant medication assessment  
IP may be resumed if there are no changes in clinical status that 
would preclude restarting IP. A follow-up telephone call should be 
conducted 2 weeks after the unscheduled visit to collect adverse 
events and concomitant medications. Four weeks after the 
unscheduled visit, the patient should return to the clinic for repeat 
assessments as outlined in the Week 1 visit. The patient’s visit 
schedule, as outlined in the protocol, may resume thereafter. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the Sponsor to ensure safety of subjects 
and trial’s integrity during the COVID outbreak. 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
8 
 
 
3. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
9.10.12. Pregnancy Test page 55 
OLD TEXT: 
No changes 
NEW TEXT: 
Added new sub-paragraph 9.10.12.1 Self Reading Pregnancy Test  
Urinary pregnancy tests for self-reading will be provided by the home 
health nurse/professional coming to the patient’s home. Results will 
be documented and provided to the site investigators. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the Sponsor to ensure safety of subjects 
during the COVID outbreak. 
 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
9 
 
 
4. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
9.10.14. Study Drug Dispensation and Collection page 56 
OLD TEXT: 
No changes 
NEW TEXT: 
Added subparagraph 9.10.14.1 Study drug distribution during the 
COVID-19 pandemic 
Prior to the COVID-19 pandemic, trial participants were assigned and 
dispensed IP during study site visits. During the study site visits, trial 
participants are sent home with IP and instructed to self-administer 
the IP each day until their next onsite study visit, at which they would 
return any unused IP. As the trial participants have been responsible 
for IP storage within their homes, as well as self-administration of the 
IP throughout the study, they are properly acquainted with these 
facets of the study. For those trial participants who discontinue 
physical site visits during COVID-19, distribution of IP may be made 
directly to the trial participants’ homes by shipment from investigator, 
through the Hospital pharmacy. IP distributed in this manner will be 
shipped via traceable courier as an expedited shipment. Given the 
stability profile of bardoxolone methyl capsules under multiple 
temperatures and relative humidity conditions, short term temperature 
excursions above 30°C and as low as 15℃ during storage are 
acceptable. For IP shipments to trial participants’ homes, 
investigators will monitor the time from shipment to receipt of the IP 
by the trial participant. In the absence of temperature monitoring, and 
if shipping time exceeds 48 hours, the investigator will immediately 
instruct the patient not to use the IP until further guidance is provided. 
The investigator site will then contact Reata (the sponsor) to 
determine whether the shipment may be used or must be replaced. 
The investigator site will contact the patient as to the disposition of 
the IP. Investigators will remain in close contact with trial participants 
receiving IP at their home and, if necessary, will provide any 
instructions needed on the use of the IP. Accountability of the IP for 
these trial participants will be conducted by home health nurses 
during home visits. After accountability is complete, the home health 
nurse will secure the kits in a bag that will be returned to the site 
when the trial participant is able to return to the site for their next 
visit. The trial participant will be instructed not to take any additional 
IP from the kits that have been placed in the plastic bag. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the sponsor to ensure safety of subjects 
during the COVID outbreak. 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
10 
 
 
5. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
10.4 Study Drug Administration page 60 
OLD TEXT: 
No changes 
NEW TEXT: 
Added subparagraph 10.4.1. Intake of IP Beyond Week 100 During 
the COVID-19 Outbreak 
The Week 100 visit (Day 700 +/- 3 days) serves to collect the final 
“on treatment” lab values from patients. To minimize any days off 
drug prior to the Week 100 visit, and given the evolving situation of 
COVID-19, sites may extend dosing by 1 week beyond the protocol 
window for the Week 100 visit. The maximum extension in dosing is 
to study Day 710 (Day 707 +/- 3 days), unless otherwise approved by 
Reata and the IRB. The Week 104 visit must be adjusted accordingly 
to ensure the Week 104 labs are collected 4 weeks after completing 
the end of treatment (last dose). 
REASON FOR 
CHANGE: 
Mitigation measures taken by the sponsor to ensure safety of subjects. 
6. 
SECTION NO., 
SECTION 
TITLE, PAGE 
NO.(S): 
15.6. Protocol Deviations page 65 
OLD TEXT: 
No changes 
NEW TEXT: 
Added new subparagraph 15.6.1. Deviation during the COVID-19 
Outbreak 
Any data that cannot be assessed remotely will be noted as missing. 
All deviations due to the impacts of COVID-19 will be identified and 
documented accordingly by the site and the Sponsor. The failure to 
complete an in-clinic protocol visit will not be considered as a reason 
for study discontinuation and, beyond the necessary documentation 
(e.g., duly documented in patient’s note by the Investigator), will not 
be considered as a major deviation. Deviations will be reported, 
evaluated, and discussed according to the study plan and in the final 
study report. Sites will continue to document and report protocol 
deviations according to their usual procedure and institutional 
requirements. 
REASON FOR 
CHANGE: 
As allowed by FDA and local guidelines for management of clinical 
trials during the COVID-19 outbreak. 
 


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
11 
 
 
5. 
CHANGES IN OTHER STUDY-RELATED DOCUMENTS 
5.1. 
Informed Consent 
A home health service provider has been appointed by the Sponsor to support visit conduct and 
patient safety management during this period. To further ensure and maintain the protection of 
patients’ rights, the master ICF document will be revised to incorporate this mitigation strategy 
as an alternate option to support continuity in care and participation.  


Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
12 
 
 
6. 
APPENDICES 
List of memos provided to study sites: 
1. Initial COVID-19 Guidance dated 10 March 2020 
2. IP shipping instructions dated 17 March 2020 
3. Lab Kit Shipping Instructions dated 19 March 2020 
4. Guidance for Direct-to-Patient Shipping of RTA-402 Drug Product Capsules During the 
Coronavirus (COVID-19) Pandemic dated 25 March 2020 
5. COVID-19 Update Memo- Q&A dated 26 March 2020 
6. IP Kits Round Two dated 06 April 2020 
















 
 
March 25, 2020 
 
 
To:     Clinical Program Operations 
           Reata Pharmaceuticals, Inc. 
 
From: Chemistry, Manufacturing & Controls / Quality Assurance 
           Reata Pharmaceuticals, Inc. 
 
Via E-mail Transmission 
 
RE: Guidance for Direct-to-Patient Shipping of RTA 402 Drug Product Capsules during the 
Coronavirus (COVID-19) Pandemic  
 
 
As a result of the coronavirus (COVID-19), certain adjustments have been made to 
ensure study patients receive their investigational product, on time, and consistently. 
 
For clinical investigators, where patients are unable to travel outside of their home to the 
site, one adjustment being implemented is the shipping of investigational product directly 
to the patient, from the clinical investigator site. 
 
As background, RTA 402 drug product capsule kits (30ct, 1g desiccant, 60 mL bottle) 
have been assessed for stability following ICH guidelines for long term and accelerated 
conditions. The results support the current labeled storage conditions of controlled room 
temperature, which is defined as 20°C to 25°C (68°F to 77°F), with brief excursions 
allowed to 15°C to 30°C (59°F to 86°F).  
 
The stability results also provide supporting data to assess potential impact of short-term 
temperature excursions outside the labeled storage conditions. More specifically, for drug 
product capsule stored as a 30ct supply in 60 ml bottle with 1g desiccant, no significant 
changes in drug product quality were observed for 6 months for accelerated (40°C/75% 
RH) and 36 months for long term (25℃/60%RH) conditions.   
 
Given the stability of the product under multiple temperatures and relative humidity 
conditions, it can be concluded that short term temperature excursions above 30°C and 
low as 15℃ during storage are acceptable.  For those excursions to non-freezing 
temperatures below 15°C but at or above 1°C, no additional risk to drug product quality 
is presented based on the well-established principal of Arrhenius degradation kinetics 
(i.e., degradation reaction rates are temperature-dependent and occur faster at higher 
temperatures and slower at lower temperatures).  
 
20


In consideration of the product stability information, the following direct-to-patient guidance is 
provided during this coronavirus (COVID-19) pandemic period: 
 
1. To mitigate any unforeseen issues impacting the shipment (i.e., lengthy delays, extreme 
temperatures, etc.), shipping only the minimum number of product required for patient dosing 
administration and priority overnight shipment is advised.  
 
2. While the data provides assurance that RTA 402 Drug Product Capsules are stable, additional 
shipping and storage studies are either planned or currently being conducted. As such, certain 
limitations have been placed on the product until these results are reported. Accordingly, 
shipment durations during this period lasting longer than 48 hours, without a temperature 
monitor, are not advised. If shipment exceeds this duration due to unforeseen shipping delays, 
the site should contact Reata for further guidance. 
 
 Additional guidance will be provided when data is available. 
 
Best regards, 
 
 
 
 
 
21










 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
26






 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
29

SAP_007.pdf: 
Reata Pharmaceuticals, Inc. 
 
402-C-1603, Phase 3 
Addendum v1 to Statistical Analysis Plan v3 
 
Page 1 of 8 
ADDENDUM TO STATISTICAL ANALYSIS PLAN  
VERSION 1.0 
DATED 30-OCT-2020 
TO 
                        STATISTICAL ANALYSIS PLAN Version 3.0  
 
Statistical Analysis Plan History 3.0 
Version 1.0 – 10 July 2019 
Version 2.0 – 15 August 2019 
Version 3.0 – 04 November 2019 
BASED ON: 
Protocol Version 4.0 (April 22, 2019) 
Protocol Version 4.0, 4.1, and Protocol 4.2 Addendum (France, Spain, UK Apr 21, 2020; Japan 
May 12, 2020; US, AUS June 05, 2020) 
                                       
STUDY DRUG: 
RTA 402, BARDOXOLONE METHYL 
PROTOCOL NUMBER: 
402-C-1603 Phase 3 
STUDY TITLE: 
A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl 
 in Patients with Alport Syndrome (“CARDINAL”) 
 
SPONSOR: 
Reata Pharmaceuticals, Inc. 
5320 Legacy Dr 
Plano, Texas 75024  
 (972) 865-2219 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 




Reata Pharmaceuticals, Inc. 
 
402-C-1603, Phase 3 
Addendum v1 to Statistical Analysis Plan v3 
 
Page 3 of 8 
 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................4 
2. 
RATIONALE FOR ADDENDUM ..............................................................................4 
3. 
CORRECTION AND CLARIFICATION TO THE SAP ............................................4 
3.1. 
Correction to Covariate Computation ...........................................................................4 
3.2. 
Clarification of Hierarchical Testing Strategy ..............................................................5 
4. 
COVID-19 IMPACT ....................................................................................................5 
4.1. 
Changes in Study Conduct ............................................................................................5 
4.2. 
Additional Disposition Categories ................................................................................5 
4.3. 
Protocol Deviations ......................................................................................................6 
4.4. 
Changes to Key Efficacy Analyses ...............................................................................6 
4.4.1. 
Extended Visit Windows ..............................................................................................6 
4.4.2. 
Accounting for Regional Differences ...........................................................................7 
4.4.3. 
No Changes Due to Temporary Interruptions in Study Treatment ...............................7 
4.5. 
Data Handling for Assessments After Positive COVID-19 Diagnosis ........................7 
4.6. 
Pre-COVID Era and Post-COVID Era Comparison .....................................................8 
4.7. 
References .....................................................................................................................8 
 
 
 


Reata Pharmaceuticals, Inc. 
 
402-C-1603, Phase 3 
Addendum v1 to Statistical Analysis Plan v3 
 
Page 4 of 8 
1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
COVID-19 
Coronavirus Disease 2019  
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
IP 
Investigational Product  
SAP 
Statistical Analysis Plan 
SARS-CoV-2  
Severe Acute Respiratory Syndrome Coronavirus 2  
2. 
RATIONALE FOR ADDENDUM 
This addendum describes clarifications to the Statistical Analysis Plan (SAP) version 3.0 as well 
as additional analyses for Year 2 of CARDINAL Phase 3 to characterize the impact of the 
COVID-19 pandemic on the trial.  
3. 
CORRECTION AND CLARIFICATION TO THE SAP 
3.1. 
Correction to Covariate Computation 
Analyses of efficacy will adjust for the duration of exposure to drug within each year of the 
study.  The fraction of expected exposure duration for Year 2 analyses (i.e., Week 100 and Week 
104), calculated as the fraction of expected exposure duration in Year 2, will be included in 
analyses as a covariate.  As outlined in Section 6.5.11 of the SAP, fraction of expected exposure 
in Year 2 (TRT_EXP2) is calculated using the date of last dose in Year 2.  However, any patient 
who permanently discontinued treatment in Year 1 would not have a Year 2 date of last dose.  As 
a result, the definition has been corrected to use the date of last dose in the study, allowing all 
randomized patients to have a TRT_EXP2 value and therefore contribute to analyses.  
Additionally, the length of exposure was extended from 700 to 707 days to account for the 
COVID-19 protocol modification, which allowed longer dose administration.  The computation 
was also corrected by adding “+1” to the date of last dose.  See Table 2 for the corrected 
definition of TRT_EXP2.  
Table 2: 
Computation of Fraction Received of Expected Two-Year Exposure  
SAP definition 
Corrected definition 
[(date of last dose in second year) – (date of 
first dose)]/700 
[(date of last dose +1) – (date of first 
dose)]/707 


Reata Pharmaceuticals, Inc. 
402-C-1603, Phase 3
Addendum v1 to Statistical Analysis Plan v3 
Page 5 of 8 
3.2. 
Clarification of Hierarchical Testing Strategy 
Section 8.4 of the SAP specifies that all endpoints tested at Year 1 and Year 2 will use a 
significance level of 0.025.  Within each year, endpoints are tested following a fixed-sequence 
hierarchical testing strategy.  The total significance level (0.05) was split between Year 1 and 
Year 2 as a strategy to reserve alpha to test Year 2 if the Year 1 testing sequence was not 
statistically significant.  Formal testing in the sequence may proceed so long as statistically 
significant evidence of benefit continues to be shown.  If in the sequence one endpoint does not 
show statistically significant evidence of benefit, formal statistical testing of subsequent 
endpoints will not occur.   
As a clarification to the SAP, if there is a significant treatment effect for both Year 1 endpoints, 
then the significance level for Year 1 (0.025) remains available to be carried forward (recycled or 
passed along) to the Year 2 testing sequence.  Thus, if both Year 1 endpoints are significant, the 
Year 2 testing sequence will be tested using a significance level of 0.05.  This approach aligns 
with the fixed-sequence method in FDA guidance (Multiple Endpoints in Clinical Trials., 
January 2017).  
4.
COVID-19 IMPACT
FDA recognizes that the COVID-19 public health emergency may impact the conduct of clinical 
trials of medical products (FDA Guidance on Conduct of Clinical Trials of Medical Products 
during COVID-19 Public Health Emergency, September 2020).  COVID-19 posed significant 
challenges to study conduct, which were not unique to the 1603 Phase 3 study including site 
closures and access restrictions, and quarantines for site personnel and patients creating barriers 
to scheduling and conducting visits according to the protocol specified schedule.  Additionally, 
the 1603 Phase 3 study population has chronic kidney disease and is therefore categorized as 
vulnerable and at higher risk for developing serious complications from COVID-19.  Specific 
guidance for these individuals varied over time and by geography, but as a group they were 
generally advised by health officials to not be in close physical contact with other people 
(https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/index.html).    
This addendum makes the following modifications to the analysis and adds additional analyses 
to address the impact of COVID-19 on the 1603 Phase 3 study.   
4.1. 
Changes in Study Conduct 
Changes to study conduct due to COVID-19 are recorded in the clinical database for each 
patient.   The overall number and percentage of patients impacted by COVID-19 will be 
summarized and listed.  The impact of COVID-19 on study visits (e.g., not done or done outside 
the window), assessments (e.g., not performed), data collection method (e.g., telephone, video 
conference, home health, and local lab) will be listed.  
4.2. 
Additional Disposition Categories 
Categories for end-of-treatment and end-of-study reasons were added to data capture and 
disposition summaries: 


Reata Pharmaceuticals, Inc. 
402-C-1603, Phase 3
Addendum v1 to Statistical Analysis Plan v3 
Page 6 of 8 
x
Terminated early from the treatment because of COVID-19; and
x
Terminated early from the study because of COVID-19.
4.3. 
Protocol Deviations
Deviations due to the impacts of COVID-19 are documented in the clinical database by the site 
and the Sponsor. These deviations will be identified in the protocol deviations data and presented 
in a data listing.  
4.4. 
Changes to Key Efficacy Analyses 
COVID-19 created logistical challenges associated with study execution, including possible 
interruptions in treatment due to quarantine and travel restrictions as well as closure or reduced 
operating hours of sites/institutions.  Many patients enrolled in the 1603 Phase 3 study had to 
travel long distances requiring full day or overnight travel for in-clinic visits.  The National 
Kidney Foundation advised clinical trial participants to avoid using public transportation when 
possible (https://www.kidney.org/covid-19).  Shipping drug directly to patients and home 
healthcare visits were added as options to keep patients on treatment per-protocol and overcome 
limitations associated with travel.  High demand for home health nurses during this global 
pandemic and varying levels of patient comfort with home health nurse interactions during 
quarantine created continued challenges and limitations with scheduling flexibility.   
Key efficacy analyses were modified as follows to address these issues related to COVID-19. 
4.4.1. 
Extended Visit Windows 
The Week 100 visit serves to collect the final “on treatment” lab values (including eGFR) from 
patients.  Given the aforementioned logistical challenges due to COVID-19, the protocol was 
amended to allow up to a two-week extension in the protocol-specified window for the Week 
100 visit to increase scheduling flexibility, as needed.  As a result, some patients were shipped 
additional study drug kits so that patients could continue treatment despite their delayed Week 
100 visits.  Accordingly, some patients were dosed for up to 2 additional weeks and the Week 
100 analysis window was adjusted to account for the extended dosing as specified in Table 3.   
Table 3: 
Analysis Window for Week 100 Visit 
Patient Treatment Status 
Target 
Study Daya 
Week 100 Analysis Window 
Originalb 
Adjusted 
Permanently discontinued 
treatment prior to Week 100 
700 
  VWXG\ GD\   
No change 
Completed treatment at 
Week 100 
700c 
  VWXG\ GD\   
  VWXG\ GD\ < 728; and 
Week 100  13 days after last dose 
a Study day is relative to the date of randomization (SAP Section 6.5.2) 
b Original Week 100 analysis window defined in SAP Section 6.5.11, Table 3 
c Target study day extended by up to 14 days to account for additional drug dispensed prior to Week 100 
Scheduling of the Week 104 visit was adjusted for patients with extended dosing duration to 
ensure that the Week 104 eGFR value is collected 4 weeks after last dose.  The SAP-specified 


Reata Pharmaceuticals, Inc. 
 
402-C-1603, Phase 3 
Addendum v1 to Statistical Analysis Plan v3 
 
Page 7 of 8 
analysis window of 14 to 35 days with a protocol-specified target of 28 days after the last dose, 
which was reinforced by the Sponsor, did not allow much flexibility in scheduling.  The Week 
104 analysis window was extended by removing the upper bound on days after last dose 
(Table 4) to avoid exclusion of available values collected beyond the original analysis window.  
If eGFR is assessed more than once within the visit window, the measurement that is closest to 
28 days after last dose (i.e., 4-weeks after the last dose as specified in the protocol) is used for 
the purpose of data analysis. 
Table 4: 
Analysis Window for Week 104 Visit 
Target Days After Last Dosea 
Week 104 Analysis Window 
Originalb 
Adjusted 
28 
14  days after last dose  35 
 days after last dose  14 
a Days after last dose in second-year dosing interval.  Patient must have been dispensed treatment in the second 
year, otherwise Week 104 is considered missing. 
b Original Week 100 analysis window defined in SAP Section 6.5.4, Table 3 
4.4.2. 
Accounting for Regional Differences  
Study 402-C-1603, Phase 3, is a global clinical trial.  The regional emergence and impact of 
COVID-19 is heterogeneous across the various countries contributing participants to the trial.  
Region (US; non-US) is added as a covariate to the models assessing Week 100 and Week 104 to 
account for differential COVID-19 impact by region. 
4.4.3. 
No Changes Due to Temporary Interruptions in Study Treatment 
A COVID-19 appendix was added to the study protocol to allow for temporary interruptions in 
study treatment.   No changes are required for analyses of Week 100 or Week 104 due to 
temporary discontinuation and reinitiation of study drug given how the key efficacy analyses 
were defined:   
x Analyses of Week 100 are based on target study day, irrespective of whether or not a 
patient is receiving study drug.   
x Analyses of Week 104 are based on days after final dose following permanent study drug 
discontinuation in the second year.  Analyses of Week 104 data will not include data 
collected during any intermediate off-treatment period. 
4.5. 
Data Handling for Assessments After Positive COVID-19 Diagnosis 
Recent studies have documented that COVID-19 can cause damage to multiple organs, such as 
the heart, liver, kidneys, and the immune system (Chen, 2020; Wang, 2020).  Therefore, the 
summary tables and analyses do not include efficacy and safety data (clinical laboratory [including 
eGFR], vital sign, electrocardiogram, visual acuity, and audiology assessments) collected after the 
start date of adverse event preferred term “coronavirus”.  If the number of patients with positive 
COVID-19 diagnosis is sufficiently large, the data collected for these patients may be 
summarized together.  All data will be presented in by-patient listings.  


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4.6. 
Pre-COVID Era and Post-COVID Era Comparison 
As an additional analysis, the pre-COVID era which will include all Week 100 and Week 104 
visits that were planned on or prior to March 1, 2020 will be compared to the same visits that 
were planned post March 1, 2020.  
4.7. 
References 
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, 
Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel 
coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 
15;395(10223):507-513. 
Wang T, Du Z, Zhu F, Cao Z, An Y, Gao Y, Jiang B. Comorbidities and multi-organ injuries in 
the treatment of COVID-19. Lancet. 2020 Mar 21;395(10228):e52.  


Reata Pharmaceuticals, Inc. 
 
402-C-1603, Phase 3 
Statistical Analysis Plan v3.0 
 
NOV 04, 2019 
 
1  
 
STATISTICAL ANALYSIS PLAN 
 
VERSION: 3.0 
DATE OF PLAN: 
04-NOV-2019 
 
Statistical Analysis Plan History 
Version 1.0 – 10 July 2019 
Version 2.0 – 15 August 2019 
 
BASED ON: 
Protocol Version 4.0 (April 22, 2019) 
 
STUDY DRUG: 
RTA 402, BARDOXOLONE METHYL 
PROTOCOL NUMBER: 
402-C-1603 Phase 3 
STUDY TITLE: 
A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl 
 in Patients with Alport Syndrome (“CARDINAL”) 
 
SPONSOR: 
Reata Pharmaceuticals, Inc. 
2801 Gateway Drive, Suite 150 
Irving, Texas 75063  
 (972) 865-2219 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 






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4  
 
Methodology: 
The Phase 3 portion of the 402-C-1603 trial is a double-blind, randomized, placebo-controlled study designed to 
evaluate the safety and efficacy of bardoxolone methyl up to 30 mg in patients with Alport syndrome.  Patients in 
Phase 3 are randomized 1:1 to receive bardoxolone methyl or placebo.  Randomization is stratified by screening 
urine albumin to creatinine ratio (ACR).  Patients randomized to placebo remain on placebo throughout the study, 
undergoing sham titration.  
$GXOW SDWLHQWV   \HDUV RI DJH UHFHLYLQJ EDUGR[RORQH PHWK\O VWDUW ZLWK RQFH-daily dosing at 5 mg.  They 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.  Patients under the age of 18 
receiving bardoxolone methyl start dosing at 5 mg every other day during the first week.  They begin once-daily 
dosing with 5 mg during the second week of the study, and then continue with once-daily dosing following the 
same aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, and 6.  Dose de-escalation is 
permitted during the study if indicated clinically; subsequent dose re-escalation is also permitted to meet the 
dosing objective of the highest tolerated dose. 
All patients receive study drug from Day 1 to Week 48.  Patients do not receive study drug treatment during a 4-
week withdrawal period (between Weeks 48 and 52).  Patients re-start study drug treatment at Week 52 at the 
same dose level that they received prior to the withdrawal period (maintaining the originally randomized 
treatment group) and continue study drug treatment through Week 100.  A follow-up visit occurs at Week 104 (4 
weeks after the last dose).  The Data Monitoring Committee (DMC) performs quarterly reviews of unblinded data 
for safety throughout Phase 3.  
The Phase 3, Year 1 efficacy is assessed first by the DMC after all patients in the Phase 3 cohort have completed 
their Week 52 visit.  If the Year 1 efficacy endpoints are met, then the Year 1 data will be analyzed by the Reata 
analysis team to proceed with regulatory filing.  Available Year 2 safety data is summarized descriptively as 
preliminary results at the time of the Year 1 final analysis.  The Phase 3, Year 2 efficacy is analyzed after all 
patients in the Phase 3 cohort have completed their Week 104 visit.   
Number of Subjects (planned and analyzed): 
Planned: 150 


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Diagnosis and main criteria for inclusion (see protocol section 8.1): 
1. Male and female patients 12  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. 6FUHHQLQJ H*)5 DYHUDJH RI 6FUHHQ $ DQG 6FUHHQ % H*)5 YDOXHV   DQG   P/PLQ P2.  The 
two eGFR values collected at Screen A and Screen B visits used to determine eligibility must have a 
percent GLIIHUHQFH  25%; 
4. $OEXPLQ WR FUHDWLQLQH UDWLR $&5  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 patLHQWV LV FRPSOHWH WKH $&5 LQFOXVLRQ FULWHULRQ LV   PJJ  
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), 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);      
Test product, dose and mode of administration: 
This study uses capsules containing bardoxolone methyl at the 5 and 15 mg strengths.  Blinded treatment kits are 
provided to patients for self-administration orally once daily.  Each dose of study drug should be administered at 
approximately the same time each day, preferably in the morning. 
Duration of study:  
100 weeks of treatment plus a 4-week follow-up 
Reference therapy, dose and mode of administration: 
This study uses matching capsules containing placebo.  Blinded treatment kits are provided to patients for self-
administration orally once daily.  Each dose of study drug should be administered at approximately the same time 
each day, preferably in the morning.   
Criteria for evaluation (see protocol section 6.2, 11.0): 
Efficacy: eGFR, Patient Global Impression of Change (PGIC), Clinical Global Impression-Improvement (CGI-I), 
the 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, and end stage kidney disease (ESKD) defined as initiation of maintenance 
dialysis or kidney transplant. 
Safety: 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, weight, visual 
acuity, and audiology.   
Statistical methods: 
Primary and secondary analysis of the efficacy data are based on the ITT population, which will include all 
patients randomized in the Phase 3 portion of the study.  Analyses at Weeks 48, 52, 100, and 104 will compare all 
bardoxolone methyl patients to all placebo patients.  Mixed models repeated measures (MMRM) analysis are 
used to evaluate the treatment effect at Week 48 and 100.  ANCOVA is used to evaluate the off-treatment effect 
at Week 52 and 104.  The body of this SAP provides additional detail on analysis of the primary and secondary 
endpoints, and analyses of exploratory endpoints. 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS .....................................................................................12 
2. 
INTRODUCTION ......................................................................................................15 
2.1. 
Trial Rationale ............................................................................................................15 
2.2. 
Background .................................................................................................................15 
3. 
STUDY ENDPOINTS ................................................................................................18 
3.1. 
Study Endpoints ..........................................................................................................18 
3.1.1. 
Phase 3 – Year 1 Endpoints ........................................................................................18 
3.1.1.1. 
Primary Endpoints ......................................................................................................18 
3.1.1.2. 
Key Secondary Endpoint ............................................................................................18 
3.1.1.3. 
Exploratory Endpoints ................................................................................................18 
3.1.2. 
Phase 3 – Year 2 Endpoints ........................................................................................18 
3.1.2.1. 
Primary Endpoints ......................................................................................................18 
3.1.2.2. 
Key Secondary Endpoint ............................................................................................19 
3.1.2.3. 
Exploratory Endpoints ................................................................................................19 
4. 
STUDY DESIGN .......................................................................................................20 
4.1. 
Summary of Study Design ..........................................................................................20 
4.2. 
Definition of Study Drugs ..........................................................................................20 
4.3. 
Sample Size Considerations .......................................................................................21 
4.3.1. 
Primary Endpoints ......................................................................................................21 
4.3.2. 
Key Secondary Endpoint ............................................................................................21 
4.4. 
Randomization ............................................................................................................22 
4.5. 
Clinical Assessments ..................................................................................................22 
5. 
PLANNED ANALYSES ............................................................................................26 
5.1. 
Year 1 Data Complete ................................................................................................26 
5.1.1. 
Final Analysis – Year 1 ..............................................................................................26 
5.1.2. 
Preliminary Analysis – Year 2 ....................................................................................27 
5.2. 
Year 2 Data Complete ................................................................................................27 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................28 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........28 
6.2. 
Data Presentation Conventions ...................................................................................28 
6.3. 
Analysis Populations ..................................................................................................29 


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6.3.1. 
ITT Population ............................................................................................................29 
6.3.2. 
Per-Protocol (PP) Population – Year 1 .......................................................................29 
6.3.3. 
Per-Protocol (PP) Population – Year 2 .......................................................................29 
6.3.4. 
Safety Population ........................................................................................................29 
6.3.5. 
Japanese Population ....................................................................................................29 
6.4. 
Baseline Definition .....................................................................................................30 
6.4.1. 
Estimated Glomerular Filtration Rate .........................................................................30 
6.4.2. 
Serum Creatinine ........................................................................................................30 
6.4.3. 
Safety Assessments .....................................................................................................30 
6.4.4. 
Urine Albumin to Creatinine Ratio .............................................................................30 
6.4.5. 
Natural log(ACR)/eGFR .............................................................................................30 
6.4.6. 
Baseline Hematuria .....................................................................................................30 
6.4.7. 
Baseline Visual Impairment .......................................................................................31 
6.4.8. 
Baseline Audiology Impairment .................................................................................31 
6.5. 
Derived and Transformed Data ..................................................................................31 
6.5.1. 
Age ..............................................................................................................................31 
6.5.2. 
Study Day ...................................................................................................................31 
6.5.3. 
Change from Baseline .................................................................................................32 
6.5.4. 
Visit Windows ............................................................................................................32 
6.5.4.1. 
Off-Treatment Visit Windows ....................................................................................33 
6.5.5. 
Laboratory Evaluations ...............................................................................................34 
6.5.6. 
Estimated Glomerular Filtration Rate (eGFR) ...........................................................34 
6.5.6.1. 
Prognosis of CKD by eGFR and Albuminuria Category ...........................................35 
6.5.7. 
Urine Albumin to Creatinine Ratio (ACR) .................................................................35 
6.5.7.1. 
Baseline Urine Albumin to Creatinine Ratio (ACR) Categorical Status ....................36 
6.5.7.2. 
ACR Category used in Stratification (ACR_STRAT) ................................................36 
6.5.8. 
Electrocardiogram Fridericia Corrected QT Interval .................................................36 
6.5.9. 
Log of The Minimum Angle of Resolution ................................................................36 
6.5.10. 
Natural log(ACR)/eGFR .............................................................................................36 
6.5.11. 
Exposure Duration ......................................................................................................36 
6.6. 
Handling of Missing Data ...........................................................................................37 
6.6.1. 
Missing Efficacy Endpoint Data .................................................................................37 
6.6.1.1. 
Missing eGFR for MMRM Analyses .........................................................................37 


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6.6.1.2. 
Missing eGFR for ANCOVA Analyses .....................................................................37 
6.6.2. 
Missing Start and Stop Dates for Concomitant Medication .......................................37 
6.6.3. 
Missing Start and Stop Dates for Adverse Events ......................................................38 
7. 
STUDY POPULATION .............................................................................................39 
7.1. 
Subjects Disposition ...................................................................................................39 
7.2. 
Screen Failures ............................................................................................................40 
7.3. 
Protocol Deviations ....................................................................................................40 
7.4. 
Demographic and Baseline Characteristics ................................................................40 
7.5. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................41 
7.6. 
Medical History ..........................................................................................................41 
7.6.1. 
Historical eGFR ..........................................................................................................41 
8. 
PRIMARY EFFICACY ..............................................................................................43 
8.1. 
General Considerations ...............................................................................................43 
8.2. 
Statement of the Null and Alternate Hypotheses ........................................................43 
8.3. 
Subgroup Analyses .....................................................................................................43 
8.4. 
Multiple Comparisons and Multiplicity ......................................................................44 
8.5. 
Handling of Missing Data ...........................................................................................45 
8.5.1. 
Missing eGFR for Sensitivity Analyses .....................................................................45 
8.5.2. 
Missing eGFR for MMRM Analyses .........................................................................45 
8.5.3. 
Missing eGFR for ANCOVA Analyses .....................................................................45 
8.6. 
Year 1:  Primary Efficacy Endpoint ...........................................................................45 
8.6.1. 
Primary Analysis of the Year 1 Primary Efficacy Endpoint ......................................45 
8.6.2. 
Sensitivity Analyses ....................................................................................................46 
8.6.2.1. 
Tipping Point ..............................................................................................................46 
8.6.2.2. 
As-Treated Analysis ...................................................................................................47 
8.6.2.3. 
Per-Protocol Population Analysis ...............................................................................47 
8.7. 
Year 1: Key Secondary Endpoint ...............................................................................47 
8.7.1. 
Primary Analysis of Year 1 Key Secondary Endpoint ...............................................47 
8.7.2. 
Sensitivity Analyses ....................................................................................................48 
8.7.2.1. 
Tipping Point ..............................................................................................................48 
8.7.2.2. 
Control-Based Multiple Imputation ............................................................................49 
8.7.2.3. 
Per-Protocol Population Analysis ...............................................................................49 
8.8. 
Year 2:  Primary Efficacy Endpoint ...........................................................................49 


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8.8.1. 
Primary Analysis of the Year 2 Primary Efficacy Endpoint ......................................49 
8.8.2. 
Sensitivity Analyses ....................................................................................................49 
8.8.3. 
Summary of Sensitivity Analyses of the Primary Efficacy Endpoint – Year 2 ..........49 
8.9. 
Year 2:  Key Secondary Endpoint ..............................................................................50 
8.9.1. 
Primary Analysis of the Year 2 Key Secondary Endpoint .........................................50 
8.9.2. 
Sensitivity Analyses ....................................................................................................50 
9. 
EXPLORATORY EFFICACY ...................................................................................51 
9.1. 
eGFR ...........................................................................................................................51 
9.1.1. 
Continuous eGFR .......................................................................................................51 
9.1.1.1. 
All Available Data ......................................................................................................51 
9.1.1.2. 
As-Treated Data ..........................................................................................................51 
9.1.2. 
Categorical eGFR Endpoints ......................................................................................51 
9.1.3. 
Distribution of Changes in eGFR ...............................................................................52 
9.2. 
Patient Global Impression of Change .........................................................................52 
9.3. 
Clinical Global Impression - Improvement ................................................................53 
9.4. 
Kidney Failure Composite Outcome ..........................................................................53 
9.4.1. 
Primary Analysis of the Kidney Failure Composite Outcome ...................................53 
9.4.2. 
Sensitivity Analysis ....................................................................................................54 
10. 
SAFETY AND TOLERABILITY ..............................................................................55 
10.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............55 
10.1.1. 
Missing and Partial AE Onset Dates ..........................................................................56 
10.1.2. 
Summaries of Adverse Events ....................................................................................56 
10.2. 
Exposure and Compliance ..........................................................................................57 
10.3. 
Concomitant Medications ...........................................................................................57 
10.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........58 
10.4. 
Prior and Concomitant Procedures and Surgeries ......................................................58 
10.5. 
Clinical Laboratory Evaluations .................................................................................58 
10.5.1. 
Continuous Summaries of Laboratory Results ...........................................................58 
10.5.1.1. 
Natural log(ACR)/eGFR .............................................................................................59 
10.5.2. 
Categorical Summaries of Laboratory Results ...........................................................59 
10.5.2.1. 
Transaminases .............................................................................................................59 
10.6. 
Vital Signs ..................................................................................................................60 
10.6.1. 
Body Weight ...............................................................................................................60 


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10.7. 
Physical Examination .................................................................................................60 
10.8. 
Electrocardiogram .......................................................................................................60 
10.9. 
Visual Acuity ..............................................................................................................61 
10.10. 
Audiology Assessment ...............................................................................................61 
10.11. 
Pregnancy ...................................................................................................................61 
11. 
PHARMACOKINETICS ...........................................................................................62 
12. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ....................................63 
12.1. 
Analysis of Key Secondary Endpoints .......................................................................63 
12.2. 
Imputation of Missing Data for the Primary Endpoints .............................................63 
13. 
REFERENCES ...........................................................................................................64 
 
 
 


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LIST OF TABLES 
Table 1.  List of Abbreviations ......................................................................................................12 
Table 2.  Schedule of Assessments ................................................................................................23 
Table 3.  Analysis Visit Windows .................................................................................................32 
Table 4.  Analysis Visits for Off-Treatment Safety Analysis ........................................................34 
Table 5. eGFR Category ................................................................................................................35 
Table 6. Albuminuria Category .....................................................................................................35 
Table 7.  Labels for Summary of Historical Change in eGFR .......................................................42 
Table 8.  Model Parameter Abbreviations .....................................................................................43 
Table 9. Pre-Specified Threshold Levels for Transaminases ........................................................59 
Table 10. Pre-Specified Threshold Levels for ECG Parameters ...................................................60 
 


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1. 
LIST OF ABBREVIATIONS 
 
Table 1.  List of Abbreviations 
Abbreviation 
Term 
ȝ BARD 
bardoxolone methyl group mean 
ȝ PLACEBO 
placebo group mean 
ARB 
angiotensin II receptor blocker 
ACE 
angiotensin-converting enzyme 
ACEi 
angiotensin converting enzyme inhibitor 
ACR 
urine albumin to creatinine ratio 
ACR_STRAT 
urine albumin to creatinine ratio use for stratification by the randomization list 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
AR(1) 
first order auto-regressive 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BARD 
bardoxolone methyl 
BCVA 
best-corrected visual acuity 
BI 
bioinformatics 
BMI 
body mass index 
BNP 
B-type natriuretic peptide 
BUN 
blood urea nitrogen 
CGI-I 
Clinical Global Impression - Improvement 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CM 
concomitant medication 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DMC 
Data Monitoring Committee 
eCRF 
electronic case report form 
eDISH 
evaluation of Drug-Induced Serious Hepatotoxicity 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
ESKD 
end stage kidney disease 
FDA 
Food and Drug Administration (US) 
FMV 
first morning void 
GFR 
glomerular filtration rate 
ICH 
International Conference on Harmonisation 


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Abbreviation 
Term 
ICH E4 
International Conference on Harmonisation Tripartite Guideline for Good 
Clinical Practice E4 
ICH E9 
International Conference on Harmonisation Tripartite Guideline for Good 
Clinical Practice E9 
IEC 
Independent Ethics Committee 
IGF-1 
insulin-like growth factor-1 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
Kg 
kilogram 
LLD 
lower limit of detection 
logMAR 
log of the minimum angle of resolution 
LS 
least squares 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
Msec 
milliseconds 
MTLDD 
maximally tolerated labeled daily dose 
NDA 
new drug application 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
OTAE 
off-treatment adverse event 
PGIC 
Patient Global Impression of Change 
pH 
potential of hydrogen 
PK 
pharmacokinetic 
PP 
per-protocol 
PT 
preferred term 
QTc 
corrected QT interval 
RBC 
red blood cell 
RBC/HPF 
red blood cells per high power field 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCr 
serum creatinine 
SD 
standard deviation 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
ULD 
upper limit of detection 
ULN 
upper limit of normal 


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Abbreviation 
Term 
US 
United States 
WOCBP 
women of child-bearing potential 
XLAS 
X-linked Alport syndrome 
 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analyses and data displays to be 
included in the Clinical Study Report (CSR) for Protocol 402-C-1603 Phase 3. 
2.1. 
Trial Rationale 
Conceptually, this trial was designed to test the biological hypothesis that bardoxolone methyl 
slows disease progression in patients with Alport syndrome, as measured by changes in eGFR.  
Since on-treatment changes in eGFR may include both reversible, pharmacodynamic effects, as 
well as irreversible structural effects, analysis of eGFR after withdrawal is used to determine if 
bardoxolone methyl affects disease progression.  
The presence of a sustained eGFR improvement after withdrawal of drug may be indicative of 
disease-modifying activity.  In contrast, a decline in kidney function relative to placebo after 
drug withdrawal would be unlikely to provide a long-term benefit and could indicate the drug 
has harmed the kidney. 
If the withdrawal analysis indicates that bardoxolone methyl improves kidney function relative to 
placebo, then this would suggest that the drug is likely to reduce underlying progression of the 
disease.  It would also suggest that the on-treatment eGFR change would likely translate into a 
long-term renal benefit.  Further, in routine clinical practice, physicians are unlikely to withdraw 
the drug, and an important element of the trial is to characterize the on-treatment eGFR change.  
Analytically, the main intent of the trial is to characterize the change from baseline in eGFR 
following a 4-week withdrawal period.  Within the two-year duration, there are two opportunities 
to test this biological hypothesis and determine if the change from baseline in eGFR is 
statistically significant relative to placebo.  If the off-treatment change from baseline in eGFR is 
not statistically significant relative to placebo at Year 1, the trial design and analysis plan allow 
for an additional comparison of the off-treatment effect relative to placebo at Year 2.  
Beyond the main intent of the trial, the trial is designed to also determine the following:  
x The clinical benefit of bardoxolone methyl while receiving treatment, as measured by 
the on-treatment assessment of eGFR. 
x Whether a treatment effect is observed over a period of up to two years. 
x Whether a treatment effect trend is seen across various subgroups, such as stages of 
disease (i.e., across a spectrum of baseline eGFRs) and the pediatric population. 
This document describes the analyses of protocol-specified endpoints to assess the effects of 
bardoxolone methyl on disease progression in patients with Alport syndrome.  
2.2. 
Background 
The original study protocol has undergone three amendments. 
Protocol Revision Chronology: 
Protocol version 1 
15-Nov-2016 
Original 


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Amendment 1 
(Protocol version 2) 
03-Aug-2017 
x 
Removed interim analysis for efficacy and 
potential changes to Phase 3 
macroalbuminuria cap 
x 
Decreased sample size in Phase 3 portion of 
study 
x 
Global Impressions of Change added as 
exploratory endpoints 
Amendment 2 
(Protocol version 3) 
30-July-2018 
x 
Added time-to-kidney failure as an 
exploratory endpoint 
x 
Increased cap on patients with 
macroalbuminuria in Phase 3 
Amendment 3 
(Protocol version 4) 
22-Apr-2019 
x 
Re-grouped objectives and endpoints into 
first and second year objectives and 
endpoints 
x 
Modified patient discontinuation and 
termination criteria 
x 
Added ESKD follow-up guidance 
This SAP was developed in accordance with International Conference on Harmonisation 
Tripartite Guideline for Good Clinical Practice E9 (ICH E9) guidelines.  All decisions regarding 
the final analysis, as defined in this SAP document, were made prior to Database Lock 
(unblinding) of the study data.  Further information can be found in the protocol.  Changes to 
protocol-specified analyses, including analysis populations, can be found in Section 12. 
The SAP is based on:  
x Protocol No. 402-C-1603, Version 4, dated April 22, 2019 
x ICH guidelines E4 and E9 (Statistical Principles for Clinical Trials)  
x Feedback received from FDA throughout clinical development, including the 
following communications: 
 FDA Meeting Minutes 
 for the October 5, 2016 Pre-IND 
meeting 
 IND Study May Proceed letter 
 dated December 15, 2016. 
 Advice/Information Request communication 
 dated February 5, 
2019.  
This SAP describes the study populations, how variables are derived, how missing data are 
handled, and details concerning the statistical methods to be used to analyze the safety and 
efficacy data from the Phase 3 portion of Study 402-C-1603.  Should the SAP and the protocol 
be inconsistent with respect to the planned analyses, the language of the SAP is governing. 
This SAP was finalized, approved by the Sponsor, and placed on file before database lock.  This 
version of the SAP describes the analyses planned prior to the database lock.  Unless otherwise 
specified, the CSR will summarize these analyses.  Any substantive changes made to the SAP 


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after the database lock will clearly be identified in the CSR, and any analyses in addition to those 
specified in the SAP prior to the database lock are considered ad hoc.  


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3. 
STUDY ENDPOINTS 
3.1. 
Study Endpoints 
In patients with Alport syndrome, the study will compare those receiving bardoxolone methyl to 
those receiving placebo with respect to several endpoints.  The timing for analyzing study 
endpoints is described in Section 5.  The strategy for protecting the overall type I error rate of 
0.05 for the trial is described in Section 8.4.  Primary efficacy analyses are described in 
Section 8, and additional exploratory efficacy analyses are described in Section 9. 
3.1.1. 
Phase 3 – Year 1 Endpoints 
3.1.1.1. 
Primary Endpoints 
x Change from baseline in estimated glomerular filtration rate (eGFR) at Week 48 
x Safety assessments through Week 52 
3.1.1.2. 
Key Secondary Endpoint 
x Change from baseline in eGFR, following a 4-week drug treatment withdrawal 
period, at Week 52 
3.1.1.3. 
Exploratory Endpoints 
x Percentage of patients with a kidney failure event by Week 48, 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). 
x Percentage of patients with an increase from baseline in eGFR of 30% or more by 
Week 48 
x Percentage of patients with a decrease from baseline in eGFR of 30% or more by 
Week 48 
x Distribution of changes from baseline in eGFR at Week 48 
x Distribution of the Patient Global Impression of Change (PGIC) scores at Week 48 
x Distribution of the Clinical Global Impression-Improvement (CGI-I) scores at 
Week 48 
3.1.2. 
Phase 3 – Year 2 Endpoints 
3.1.2.1. 
Primary Endpoints 
x Change from baseline in eGFR at Week 100 
x Safety assessments through Week 104 


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3.1.2.2. 
Key Secondary Endpoint 
x Change from baseline in eGFR, following a 4-week drug treatment withdrawal 
period, at Week 104 
3.1.2.3. 
Exploratory Endpoints   
x Time to first kidney failure composite 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). 
x Percentage of patients with a kidney failure event by Week 100, 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). 
x Percentage of patients with an increase from baseline in eGFR of 30% or more by 
Week 100 
x Percentage of patients with a decrease from baseline in eGFR of 30% or more by 
Week 100 
x Distribution of changes from baseline in eGFR at Week 100 
x Distribution of the Patient Global Impression of Change (PGIC) scores at Week 100 
x Distribution of the Clinical Global Impression-Improvement (CGI-I) scores at 
Week 100 


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4.
STUDY DESIGN
4.1.
Summary of Study Design
The Phase 3 portion of the 402-C-1603 trial is a double-blind, randomized, placebo-controlled 
study designed to evaluate the safety and efficacy of bardoxolone methyl up to 30 mg in patients 
with Alport syndrome.  Patients in Phase 3 are randomized 1:1 to receive bardoxolone methyl or 
placebo.  Randomization is stratified by screening urine albumin to creatinine ratio (ACR).  
Patients randomized to placebo remain on placebo throughout the study, undergoing sham 
titration. 
$GXOW SDWLHQWV   \HDUV Rf age) receiving bardoxolone methyl start with once-daily dosing at 
5 mg.  They 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.  Patients under the age of 18 receiving bardoxolone methyl start dosing at 5 mg every 
other day during the first week; they begin once-daily dosing with 5 mg during the second week 
of the study, and then continue with once-daily dosing following the same aforementioned dose-
titration scheme based on baseline ACR at Weeks 2, 4, and 6.  Dose de-escalation is permitted 
during the study if indicated clinically; subsequent dose re-escalation is also permitted to meet 
the dosing objective of the highest tolerated dose. 
All patients receive study drug from Day 1 to Week 48.  Patients do not receive study drug 
treatment during a 4-week withdrawal period (between Weeks 48 and 52).  Patients re-start study 
drug treatment at Week 52 at the same dose level that they received prior to the withdrawal 
period (maintaining the originally randomized treatment group) and continue study drug 
treatment through Week 100.  A follow-up visit occurs at Week 104 (4 weeks after the last dose).  
The Data Monitoring Committee (DMC) performs quarterly reviews of unblinded data for safety 
throughout Phase 3 and will evaluate the initial Year 1 results as described in Section 8.1.  
      
Figure 1.  Schema for the Phase 3 Portion of the Study
4.2.
Definition of Study Drugs
This study uses capsules containing bardoxolone methyl at the 5 and 15 mg strengths, or the 
corresponding placebos.   


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4.3. 
Sample Size Considerations 
The Year 1 and Year 2 endpoints are not independent hypothesis sets.  The endpoints are 
analyzed using a combination of the Bonferroni and fixed-sequence approaches for type 1 error 
control (Section 8.4).  
The protocol specified enrollment of approximately 150 patients in the Phase 3 cohort.  Actual 
enrollment in the Phase 3 cohort was 157.  Sample size calculations for each year based on the 
actual number of patients enrolled are presented below. 
4.3.1. 
Primary Endpoints 
With 157 patients enrolled (78 in one group and 79 in the second group), the study will have 
approximately 80% power to detect a difference between the two treatment groups in change 
from baseline in eGFR of 3.4 mL/min/1.73 m2 for the primary endpoint at Week 48 in Year 1.  
The power calculation for Year 1, which was based on mixed-model repeated measures 
(MMRM) analysis, assumes the following: 
x 9 repeated measurements (Weeks 1, 2, 4, 6, 8, 12, 24, 36, and 48) having compound 
symmetry covariance structure 
x The correlation between observations on the same subject is 0.7 
x Two-sided Type I error rate of 0.025 
x Standard deviation of change from baseline in eGFR of 8 mL/min/1.73 m2  
x Analyses at Week 48 are based on the intent-to-treat (ITT) population 
Analysis of the Year 2 primary endpoint, which also will use the ITT population, will have 
approximately 80% power to detect a difference of 3.3 mL/min/1.73 m2 assuming 13 repeated 
measurements, a correlation of 0.7 between observations, a standard deviation of 8 mL/min/1.73 
m2, and a two-sided type I error rate of 0.025.  The primary analysis of efficacy will use an 
unstructured covariance structure, which is expected to have approximately the same power as 
the analysis with compound symmetry used for study planning.   
4.3.2. 
Key Secondary Endpoint 
With 157 patients enrolled, the study will have a minimum detectable difference (i.e., 50% 
power) between the two treatment groups in change from baseline in eGFR of approximately 
2.9 mL/min/1.73 m2, and 80% power to detect a difference of 4.0 mL/min/1.73 m2 for the key 
secondary endpoint at Year 1 and at Year 2.  The power calculation, which was based on a 2-
sample t-test as an estimate for the planned ANCOVA analysis, assumes the following: 
x Two-sided Type I error rate of 0.025 for Year 1 and 0.025 for Year 2 
x Standard deviation of change from baseline in eGFR of 8 mL/min/1.73 m2  
x Multiple imputation is used for missing data 
x Analyses of the key secondary endpoint are based on the ITT population 


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4.4. 
Randomization 
Patients enrolled in the Phase 3 cohort are randomized 1:1 to either bardoxolone methyl (BARD) 
or placebo.  Randomization is stratified by screening ACR (<= 300, > 300 to 1000, and 1000 to 
3500).  Patients with macroalbuminuria (300 mg/g < ACR   mg/g) at the Screen B visit do 
not comprise more than approximately 40% of patients enrolled in the Phase 3 cohort.  
Randomization is generated using a centralized Interactive Web Response System (IWRS).  
4.5. 
Clinical Assessments 
All patients in the study follow the same visit and assessment schedule for the 2 years of total 
follow-up.  Table 2 lists the overall schedule of assessments for the study.  Following the first 
dose of study drug on Day 1, patients are scheduled for in-person assessments during Year 1 of 
treatment at Weeks 1, 2, 4, 6, 8, 12, 24, 36, and 48, as well as by telephone contact on Days 3, 
10, 21, 31, 38, and 45.  Patients temporarily discontinue study treatment at Week 48 and are 
assessed at an in-person Year 1 follow-up visit at Week 52 (4 weeks after the last dose).  Patients 
are dispensed treatment at the end of their Week 52 visit at the same dose level (or matching 
placebo) as the last dose at Week 48.  Patients are assessed for in-person assessments during 
Year 2 of treatment Weeks 64, 76, 88, and 100.  Patients are assessed at an in-person, Year 2 
follow-up visit at Week 104 (4 weeks after the last dose).   
 






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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 is performed at the Screen A visit for WOCBP or at any point in time if a pregnancy is suspected.  All other pregnancy assessments are urine pregnancy 
tests.  Additional pregnancy assessments are performed more frequently if required by local law or requested by local regulatory authorities or IRBs/IECs.   
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 is measured by first morning void spot urine collection.  Appropriate containers for the collection are 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 are 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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5. 
PLANNED ANALYSES 
The trial design includes hypothesis tests following one and two years of treatment.  All 
available study data are analyzed (1) when Year 1 data are complete, and (2) when Year 2 data 
are complete.  Details of the database lock plans and blinding are described in the Interim 
Database Deliverable Plan.  The strategy for protecting the overall type I error rate of 0.05 for 
the primary and key secondary endpoints at Year 1 and Year 2 is described in Section 8.4.   
A Data Access Plan describes how the sponsor plans to control access to unblinded data 
following the Year 1 analysis.  In the period between the Year 1 analysis and the Year 2 analysis, 
all patients, investigators, and site personnel will remain blinded to treatment assignments.  
The trial design allows for the opportunity to efficiently submit data for regulatory review 
following demonstration of efficacy after Year 1 while continuing to collect data through Year 2.  
A limitation of releasing results of the Year 1 analyses prior to all patients completing Year 2 
might include patients’ perception of their treatment assignment.  Note, however, that calculation 
of eGFR is an objective measure that is expected to be unaffected by such perceptions, and many 
patients will be well into their 2nd year of treatment at the time of the release of the Year 1 
results.  Patients and investigators will be reminded of the importance of their commitment to 
continue participation in the trial as part of an ongoing messaging campaign that began at the 
start of the trial.  To minimize dropouts the sponsor has a patient retention plan in place, which 
includes an extended access trial (402-C-1803; EAGLE) with open-label treatment for eligible 
patients completing the 402-C-1603 (CARDINAL) trial.     
5.1. 
Year 1 Data Complete 
Year 1 data are considered complete after the last patient enrolled has completed through Week 
52 and the database through Week 52 has been locked.  All available data will be analyzed when 
Year 1 data are complete.  An assessment of the Year 1 data by the DMC will occur prior to 
releasing the randomization to the Reata analysis team.  The DMC will assess the final Year 1 
primary and key secondary efficacy endpoints for statistical significance prior to Reata being 
unblinded. This process is designed to prevent Reata from becoming unblinded to Year 1 data in 
the event that the Year 1 primary and key secondary endpoints do not demonstrate statistically 
significant evidence of efficacy.  The DMC will inform Reata whether or not both the primary 
and key secondary efficacy endpoints demonstrate statistically significant evidence of efficacy 
(i.e., p<0.025). If both the Year 1 primary and key secondary endpoints are not statistically 
significant, then Reata will not to unblind until the Year 2 data are complete.  However, if both 
the Year 1 primary and key secondary endpoints are statistically significant, then Reata will 
unblind and the final analysis of Year 1 data and a preliminary assessment of Year 2 safety data 
will be performed as described in Section 5.1.1 and Section 5.1.2. 
5.1.1. 
Final Analysis – Year 1 
At the time of Year 1 data complete, results from analyses of data through Week 52, including 
the primary and key secondary efficacy endpoints, are considered final.  Because patients will be 
continuing in the trial, the interim CSR will not include by-patient data listings or patient 


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narratives to minimize the number of individuals having access to patients’ treatment 
assignments.   
5.1.2. 
Preliminary Analysis – Year 2 
At the time of the Year 1 data complete and prior to Year 2 data complete, many patients will 
have completed visits beyond Week 52.  Available safety data for Year 2 visits will be 
summarized descriptively, including summaries of AEs, vital sign assessments, and laboratory 
results (including descriptive summaries of eGFR for safety).  Year 2 efficacy endpoints will not 
be assessed with the preliminary Year 2 analysis.  The interim CSR will include  the preliminary 
Year 2 safety results.    
5.2. 
Year 2 Data Complete 
Year 2 data are considered complete after the last patient enrolled has completed through Week 
104 and the database through Week 104 has been locked.  Year 2 efficacy endpoints will be 
assessed only when Year 2 data are complete.  The interim CSR will be amended to add Year 2 
efficacy results, and to finalize Year 2 safety results.  Because the trial is complete when Year 2 
data are complete, the final CSR will include by-patient data listings and patient narratives.   


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
The efficacy and safety analyses use the analysis sets defined in Section 6.3.  Patient listings (as 
appropriate) of all analysis data that support summary tables and/or figures are provided along 
with their source data.  The summary tables do not include measurements from patients excluded 
from the pre-defined analysis sets or extra measurements (such as unscheduled or repeat 
assessments) not closest to the target study day unless specified otherwise, but the patient listings 
do include these data.  Missing data are not imputed, unless otherwise specified.  In general, 
patient listings are sorted by patient number and assessment date (time and parameter, as 
applicable).  Any laboratory value (including eGFR), vital sign assessment, or ECG value 
collected after starting dialysis or after receiving a kidney transplant is considered invalid and 
will be treated as missing.     
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Results of statistical analyses are reported using summary tables, listings, and figures (TLFs).  
All TLFs will use ICH numbering conventions.  The strategy for controlling the overall Type I 
error rate for the Year 1 and Year 2 primary and key secondary efficacy endpoints and other 
select exploratory endpoints is described in Section 8.4.  For endpoints not described in 
Section 8.4, the reported significance levels are nominal and the following statistical conventions 
are used: 
x Unless otherwise noted, all statistical testing is two-sided and is performed at the 0.05 
significance level.  
x Tests are declared statistically significant if the calculated p-value is <0.05. 
All analyses and summaries are produced using SAS® version 9.3 (or higher). 
6.2. 
Data Presentation Conventions 
Unless otherwise specified, descriptive statistics for continuous variables include the number of 
patients with data (N), mean, standard deviation (SD), median, minimum, and maximum.  The 
same number of decimal places as in the observed value are presented when reporting minimum 
and maximum; 1 more decimal place than in the observed value is presented when reporting 
mean and quartiles; and 2 more decimal places than in the observed value is presented when 
reporting SD.  
Categorical data are presented using frequency counts and percentages.  All percentages are 
rounded to 1 decimal place, unless otherwise specified.  Percentages equal to 100 are presented 
as 100% and no percentages are presented for zero frequencies.  Where individual variable 
values are missing, summaries of categorical data are based on reduced denominators (i.e., the 
denominators include only patients with available data) and the number of missing values is 
presented.  For summaries of AEs and concomitant medications (CM), the percentages are based 
on the total number of patients in each treatment group. 


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6.3. 
Analysis Populations  
Analysis populations defined in this section pertain to patients enrolled in the Phase 3 portion of 
the trial. 
6.3.1. 
ITT Population 
The intent-to-treat analysis set is defined as all enrolled patients categorized by their randomized 
treatment group (whether or not they received study drug).  Note that this is the same definition 
for both the Year 1 and Year 2 analyses. 
6.3.2. 
Per-Protocol (PP) Population – Year 1 
A sensitivity analysis exploring the robustness of the primary ITT findings of Year 1 endpoints is 
based on the patients in the per-protocol, Year 1 population.   
The per-protocol (Year 1) population is defined as patients who: 
x Received study drug through Week 48; and 
x Had no protocol deviation that could potentially affect the efficacy conclusions. 
Review of protocol deviations for determining the Year 1 per-protocol population will be 
performed by a blinded team prior to Year 1 database lock. 
6.3.3. 
Per-Protocol (PP) Population – Year 2 
A sensitivity analysis exploring the robustness of the primary ITT findings of Year 2 endpoints is 
based on the patients in the per-protocol, Year 2 population.   
The per-protocol (Year 2) population is defined as patients who: 
x Received study drug through Week 100; and 
x Had no protocol deviation that could potentially affect the efficacy conclusions. 
Review of protocol deviations for determining the Year 2 per-protocol population will be 
performed by a blinded team prior to the final database lock. 
6.3.4. 
Safety Population 
Safety analyses are based on all enrolled patients.  The safety population includes all patients 
who received at least 1 dose of randomized study drug in Year 1.  The safety population is used 
for evaluation of safety variables.  Patients who received at least one dose of bardoxolone methyl 
will be classified in the bardoxolone methyl group.  Patients who received at least one dose of 
placebo and no dose of bardoxolone methyl will be classified in the placebo group.  The safety 
population is based on this definition for both the Year 1 and Year 2 analyses. 
Safety population treatment groups will not be modified after the Year 1 analysis.  Patients in the 
placebo group receiving a dose of bardoxolone methyl in Year 2 are listed. 
6.3.5. 
Japanese Population 
The Japanese population includes all patients enrolled at sites located in Japan.  A sensitivity 
analysis exploring safety and efficacy in Japanese patients is performed as appropriate using the 


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Japanese population.  The Japanese population is used for evaluation of efficacy and safety 
overall and by relevant subgroups to support potential future regulatory submissions to PMDA in 
Japan. 
6.4. 
Baseline Definition 
Baseline values are defined as the last non-missing assessment prior to the first study drug 
administration, unless otherwise specified below.  If the first study drug administration occurs 
after the date of randomization, the last measurement prior to the first study drug administration 
is considered the Day 1 measurement for the calculation of baseline.  Assessments without time-
stamp collected on the same date as the first date of study drug administration are considered to 
occur before the first dose of study drug administration.   
6.4.1. 
Estimated Glomerular Filtration Rate 
Baseline eGFR is defined as the average of screening and Day 1 eGFR measurement, calculated 
as shown below:  
x Screening eGFR = average of the last two eGFR measurements collected prior to the 
Day 1 eGFR collection 
x Day 1 eGFR = the measurement on the date of first study drug administration prior to 
the first study drug administration 
x Baseline eGFR = (0.5 × Day 1 eGFR) + (0.5 × Screening eGFR)  
6.4.2. 
Serum Creatinine 
Baseline serum creatinine (SCr) is defined in the same way as baseline eGFR (Section 6.4.1).  
6.4.3. 
Safety Assessments 
Baseline for continuous safety assessments (i.e., vital sign assessments, weight, BMI, and 
laboratory measurements) is defined as the average value of measurements collected up through 
the date of, but not after, first study drug administration.    
6.4.4. 
Urine Albumin to Creatinine Ratio 
Baseline ACR is defined as the last ACR value prior to the first study drug administration.  
Baseline ACR is summarized using the geometric mean of ACR values.  
6.4.5. 
Natural log(ACR)/eGFR 
Baseline of natural log(ACR)/eGFR is defined as the ratio of the natural log of baseline ACR 
(Section 6.4.4) divided by baseline eGFR (Section 6.4.1). 
6.4.6. 
Baseline Hematuria 
Presence of hematuria at baseline is defined as red blood cells per high power field (RBC/HPF) 
> 2 in two measurements prior to the first dose of study drug.  If only one RBC/HPF 
measurement is available prior to the first dose of study drug, that measurement is used to 
determine baseline hematuria.  


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If no RBC/HPF measurements are available prior to the first dose of study drug, urine occult 
blood dipstick measurements is used to determine baseline hematuria.  If the two occult blood 
measurements prior to the first dose of study drug result is not ‘trace’ or ‘negative’ (e.g., result is 
+1,+2, or +3), then the patient is considered to have baseline hematuria.  If no RBC/HPF 
measurement is available and only one occult blood measurement prior to the first dose of study 
drug is available, then the patient is considered to have baseline hematuria if the results are not 
‘trace’ or ‘negative’.  
6.4.7. 
Baseline Visual Impairment 
Patients with normal visual acuity are those with 20/20 vision or better (e.g., 20/15, 20/10, etc.) 
in both eyes.  Any patient whose vision is worse than 20/20 in either eye is considered to have 
visual impairment.  
6.4.8. 
Baseline Audiology Impairment 
Patients with normal hearing are those with pure tone audiometry (PTA) < 25 decibels in both 
ears.  Any patient with > 25 decibel hearing in either ear is considered to have audiology 
impairment.  
6.5. 
Derived and Transformed Data 
6.5.1. 
Age  
Subject’s baseline age is defined as the age at consent (Screen A).  Subject’s age used for each 
eGFR calculation (Section 6.5.6) is the age on the date of each serum creatinine collection.  
Calculated age is rounded down to the nearest whole year and expressed as an integer: 
x Age (year) = Floor ((visit date – date of birth)/365.25) 
6.5.2. 
Study Day 
Study day is the day relative to the date of randomization.  Day 1 is defined as the date of 
randomization.  Assessments that occur after randomization but before the first dose of study 
drug are considered to occur on study Day 1.   
Assessments without time-stamp collected on the same date as the first date of study drug 
administration are considered to occur before the first dose of study drug administration. 
For visits (or events) after randomization, day is calculated as: 
x Study day = visit (or event) date - date of randomization + 1 
For visits (or events) before randomization, day is calculated as: 
x Study day = visit (or event) date - date of randomization 
The quantity ‘days since first dose’ is defined as: 
x days since first dose  = visit (or event) date – date of first  + 1  
The quantity ‘days since last dose’ is defined as: 
x days since last dose = visit (or event) date - date of last dose 


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For summaries that present distribution of time expressed in weeks and months, weeks are 
defined as days divided by seven and months as days divided by 30.4. 
6.5.3. 
Change from Baseline 
Change from baseline is calculated using the baseline value (Section 6.4) and the value closest to 
the target study day, using the rules defined in Section 6.5.4. 
6.5.4. 
Visit Windows 
Analysis visits and their windows are defined using derived study day (Section 6.5.2) instead of 
relying on visit labels in the clinical database because clinical visits may occur outside protocol-
specified windows.  Study day and days after last dose are calculated using the actual date of 
each scheduled and unscheduled assessment and compared to the target for each analysis visit as 
specified in Table 3 and Table 4.  They are included in analyses of safety and efficacy as 
follows: 
x Efficacy analyses for endpoints assessed at Week 48 or Week 100 use the analysis 
windows based on target study day in Table 3, irrespective of whether or not a patient is 
receiving treatment of study drug efficacy analyses for Week 100 will not include the 
Week 52 data. 
x Efficacy analyses for endpoints assessed at Week 52 or Week 104 use the off-treatment 
analysis windows based on days after last dose in Table 3.   
x Safety analyses use the analysis windows defined in Table 3 so long as the patient is 
receiving treatment of study drug.  Safety follow-up at Week 52 will also be summarized 
according to Table 3 so long as the patient has not permanently discontinued treatment 
prior to Week 52.  Similarly, safety follow-up at Week 104 is summarized according to 
Table 3 for patients completing treatment through Week 100.  Once a patient 
permanently discontinues study treatment, safety data are summarized according to time 
since last dose as defined in Table 4.  
If a parameter is assessed or measured more than once within a visit window, the one that is 
closest to the protocol-scheduled time point (i.e., target) is used for the purposes of data analysis 
and summary.  If two assessments are equidistant from a target, the earlier assessment is used.  If 
the visit used for analysis includes two assessments on the same day, the average of the two 
measurements is used.  
Records from visits not closest to the target study day, and therefore not used in analyses, are 
presented in by-subject data listings. 
Table 3.  Analysis Visit Windows 
Analysis Visit  
Label 
Target  
Analysis Window 
Study 
Daya 
Days After 
Last Dose 
0 
Day 1b 
1 
- 
1 
1 
Week 1 
7 
- 
2   study day  10 
2 
Week 2 
14 
- 
11  study day  21 


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Analysis Visit  
Label 
Target  
Analysis Window 
Study 
Daya 
Days After 
Last Dose 
4 
Week 4 
28 
- 
22  study day  35 
6 
Week 6 
42 
- 
36  study day  49 
8 
Week 8 
56 
- 
50  study day  70 
12 
Week 12 
84 
- 
71  study day  126 
24 
Week 24 
168 
- 
127  study day  210 
36 
Week 36 
252 
- 
211  study day  294 
48 
Week 48c 
336 
- 
295  study day  350 
52 
Week 52d 
- 
28 
14  Days after last dosee  35 
64 
Week 64 
448 
- 
407  study day  490 
76 
Week 76 
532 
- 
491  study day  574 
88 
Week 88 
616 
- 
575  study day  658 
100 
Week 100f 
700 
- 
659  study day  714 
104 
Week 104g 
- 
28 
14  days after last doseh  35 
a Study Day is relative to the date of randomization (Section 6.5.2).   
b Day 1 is the last measurement prior to the first study drug administration.   
c Week 48 is the end of the first-year dosing interval and should coincide with the last dose in the first year.  
d Week 52 is the first-year dosing interval 4-week follow-up; must be after the last dose in the first year and before 
receiving treatment in the second year.  
e Last dose for analysis visit 52 is the Week 48 dose or date of last dose for permanent study drug discontinuation 
prior to Week 48.  
f Week 100 is the end of the second-year dosing interval and should coincide with the last dose in the second year. 
g Week 104 is the second-year dosing interval 4-week follow-up; patient must have been dispensed treatment in the 
second year (i.e., Week 52), otherwise Week 104 is considered missing.  
h Last dose for analysis visit 104 is the Week 100 dose or date of last dose for permanent study drug discontinuation 
after Week 52 and prior to Week 100.  
 
6.5.4.1. 
Off-Treatment Visit Windows 
Patients who permanently discontinue study drug prior to Week 100 are asked to resume the 
planned assessments according to the study schedule in the protocol.  Off-treatment values for 
clinical laboratory evaluations (Section 10.5), vital signs (Section 10.6), and electrocardiograms 
(Section 10.8) are those that occur after the last dose date for patients permanently discontinuing 
study drug prior to Week 100, and is summarized relative to their last dose of study drug.  Off-
treatment safety assessments are grouped for analyses according to the strategy in Table 4.  
Assessments that occur on the date of last dose are considered on treatment. 


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Table 4.  Analysis Visits for Off-Treatment Safety Analysis 
Off-
Treatment 
Analysis 
Visit 
Label 
Target Study Day 
(days after last 
dose) 
Analysis Window 
0 
Last dose 
(on-treatment)a 
0 
0 
4 
Off Treatment 
4-weeksb 
28 
14  days after last dose  35 
8 
Off Treatment 
8-weeksb 
56 
36  days after last dose   
12 
Off Treatment 
12-weeksb 
84 
  days after last dose   
24 
Off Treatment 
24-weeksb 
168 
  days after last dose   
48 
Off Treatment 
48-weeksb 
336 
  days after last dose   
a Last dose for patients permanently discontinuing study drug prior to Week 100 Assessments that occur on the date 
of last dose or less than 14 days after last dose are considered on treatment 
b The off-treatment values indicate the value closest to the date of last dose.  Results are summarized by Year 1, 
Year 2, and overall.  
 
6.5.5. 
Laboratory Evaluations 
Post-baseline laboratory assessments less than the lower limit of detection (i.e., < LLD) are 
imputed as LLD/2.  If no LLD is available, then the imputed value is the minimum numeric 
value listed divided by 2 (e.g., < 25 is 25/2=12.5).  Laboratory assessments above the ULD are 
imputed as the ULD.  If the lab result is qualitative but presented as > X and X is 10 times 
greater than the ULN, then the value X is used in the analysis.  
6.5.6. 
Estimated Glomerular Filtration Rate (eGFR) 
The eGFR is calculated using the formula below according to patient’s age at the date of consent.  
The formula will not change throughout the study.  The Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation is used for adult patients (age at consent at least 18 years): 
x eGFR (mL/min/1.73 m2) = 141 × min(Scrț Į × max(Scrț -1.209 × 0.993Age ×  
1.018 [if female] × 1.159 [if black] 
The Bedside Schwartz equation is used for pediatric patients (age at consent of 12 to 17): 
x eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Scr  
where Scr LV VHUXP FUHDWLQLQH PJG/ ț LV  IRU IHPDOHV RU  IRU PDOHV DQG Į LV -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scrț DQG  DQG PD[ LQGLFDWHV WKH
maximum of Scrț DQG .  Age indicates age at time of serum creatinine collection.  Height 
indicates height at time of serum creatinine collection. 


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6.5.6.1. 
Prognosis of CKD by eGFR and Albuminuria Category 
Prognosis of CKD is determined by the intersection of the following eGFR and albuminuria 
categories (KDIGO 2012): 
Table 5. eGFR Category 
eGFR 
Category 
eGFR (mL/min/1.73 m2) 
1 
  
2 
60 to < 90 
3a 
45 to < 60 
3b 
30 to < 45 
4 
15 to < 30 
5 
< 15 
 
Table 6. Albuminuria Category 
ACR 
Category 
ACR (mg/g) 
1 
< 30 
2 
30 to  300 
3 
> 300 
 
6.5.7. 
Urine Albumin to Creatinine Ratio (ACR) 
ACR is provided in the central laboratory database as the ratio of urine albumin to urine 
creatinine from the first morning void (FMV) urine collection.  The ACR value is reported in the 
central laboratory database as missing when the FMV urine albumin result is < LLD.  Urine 
albumin results < LLD and the corresponding ACR missing values are imputed as follows: 
x If urine albumin result = < LLD, then  
 Imputed urine albumin result (mg/dL) = LLD/2  
 Imputed ACR(mg/g) = (imputed urine albumin result in mg/dL) / [(urine 
creatinine in mg/dL) /1000] 


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The ACR results are log-transformed for analysis to produce data that are more normally 
distributed.  Any imputed ACR result where ACR=0 is considered to be 0.1 mg/g for purposes of 
calculating the geometric mean. 
6.5.7.1. 
Baseline Urine Albumin to Creatinine Ratio (ACR) Categorical Status 
Baseline ACR status will also be grouped by the following categories using baseline ACR: 
x < 30 mg/g 
x 30 mg/g < ACR <= 300 mg/g 
x 300 mg/g < ACR <= 1000 mg/g 
x 1000 mg/g < ACR <= 3500 mg/g 
x ACR > 3500 mg/g 
6.5.7.2. 
ACR Category used in Stratification (ACR_STRAT) 
The ACR category used for stratification (ACR_STRAT) is determined by the randomization list 
with the following categories: 
x ACR <= 300 mg/g 
x 300 mg < ACR <= 1000 mg/g 
x 1000 mg/g < ACR <=3500mg/g 
6.5.8. 
Electrocardiogram Fridericia Corrected QT Interval 
Electrocardiogram intervals are assessed locally at each site.  The following formula is used to 
calculate the QTcF interval for analysis from QT and RR intervals:  
x ܳܶܿܨ=  ܳܶ/ξܴܴ
య
 
where RR = 60 / (Heart Rate). 
6.5.9. 
Log of The Minimum Angle of Resolution  
Best-corrected visual acuity (BCVA) assessments are performed at time points specified in the 
scheduled assessments in Table 2.  The Snellen chart values are used to derive the log of the 
minimum angle of resolution (logMAR) value as below: 
x LogMAR = - log10 (Snellen) 
6.5.10. 
Natural log(ACR)/eGFR 
To evaluate ACR after adjusting for filtration rate, ln(ACR)/eGFR (Sections 6.5.7 and 6.5.6) is 
assessed. 
6.5.11. 
Exposure Duration 
Exposure duration is used in analysis of efficacy to adjust analysis of off-treatment eGFR for the 
exposure duration within each year.  Fraction of expected exposure duration is calculated for the 
first and second years of treatment as follows: 


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x First year exposure (TRT_EXP1) =  
[(date of last dose in first year) – (date of first dose)]/336 
x Second year exposure (TRT_EXP2) =  
[(date of last dose in second year) – (date of first dose)]/700 
where 336 is the number of days in the first year (i.e., 48-week) treatment interval, and 700 is the 
number of days in the second year (i.e., 100-week) treatment interval.  Exposure in the second 
year is simply total exposure and does not subtract the 4-week off-treatment period at the end of 
the first year. 
6.6. 
Handling of Missing Data 
6.6.1. 
Missing Efficacy Endpoint Data 
The primary analysis of efficacy is based on an assumption of missing at random (MAR) 
(Section 8.5).  The tipping point sensitivity analysis (Section 8.6.2.1) is performed to assess how 
severe departures from MAR must be in order to overturn conclusions from the primary analysis. 
6.6.1.1. 
Missing eGFR for MMRM Analyses 
Missing eGFR data are not imputed for the primary MMRM analysis of the primary endpoints 
(Week 48 and Week 100).  A set of sensitivity analyses is included to assess the robustness of 
conclusions to the MAR assumption (see Section 8.6.2 and Section 8.8.2) for the primary 
analysis of the primary endpoints (Week 48 and Week 100).  
6.6.1.2. 
Missing eGFR for ANCOVA Analyses 
Missing eGFR data are imputed for the primary ANCOVA analysis of the key secondary 
endpoints (Week 52 and Week 104) using multiple imputation based on an assumption of MAR.  
A set of sensitivity analyses is included to assess the robustness of conclusions to the MAR 
assumption (see Section 8.7.2 and Section 8.9.2) for the primary analysis of the key secondary 
endpoints (Week 52 and Week 104).  
6.6.2. 
Missing Start and Stop Dates for Concomitant Medication 
Missing start dates for concomitant medications are not imputed.   
Concomitant medications with incomplete end dates are considered concomitant medications if: 
x Day and month are missing, and the year is equal to or after the year of the first date 
of study drug administration;  
x Day is missing and the year is after the year of the first date of study drug 
administration;  
x Day is missing and the year is equal to the year of the first date of study drug 
administration and the month is equal to or after the month of the first date of study 
drug administration; or 
x Year is missing. 


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6.6.3. 
Missing Start and Stop Dates for Adverse Events 
Treatment-emergent adverse events (TEAEs) are events that either: 
x Have a date of onset on or after the date of the first dose and not more than 30 days 
after the date of the last dose of study drug, or  
x Have no recorded date of onset with a stop date after the first dose of study drug, or 
x Have no recorded date of onset or stop date. 
Adverse events with incomplete start dates are considered after the date of first dose if: 
x Day and month are missing and the year is equal to or after the year of the first date 
of study drug dosing;  
x Day is missing and the year is after the year of the first date of study drug dosing;  
x Day is missing and the year is equal to the year of the first date of study drug dosing 
and the month is equal to or after the month of the first date of study drug dosing; or 
x Year is missing. 
Adverse events with incomplete start dates are considered on or within 30 days of last dose, if: 
x Day and month are missing and the year is equal to or before the year of the date of 
last dose of study drug plus 30 days; 
x Day is missing and the year is equal to or before the year of the date of last dose of 
study drug plus 30 days and month is equal to or before the month of the date of last 
dose of study drug plus 30 days; 
x Year is missing. 


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7. 
STUDY POPULATION 
7.1. 
Subjects Disposition 
A disposition summary includes the number and percentage of patients in all analysis 
populations in the following categories:  
 
Disposition - Year 1 
x Per-protocol Population – Year 1 
x Completed treatment through Week 48 
x Discontinued treatment prior to Week 48 
 reason for discontinuing treatment 
x Completed study follow-up through Week 52 
 on-treatment 
 discontinued treatment early but completed in-person study visits 
 continued to Year 2 follow-up 
x Terminated from the trial before Week 52 
x Follow-up by Year 1 study week 
 discontinued treatment 
 follow-up in-clinic 
 follow-up phone 
 
Disposition - Year 2 
x Per-protocol Population – Year 2 
x Received at least one dose in Year 2 
x Completed treatment through Week 100 
x Discontinued treatment prior to Week 100 
 reason for discontinuing treatment 
x Completed study follow-up through Week 104 
 on-treatment 
 discontinued treatment early but completed study visits 
x Terminated from the trial before Week 104 
x Follow-up by Year 2 study week 


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 discontinued treatment 
 follow-up in-clinic 
 follow-up phone 
Patients who completed follow-up are defined as those who were followed by phone or in-person 
through the Week 104 visit.  A listing of disposition is provided for all enrolled patients.   
7.2. 
Screen Failures 
Screen failures are not summarized. 
7.3. 
Protocol Deviations 
Prior to database lock at Year 1, a blinded team will perform a blinded data review to identify all 
deviations, including major protocol deviations that could potentially affect the efficacy 
conclusions of the study, to define the Per-Protocol population (see Section 6.3.2 and 
Section 6.3.3).  A blinded team will repeat the blinded data review process for Year 2 deviations 
prior to the Year 2 database lock.  Protocol deviations for excluded medications, patients who 
entered the study even though they did not satisfy all entry criteria, patients who received the 
wrong treatment or incorrect dose, and major protocol deviations are listed.    
7.4. 
Demographic and Baseline Characteristics 
Summaries of demographic and other baseline characteristic data are presented by treatment 
group for all analysis populations.  They may also be summarized by select subgroups (including 
US and non-US) as appropriate (Section 8.3).   
The demographic and other baseline characteristics include:  
x Baseline Age, Age category (<   18) 
x Sex, Race, Ethnicity 
x Weight (kg), Height (cm), BMI (kg/m2) 
x Diastolic and systolic blood pressure (mmHg), Heart rate (bpm) 
x Serum creatinine, eGFR, eGFR categorical status (<   60) 
x ACR, ACR categorical status ( 300; > 300), ACR Stratum 
x Prognosis of CKD by eGFR and Albuminuria categories 
x Hematuria (present/absent) 
x Angiotensin converting enzyme (ACE)-inhibitor treatment and/or Angiotensin II 
receptor blocker (ARB) (yes/no) 
x Other baseline variables of interest 
Alport syndrome related information includes: 
x Age at Alport syndrome diagnosis 


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x Genetic subtype (x-linked, autosomal, unknown) 
x Genotype (COL4A3, COL4A4, COL4A5, Unknown) 
x Confirmed histologic diagnosis 
x Hearing loss (yes/no) 
x Visual impairment (yes/no)  
7.5. 
Listing of Subject Inclusion and Exclusion Criteria 
A listing of enrolled patients who did not meet inclusion or exclusion criteria is generated. 
7.6. 
Medical History  
Medical history is summarized by treatment.  Medical history is coded using MedDRA (Medical 
Dictionary for Regulatory Activities) version 19.1.  Medical history items are summarized by 
MedDRA SOC and PT.   
7.6.1. 
Historical eGFR 
To characterize disease progression prior to trial entry, up to 5 years of historical serum 
creatinine values are collected for each patient as part of their medical history.  Collection of 
historical serum creatinine is subject to availability of data from medical records; therefore, the 
number of available values will vary by patient and some patients may have no historical values.  
Historical serum creatinine values are converted to mg/dL and eGFR are calculated for analysis 
according to the appropriate equation (Section 6.5.6) using the patient age at laboratory 
collection for adult patients, or patient height at Screening for pediatric patients.  Historical 
serum creatinine values were analyzed at various local laboratories (i.e., not collected as part of 
central lab data).  Therefore, historical serum creatinine and corresponding eGFR values are 
considered part of a patient’s medical history, and distinct from central lab assessments collected 
as part of the trial.   
The eGFR values used in the analysis dataset for the baseline label are the baseline eGFR values 
for each patient (defined in Section 6.4.1), not the individual Screen A, Screen B, and Day 1 
eGFR values.   
Historical values are prior to first dose and have a negative Study Day value: 
x Study Day = (Date of Historical Lab Collection) – (Date of Screen A) 
 
 


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Summary statistics of available historical eGFR results are based on the following analysis 
windows:  
Table 7.  Labels for Summary of Historical Change in eGFR 
Analysis Visit 
Label 
Study Day Windows 
-5 
Historical Year 5 
1825 to 1461 days prior to Screen A 
-4 
Historical Year 4 
1460  to 1096 days prior to Screen A 
-3 
Historical Year 3 
1095  to 731 days prior to Screen A 
-2 
Historical Year 2 
730 to 366 days prior to Screen A 
-1 
Historical Year 1 
365 to 1 days prior to Screen A 
0 
Baseline 
Screen A to Day 1 
The summary statistics will include the average eGFR value by patient and analysis time point.  
For instance, if multiple values are listed in the historical Year 1 results for a given patient, the 
average of those values is used to calculate the summary statistics.   
Summary statistics of eGFR results by historical year (listed in Table 7) will also be summarized. 


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8. 
PRIMARY EFFICACY  
Analyses of efficacy described in this section are the primary analyses of the Phase 3 efficacy 
endpoints, and pertain to the ITT population (i.e., all patients randomized in the Phase 3 portion 
of the study).  The trial includes endpoints following one and two years of treatment. Additional 
details regarding the statistical approach and pseudo SAS code are available in the programming 
conventions document. 
The following abbreviations are used in descriptions of the analysis models: 
Table 8.  Model Parameter Abbreviations 
Abbreviation 
Model Term 
ACR_STRAT 
ACR strata used in randomization 
BASE_eGFR 
Baseline eGFR 
BASE_eGFR x VISIT 
the interaction between baseline eGFR and time 
TRT 
treatment group 
TRT_EXP1_ 
fraction of one-year exposure to treatment (Section 6.5.11) 
TRT_EXP2 
fraction of two-year exposure to treatment (Section 6.5.11) 
TRT x VISIT 
the interaction between treatment and time 
VISIT 
analysis visit used as time 
8.1. 
General Considerations 
Analyses are performed for all bardoxolone methyl patients in comparison with all placebo 
patients.  Summary statistics for observed values, change from baseline, and percent change from 
baseline are presented by randomized treatment group.  Missing values are imputed as described 
in Section 8.5.   
8.2. 
Statement of the Null and Alternate Hypotheses 
All primary and key secondary efficacy endpoints compare the change from baseline in eGFR 
for patients randomized to bardoxolone methyl (ȝ BARD) to the change from baseline in eGFR for 
patients randomized to placebo (ȝ placebo) at the endpoint-specified visit according to the 
following hypotheses: 
x H0: (ȝ BARD) – (ȝ placebo) = 0 mL/min/1.73 m2  
x H1: (ȝ BARD) – (ȝ placebo)   mL/min/1.73 m2 
Because eGFR decreases with disease progression, an increase in eGFR relative to placebo is 
considered evidence of benefit. 
8.3. 
Subgroup Analyses 
The primary and key secondary efficacy endpoints are analyzed for subgroups of interest to 
assess homogeneity of the effect size for those subgroups that are sufficiently large to warrant 
these analyses.  Exploratory endpoints are also analyzed for these subgroups.   


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The following subgroup analyses are tabulated: 
x Age (years): < 18;  18 
x Sex: female; male  
x Geographic location: US;  Non-US 
x Ethnicity:  Non-Hispanic/Latino; Hispanic/Latino 
x Race: White; Non-White 
x Baseline BMI (kg/m2): < 30;   
x Baseline eGFR (mL/min/1.73 m2  60; > 60 
x Baseline ACR (mg/g)   !  
x Baseline ACEi/ARB use: Yes; No  
x Genetic subtype: X-linked Alport syndrome (XLAS); Non-XLAS 
Subgroup analyses will include nominal significance levels for descriptive purposes only.  Forest 
plots are generated for change from baseline eGFR results in each subgroup at Weeks 48, 52, 
100, and 104.  
8.4. 
Multiple Comparisons and Multiplicity 
The trial includes separate Phase 2 and Phase 3 cohorts, where the cohorts constitute independent 
sets of patients.  Therefore, the Phase 2 analysis has no impact on the Type I error rate for the 
Phase 3 analysis.   
The Phase 3 cohort includes a family of hypothesis tests following the first year of treatment and 
a second family of hypothesis tests following the second year of treatment.  All endpoints tested 
at Year 1 will use a significance level of 0.025 and those tested at Year 2 will also use a 
significance level of 0.025. Within each year, endpoints are tested following a fixed-sequence 
hierarchical testing strategy.  Formal testing in the sequence may proceed so long as statistically 
significant evidence of benefit continues to be shown.  At such point in the sequence that one 
endpoint does not show statistically significant evidence of benefit, formal statistical testing of 
subsequent endpoints will not occur.   
Testing endpoints in the following sequence protects the overall type I error rate of 0.05 for the 
study: 
Year 1 Testing Sequence (all significance levels = 0.025) 
1. eGFR at Week 48 (primary at Year 1)  
2. eGFR at Week 52 (key secondary at Year 1)  
 
Year 2 Testing Sequence (all significance levels = 0.025) 
1. eGFR at Week 100 (primary at Year 2) 
2. eGFR at Week 104 (key secondary at Year 2) 


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3. time-to first kidney failure composite (exploratory at Year 2) 
4. distribution of PGIC at Week 100 
5. distribution of CGI-I at Week 100 
All remaining endpoints are considered “Exploratory” and presented with nominal significance 
levels for descriptive purposes only.  
8.5. 
Handling of Missing Data 
Missing data will not be imputed for analysis of exploratory efficacy endpoints. 
8.5.1. 
Missing eGFR for Sensitivity Analyses 
Multiple imputation is the primary approach used to account for missing data in sensitivity 
analyses of the primary efficacy endpoints (i.e., Week 48 and Week 100) and the key secondary 
endpoints (i.e., Week 52 and Week 104).  Results of sensitivity analyses are summarized in 
tables and forest plots.  
8.5.2. 
Missing eGFR for MMRM Analyses 
The primary analysis of efficacy endpoints is based on the assumption of missing at random 
(MAR).  Missing data are not imputed for the primary analysis of eGFR where the analysis 
method is defined as MMRM (i.e., Week 48 and Week 100) (Section 6.6.1.1).   
8.5.3. 
Missing eGFR for ANCOVA Analyses 
Missing eGFR data are imputed using multiple imputation for the primary analysis of eGFR 
where the analysis method is defined as ANCOVA (i.e., Week 52 and Week 104) 
(Section 6.6.1.2).  For the primary analysis, multiple imputation is based on the treatment group 
to which the subject is assigned.  A tipping point analysis is used to assess the validity of the 
MAR assumption. 
8.6. 
Year 1:  Primary Efficacy Endpoint 
The analyses of the primary and key secondary endpoints are described in Sections 8.6 and 8.7.  
Additional details and pseudo SAS code are provided in a separate document. 
8.6.1. 
Primary Analysis of the Year 1 Primary Efficacy Endpoint 
The Year 1 primary endpoint of this study is the change in eGFR at Week 48 (i.e., the end of the 
first year of drug exposure).  The change from baseline eGFR for patients treated with 
bardoxolone methyl is compared with placebo at Week 48 using mixed models repeated 
measures (MMRM) analysis, with baseline eGFR (BASE_eGFR),  ACR strata (ACR_STRAT), 
and fraction of one-year exposure to treatment (TRT_EXP1) as covariates and the following 
fixed factors: treatment group (TRT), time (i.e., VISIT; analysis visit number), the interaction 
between treatment and time (TRT x VISIT), and the interaction between baseline eGFR and time  
(BASE_eGFR x VISIT) as covariates.  Inclusion of the fraction of expected one-year exposure to 
treatment (Section 6.5.11) in the MMRM model as a covariate provides an adjustment for eGFR 
values collected from early discontinuation patients having less than 1-year of drug exposure.   


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The trial design separates discontinuation of study drug from discontinuation of study follow-up.  
Therefore, patients may discontinue early from study drug while continuing follow-up with study 
visits and assessments.  The primary analysis of eGFR at Week 48 uses available eGFR values 
irrespective of whether or not a patient is receiving treatment.  The MMRM analysis uses all 
eGFR values collected through Week 48 according to analysis visits 0, 1, 2, 4, 6, 8, 12, 24, 36, 
and 48 (Section 6.5.4).  An unstructured covariance matrix is used. 
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures are substituted, in the order listed.  Each subsequent covariance 
structure is used only if each previous covariance structure is used and no previous model 
converged. 
1. Heterogeneous Toeplitz covariance structure (assuming different variances at each time 
point and that measurements taken closer together in time are more highly correlated than 
those taken farther apart). 
2. Toeplitz covariance structure (assuming measurements taken closer together in time are 
more highly correlated than those taken farther apart). 
3. First order auto-regressive [AR(1)] covariance structure (assuming measurements taken 
closer together in time are more highly correlated than those taken farther apart, but the 
correlation is more constrained than the Toeplitz structure). 
4. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a patient, regardless of how far apart in time they were taken).  A compound 
symmetry covariance structure was assumed in the sample size calculation. 
The difference between bardoxolone methyl and placebo in change from baseline of eGFR is 
estimated along with the 95% confidence interval at Week 48 for the primary analysis of the 
Year 1 primary endpoint.   
8.6.2. 
Sensitivity Analyses 
Sensitivity analyses are included to assess the robustness of conclusions to the primary analysis 
of the Year 1 primary efficacy endpoint (i.e., change in eGFR at Week 48), and to assess the 
assumption of MAR.  The following sets of sensitivity analyses will be summarized in tables and 
forest plots: tipping point with multiple imputation, control-based imputation, MMRM fit to the 
as-treated population, and MMRM fit to the per protocol population.  Additional sensitivity 
analyses may be performed as appropriate. 
8.6.2.1. 
Tipping Point 
The following tipping point sensitivity analysis is performed to assess how severe departures 
from MAR must be in order to overturn conclusions from the primary analysis: 
1. The PROC MI procedure in SAS is used to generate 100 datasets satisfying the 
assumption of monotone missingness, imputing any missing eGFR values using multiple 
imputation.  Imputation is based on the non-missing observations within each treatment 
group.  


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2. The PROC MI procedure in SAS is applied to each of the 100 datasets subsetted to the 
placebo group and all missing values in the placebo group are imputed.  These 100 
datasets will then be used for the tipping point analysis. 
3. For the tipping point analysis with a shift parameter, patients in the bardoxolone methyl 
group with a missing value will be multiply imputed separately from the placebo-
treatment arm and are assigned a shift parameter in the imputation procedure for 
progressively worse (lower) scores to find the point at which statistical significance is 
lost.  Specifically, if the outcome of the hypothesis test favors bardoxolone methyl over 
the placebo group (p-value <0.025), then one point is subtracted as a shift parameter in 
the imputation for the bardoxolone methyl group, while keeping the data for the placebo 
group unchanged.  
4. A mixed model repeated measures (MMRM) model (see Section 8.6.1) is used to analyze 
each of the 100 completed data sets.  PROC MIANALYZE is used to combine these 
results to obtain the final estimates for the given value of the shift parameter. 
5. This “eGFR shifting”, as outlined in steps 3 and 4, is repeated with one shift point at a 
time until the hypothesis test no longer rejects the null hypothesis in favor of the 
bardoxolone methyl group over the placebo group (i.e., when the p-value becomes 
greater than 0.025).  Additional increments may be used to locate the tipping point.  If the 
result is not quite statistically significant, progressively higher scores are added to find 
the point at which statistical significance is attained. 
8.6.2.2. 
As-Treated Analysis 
The primary analysis of efficacy includes all eGFR values collected during trial follow-up 
through Week 48, regardless of patient receiving study drug.  The as-treated sensitivity analysis 
to assess the treatment effect while receiving study drug is based on the ITT population, but 
excludes any eGFR values collected after final dose.  The as-treated analysis is performed using 
the MMRM statistical model defined in Section 8.6.1, with eGFR values collected after final 
dose treated as missing.  Missing data are not imputed for the as-treated sensitivity analysis.  
8.6.2.3. 
Per-Protocol Population Analysis 
The per-protocol population analysis is performed for the per-protocol population (Year 1) using 
the MMRM statistical model defined in Section 8.6.1.  Missing data will not be imputed for the 
per-protocol population sensitivity analysis. 
8.7. 
Year 1: Key Secondary Endpoint 
8.7.1. 
Primary Analysis of Year 1 Key Secondary Endpoint 
The Year 1 key secondary endpoint of this study is the change in eGFR at Week 52 (i.e., 4 weeks 
following the last dose after one year of drug exposure).  Analysis of Week 52 assesses the 
preserved drug benefit (relative to placebo) following withdrawal of treatment; therefore, 
analysis of Week 52 data does not include the eGFR values collected during treatment.   
The change from baseline eGFR at Week 52 for patients treated with bardoxolone methyl is 
compared to placebo using an analysis of covariance (ANCOVA) model, with BASE_eGFR, 


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ACR_STRAT, and TRT_EXP1 as covariates, and TRT as the fixed effect.  Inclusion of the 
fraction of expected one-year exposure to treatment (TRT_EXP1; Section 6.5.11) in the 
ANCOVA model as a covariate provides an adjustment for eGFR values collected from early 
discontinuation patients having follow-up collected after less than 1-year of drug exposure.   
The ANCOVA analysis uses eGFR values collected in the Week 52 analysis window 
(Section 6.5.4), which includes the follow-up assessment for patients who discontinued treatment 
early in the first year.  Missing Week 52 eGFR data are imputed as defined in Section 8.5.3 using 
standard imputation.  
The difference between bardoxolone methyl and placebo in change from baseline of eGFR is 
estimated along with the 95% confidence interval at Week 52.   
8.7.2. 
Sensitivity Analyses 
Sensitivity analyses are included to assess the robustness of conclusions to the primary analysis 
of the Year 1 key secondary efficacy endpoint (i.e., change in eGFR Week 52), and to assess the 
assumption of MAR.  The following sets of sensitivity analyses are summarized in tables and 
forest plots: tipping point with multiple imputation, control-based multiple imputation, and the 
ANCOVA model fit to the per protocol population.  Additional sensitivity analyses may be 
performed as appropriate. 
8.7.2.1. 
Tipping Point 
The following tipping point sensitivity analysis is performed to assess how severe departures 
from MAR must be in order to overturn conclusions from the primary analysis: 
1. The PROC MI procedure in SAS is applied to create 100 datasets with all missing values 
in the placebo group imputed based on the subjects in the placebo group.  These 100 
datasets will then be used for the tipping point analysis. 
2. For the tipping point analysis with a shift parameter, patients in the bardoxolone methyl 
group with a missing value will be multiply imputed separately from the placebo-
treatment arm and are assigned a shift parameter in the imputation procedure for 
progressively worse (lower) scores to find the point at which statistical significance is 
lost.  Specifically, if the outcome of the hypothesis test favors bardoxolone methyl over 
the placebo group (p-value <0.025), then one point is subtracted as a shift parameter in 
the imputation for the bardoxolone methyl group, whilst the data for the placebo group 
will not be changed.  
3. The ANCOVA model (see Section 8.7.1) is used to analyze each of the 100 completed 
data sets and PROC MIANALYZE is used to combine these results to obtain the final 
estimates for the given value of the shift parameter. 
4. This “eGFR shifting”, as outlined in steps 2 and 3, is repeated with one shift point at a 
time until the hypothesis test no longer rejects the null hypothesis in favor of the 
bardoxolone methyl group over the placebo group (i.e. when the p-value becomes greater 
than 0.025).  Additional increments may be used to locate the tipping point.  If the result 
is not quite statistically significant, progressively higher scores are added to find the point 
at which statistical significance is attained. 


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8.7.2.2. 
Control-Based Multiple Imputation 
As a sensitivity analysis, all missing Week 52 eGFR values are imputed with multiple imputation 
using the Week 52 data from the placebo group.  The control-based sensitivity analysis is 
performed using the ANCOVA statistical model defined in Section 8.7.1. 
8.7.2.3. 
Per-Protocol Population Analysis 
The per-protocol population analysis is performed for the per-protocol population (Year 1) using 
the ANCOVA statistical model defined in Section 8.7.1.  Missing data will not be imputed for 
the per-protocol population sensitivity analysis. 
8.8. 
Year 2:  Primary Efficacy Endpoint 
The analyses of the primary and key secondary endpoints for the Year 2 analyses are described 
in Sections 8.8 and 8.9.  Additional details and pseudo SAS code are provided in a separate 
document. 
8.8.1. 
Primary Analysis of the Year 2 Primary Efficacy Endpoint 
The Year 2 primary endpoint of this study is the change in eGFR at Week 100 (i.e., the end of 
the second year of exposure).  The change from baseline in eGFR for patients treated with 
bardoxolone methyl is compared with placebo at Week 100 using the statistical model defined in 
Section 8.6.1 with the following modifications:   
x The analysis uses all eGFR values collected through Week 100 according to analysis 
visits 0, 1, 2, 4, 6, 8, 12, 24, 36, 48, 64, 76, 88, and 100 (Section 6.5.4).  
x TRT_EXP2 is added as a covariate and TRT_EXP1 is removed.  
Inclusion of the fraction of expected two-year exposure to treatment (TRT_EXP2; 
Section 6.5.11) in the MMRM model as a covariate provides an adjustment for eGFR values 
collected from early discontinuation patients having less than 2-years of drug exposure.  All 
eGFR values collected in the Week 52 analysis window assess the effect following 4-weeks of 
drug withdrawal and therefore are not included in the MMRM analysis of Week 100.   
8.8.2. 
Sensitivity Analyses 
The sensitivity analyses described in Section 8.6.2 (i.e., tipping point, control-based imputation, 
as-treated, and per-protocol) are performed to assess the robustness of conclusions of the 2-year 
primary efficacy endpoint analysis of 2-year efficacy.  The per-protocol population (Year 2) is 
used for the per-protocol sensitivity analysis. 
8.8.3. 
Summary of Sensitivity Analyses of the Primary Efficacy Endpoint – Year 2 
The following sets of sensitivity analyses are summarized in tables and forest plots: tipping point 
with multiple imputation, control-based imputation, MMRM fit to the as-treated population, and 
MMRM fit to the per protocol population.  


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8.9. 
Year 2:  Key Secondary Endpoint 
8.9.1. 
Primary Analysis of the Year 2 Key Secondary Endpoint 
The Year 2 key secondary endpoint of this study is the change in eGFR at Week 104 
(i.e., 4-weeks following the last dose after two years of drug exposure).  Analysis of Week 104 
assesses for retained drug benefit (relative to placebo) following withdrawal of treatment; 
therefore, the analysis of Week 104 data does not include eGFR values collected during 
treatment.   
The change from baseline eGFR at Week 104 for patients treated with bardoxolone methyl are 
compared with placebo in a manner similar to the ANCOVA analysis of Week 52 in Year 1 
(Section 8.7.1) with the following modification: 
x TRT_EXP2 is added as a covariate and TRT_EXP1 is removed  
The analysis uses eGFR values collected in the Week 104 analysis window (Section 6.5.4), 
which includes the follow-up assessment for patients who discontinued treatment early in the 
second year.  Discontinuing treatment in the second year requires that patients received at least 
one dose of study drug in the second year.  Missing Week 104 eGFR data are imputed as 
described in Section 8.5.3. 
The difference between bardoxolone methyl and placebo in change from baseline of eGFR are 
estimated along with the 95% confidence interval at Week 104. 
8.9.2. 
Sensitivity Analyses 
Sensitivity analyses described in Section 8.7.2 are performed to assess the robustness of 
conclusions of the 2-year key secondary efficacy endpoint.  The following sets of sensitivity 
analyses are summarized in tables and forest plots: tipping point with multiple imputation, 
control-based multiple imputation, and the ANCOVA model fit to the per protocol population 
(Year 2). 


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9. 
EXPLORATORY EFFICACY  
The following data summaries and analyses are presented for the ITT analysis set.  Additional 
sensitivity analyses may be performed as appropriate. 
All data values within the appropriate visit windows contribute to the analysis.  The exception to 
this rule applies to any patients who begin receiving dialysis.  For them, all their on-dialysis 
eGFR measurements are considered missing.   
9.1. 
eGFR 
9.1.1. 
Continuous eGFR  
Results are presented in tables with nominal significance levels for descriptive purposes only.   
9.1.1.1. 
All Available Data 
Changes in eGFR for the bardoxolone methyl group  compared to the placebo group are 
evaluated at Week 48 as the Year 1 primary endpoint, and are evaluated at Weeks 1, 2, 4, 6, 8, 
12, 24, and 36 as exploratory analyses using the statistical model defined in Section 8.6.1. 
Changes in eGFR for the bardoxolone methyl group compared to the placebo group are 
evaluated at Week 100 as the Year 2 primary endpoint, and are evaluated at Weeks 64, 76, and 
88 as exploratory analyses using the statistical model defined in Section 8.8.1. 
Analyses of eGFR using all available data use all eGFR values collected, irrespective of whether 
or not a patient is receiving treatment. 
9.1.1.2. 
As-Treated Data 
To assess the effect over time of receiving bardoxolone methyl treatment, bardoxolone methyl 
will be compared to placebo using the statistical models defined in Section 8.6.1 (Year 1) to 
analyze change from baseline in eGFR values collected while receiving treatment at the on-
treatment visits for Year 1 (i.e., Weeks 1, 2, 4, 6, 8, 12, 24, 36, 48).  Similarly, the statistical 
models defined in Section 8.8.1 (Year 2) will be used to analyze change from baseline in eGFR 
values collected while receiving treatment through the on-treatment visits in Year 2 (i.e., 64, 76, 
88, and 100).  
eGFR values collected 14 days or more after the last dose of study drug will be excluded from 
the as-treated analysis. 
9.1.2. 
Categorical eGFR Endpoints 
A 30% decline or eGFR <  LV FRQVLGHUHG FRQILUPHG ZKHQ WKH WKUHVKROG LV DFKLHYHG DW  2 
visits.  Patients who achieved the threshold at their last visit, but did not have a second 
confirmatory visit, are considered confirmed cases.  Similarly, for a 30% or more increase in 
eGFR, a second confirmatory visit is needed with the exception of the last visit.  Patients with a 
decrease from baseline in eGFR of  30% at the last on-treatment visit are considered to have a 
30% or more decrease from baseline eGFR.  In the event a patient has both an increase from 
baseline in eGFR of 30% or more and a decrease from baseline in eGFR of 30% or more, only 
the decrease from baseline is considered in composite endpoint analyses.  Otherwise, if a patient 


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has more than one confirmed event, all events are counted in the categorical summaries.  
Confirmation of kidney failure components is based on all on-treatment eGFR values, 
irrespective of analysis windows.     
The following categorical analyses of eGFR are summarized for the first year of treatment: 
x The percentage of bardoxolone methyl versus placebo patients with an increase from 
baseline in eGFR of 30% or more after 48 weeks of treatment. 
x The percentage of bardoxolone methyl versus placebo patients with a decrease from 
baseline in eGFR of 30% or more after 48 weeks of treatment. 
x The distribution of changes from baseline in eGFR in bardoxolone methyl versus 
placebo patients after 48 weeks of treatment. 
The following categorical analyses of eGFR are summarized for the second year of treatment: 
x The percentage of bardoxolone methyl versus placebo patients with an increase from 
baseline in eGFR of 30% or more after 100 weeks of treatment. 
x The percentage of bardoxolone methyl versus placebo patients with a decrease from 
baseline in eGFR of 30% or more after 100 weeks of treatment. 
Newcombe’s test for the common treatment difference and the corresponding confidence interval 
adjusting for the randomization strata for each criterion are reported.   
9.1.3. 
Distribution of Changes in eGFR 
The proportion of patients at Week 48 and Week 100 with an eGFR change from baseline of 
0 mL/min/1.73/m2 to +10 mL/min/1.73 m2 at 1-point increments of increased or decreased eGFR 
HJ    ±  ±  ±  ±  ±  ±  ± ±   ±  ±10) is summarized by 
treatment group.  The data are summarized similarly for 1-point increments of decreased eGFR 
to -10 mL/min/1.73 m2.  
A plot of the cumulative distribution of eGFR change from baseline at Week 48 and at Week 100 
is generated.  A Kruskal-Wallis rank sum test by treatment group of eGFR change from baseline 
at Week 48 and at Week 100 is used to examine the difference in distributions of eGFR changes 
between treatment groups at each of these visits.    
Waterfall plots of eGFR change from baseline, labeled by treatment group at Week 48 and at 
Week 100 are generated. A cumulative distribution plot showing the distribution of change from 
baseline eGFR by treatment group will be generated at Weeks 48, 52, 100, and 104. 
Each quartile of change from baseline in eGFR at Week 48, 52, 100, and 104 will be summarized 
descriptively. 
9.2. 
Patient Global Impression of Change 
The Patient Global Impression of Change (PGIC) is a 7-point scale that asks patients to assess 
how much their illness has improved or worsened relative to a baseline state at the beginning of 
an intervention (Guy 1976).  The PGIC is assessed by completing the following statement “Since 
I began trial treatment, my overall status is: very much improved (1), much improved (2), 
minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse 


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(7).”  All PGIC values collected at each visit using the appropriate analysis windows 
(Section 6.5.4) are used; the number of patients in each category is summarized at each analysis 
visit by treatment group.  
The analysis of PGIC assesses the distribution of responses in the bardoxolone methyl vs. 
placebo group at each analysis visit; the distributions are compared using ANCOVA with 
BASE_eGFR, ACR_STRAT, TRT_EXP1 (or TRT_EXP2 for Year 2), and treatment group as 
covariates and treatment as the fixed effect.   
9.3. 
Clinical Global Impression - Improvement 
The Clinical Global Impression-Improvement (CGI-I) is a 7-point scale that asks the clinician to 
assess how much the patient's illness has improved or worsened relative to a baseline state at the 
beginning of an intervention (Guy 1976).  The scale is assessed by completing the following 
statement “Compared to the patient’s condition at the start of the trial, this patient’s overall status 
is: very much improved (1), much improved (2), minimally improved (3), no change (4), 
minimally worse (5), much worse (6), very much worse (7).”   
CGI-I is analyzed using the same methods specified for PGIC in Section 9.2. 
9.4. 
Kidney Failure Composite Outcome 
9.4.1. 
Primary Analysis of the Kidney Failure Composite Outcome 
The kidney failure composite outcome is defined as reaching one of the following: 
x Confirmed 30% decline from baseline in eGFR; or 
x Confirmed eGFR < 15 mL/min/1.73 m2; or 
x ESKD (initiation of maintenance dialysis or kidney transplant). 
A 30% decline or eGFR <  LV FRQVLGHUHG FRQILUPHG ZKHQ WKH WKUHVKROG LV DFKLHYHG DW  2 
visits.  Patients who achieved the threshold at their last visit, and did not have a second 
confirmatory visit, are considered confirmed.  The analysis uses initiation of maintenance 
dialysis or kidney transplant as reported in the database by the investigator.  Patients with a 
decrease from baseline in eGFR of 30% or more at the last on-treatment visit are considered to 
have a 30% or more decrease from baseline eGFR.  In the event a patient has both an increase 
from baseline in eGFR of  30% or more and a decrease from baseline in eGFR of 30% or more, 
only the decrease from baseline is considered in composite endpoint analyses.  Confirmation of 
kidney failure components is based on all on-treatment eGFR values, irrespective of analysis 
windows.  The date of the first eGFR meeting the kidney failure component is used in time-to-
event analyses as the date of the event. 
For the Year 1 analysis, the number and percentage of patients in each treatment group having a 
kidney failure composite by Week 52 are summarized using only on-treatment eGFR values.  
The proportion of patients with a given event is evaluated using Newcombe’s test accounting for 
ACR_STRAT.  Similarly, the number and percentage of patients in each treatment group having 
a kidney failure composite by Week 104 are summarized for the Year 2 analysis.   
For the Year 2 endpoint (Section 3.1.2.3), a time-to-event analysis of the kidney failure 
composite is performed using only on-treatment eGFR values.  Missing eGFR data are not 


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imputed for time-to-event analyses.  Hazard ratios and 95% CIs are computed using Cox 
proportional hazards regression models.  Patients who do not experience a confirmed event are 
censored for time-to-event analysis using the following conventions: 
x patients who died from any cause prior to the end of the study are censored at the date of 
death;  
x patients who discontinued the study prematurely, withdrew consent, or were lost to 
follow-up prior to the end of the study are censored at their last date of contact;  
x patients who are alive and still being followed are censored on the study termination (for 
early termination) or study completion date at Week 104.  
9.4.2. 
Sensitivity Analysis 
The primary time-to-event analysis described in Section 9.4.1 is repeated as a sensitivity analysis 
with all-cause death added to the kidney failure composite.   


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10. 
SAFETY AND TOLERABILITY 
Safety and tolerability are evaluated by AEs, SAEs, clinical laboratory test results, body weight, 
vital signs, 12-lead ECG findings, physical examination, visual acuity, and audiology 
assessment.  All analyses of the safety data are performed using the safety analysis set.  
Descriptive statistics are presented by treatment group assignment in the safety analysis set.  No 
formal statistical testing is performed for safety analyses.  Safety is also summarized by the 
subgroups defined in Section 8.3.  On-treatment values are summarized according to the analysis 
study windows in Section 6.5.4; off-treatment values are summarized according to the analysis 
study windows in Section 6.5.4.1.  Safety data summaries are grouped by treatment year. 
Continuous safety parameters (including selected clinical chemistries and vital signs) may be 
summarized using the methodology described in Section 8.6.1, Section 8.7.1, Section 8.8.1, and 
Section 8.9.1.  Only the visit windows outlined in Table 3 are included in these analyses.  
10.1. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
AEs are summarized by treatment as defined by the safety analysis set.  In addition to being 
summarized by treatment year, AEs are also summarized overall.  General considerations for AE 
summaries and calculations are: 
x Multiple events by preferred term (PT) and system organ class (SOC) are counted 
once only per patient for summaries of AE incidence. 
x For summaries of AE incidence by severity, only the most severe event is counted per 
patient. 
x For summaries of AE incidence by relationship, only the most related event is 
counted per patient. 
x An AE with a missing resolution date or incomplete date that is not identified as 
continuing is assumed to be continuing and no duration is calculated. 
x Treatment-emergent adverse events (TEAEs) are summarized separately from off-
treatment adverse events (OTAEs). 
x For summaries of the number of AE events, all AEs are counted. 
AEs are coded using MedDRA (Medical Dictionary for Regulatory Activities) version 19.1.  In 
MedDRA, each verbatim term is mapped to a preferred term and high level term (HLT), which is 
then mapped to a system organ class.  Tables and listings will present data at the SOC and PT 
level. 
Treatment-emergent adverse events (TEAEs) are events that either: 
x Have a date of onset on or after the date of the date of first dose and not more than 30 
days after the date of the last dose of study drug, or  
x Have no recorded date of onset with a stop date after the first dose of study drug, or 
x Have no recorded date of onset or stop date 


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AEs with an onset greater than 30 days after the last dose of study drug, and therefore not 
treatment-emergent AEs (TEAEs), are classified as off-treatment AEs (OTAEs).  Analyses 
described for TEAEs are also performed for OTAEs and tabulated separately.   
The investigator grades the severity of the AEs as mild, moderate, or severe as defined in the 
study protocol.  The investigators graded association or relatedness to the study medication 
according to criteria specified in Section 11.4 of the study protocol. 
As defined in the protocol, a serious adverse event (SAE) is an adverse event that results in any 
of the following: 
x Death; 
x A life-threatening adverse drug experience; 
x Inpatient hospitalization or prolongation of existing hospitalization; 
x Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
x Results in a congenital anomaly or birth defect in an offspring of a patient taking 
study drug; 
x Is an important medical event. 
10.1.1. 
Missing and Partial AE Onset Dates 
Rules for handling missing or partial AE Onset Dates are included in Section 6.6.3. 
10.1.2. 
Summaries of Adverse Events  
TEAEs and OTAEs are summarized by treatment based on year of AE onset, and overall.  For 
each treatment, SOC, and PT, the number and percentage of patients reporting an event is 
calculated.  In summary tables, SOC is presented alphabetically and events within SOC are 
presented by decreasing frequency count. 
Summary tables (number and percentage of patients and events) of AEs (by SOC and PT) are 
provided by treatment as follows: 
x All treatment-emergent AEs 
x All treatment-emergent related AEs (definitely, probably, or possibly related) 
x All treatment-emergent AEs by severity 
x All treatment-emergent serious adverse events (including deaths) 
x All related treatment-emergent serious adverse events (including deaths) 
x All treatment-emergent adverse events leading to permanent discontinuation of study 
drug 
Listings are provided showing: 
x All AEs 
x Serious adverse events (including deaths) 


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x AEs leading to permanent discontinuation of study drug 
10.2. 
Exposure and Compliance 
The duration of study drug exposure is defined as the number of days on treatment from the first 
dose of study drug until the last dose of study drug (last dose – first dose + 1).  Study drug 
exposure is summarized by descriptive statistics.  Summaries include the total dose (mg) 
received (based on the number of pills returned), study drug compliance, and duration (days) of 
exposure during the study treatment period.  In addition, a summary of the number and 
percentage of patients by dose (placebo, 5 mg, 10 mg, 20 mg, 30 mg) and by visit is generated.  
If a patient received more than one dose during a visit window, the duration of the longest dose 
exposure is used to calculate study drug dose during a given visit window.  Summaries of the 
number and percentage of patients by dose include a subgroup analysis by baseline ACR 
(ACR  300 mg/g vs. ACR > 300 mg/g).  
Total number of doses dispensed and total dose (mg) dispensed is calculated from total number 
of kits (bottles) recorded on the Study Drug Dispensation eCRF.  Total number of doses received 
is calculated from information on the eCRF of Study Drug Return and Study Drug Dispensation, 
as the (total number of doses dispensed – total number of doses returned).  Study drug 
compliance (%) is calculated as 100 × total number of doses received / total number of study 
days of study participation, excluding the off-treatment periods between Week 48 to Week 52 
and Week 100 to Week 104.  
10.3. 
Concomitant Medications 
Concomitant medications are coded using the World Health Organization (WHO) drug 
dictionary (Enhanced version, March 2016, B2 format) for anatomical therapeutic chemical 
classification (ATC) and preferred drug name.  A patient who used multiple medications is 
counted only once for each ATC and preferred drug name.  ATC and preferred drug name within 
each ATC are sorted alphabetically.  Coded concomitant medications are summarized by 
treatment by WHO ATC class and preferred name.  Percentages are based on the number of 
patients in the safety analysis set.  Each summary is ordered by descending order of incidence of 
ATC class and preferred name within each ATC class.  
A concomitant medication is any medication taken at the time of first study treatment or a 
medication that was started after the start of study drug dosing.  Specifically, concomitant 
medications are medications 
x that are continued from screening and continued after the first study drug dosing, or 
x that have start dates or stop dates within the treatment period, or 
x that have no end date.  
Medications with an end date on the date of first study drug administration are not considered 
concomitant medications.  
Patients who take excluded medications (defined in the Protocol Section 9.3.1) during the study 
are listed. 


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10.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
Missing and partial concomitant medication start and stop dates are detailed in Section 6.6.2. 
10.4. 
Prior and Concomitant Procedures and Surgeries 
Prior and concomitant procedures and surgeries are listed. 
10.5. 
Clinical Laboratory Evaluations 
Laboratory data are summarized at baseline and at each time point by treatment.   
10.5.1. 
Continuous Summaries of Laboratory Results 
Selected laboratory evaluations and change from baseline are summarized by treatment, 
laboratory category (hematology, chemistry), test, and study visit using continuous statistics.  
The estimated glomerular filtration rate (eGFR) results are calculated using formulas described 
in Section 6.5.6.   
The change from baseline in select laboratory evaluations at protocol endpoint time points (i.e., 
Week 48, 52, 100, and 104) for patients treated with bardoxolone methyl compared to placebo 
may be performed using the analysis of covariance (ANCOVA) model described in Section 8.7.1 
and Section 8.9.1 .   
Box plots and line graphs are generated for selected laboratory test results, such as eGFR, ACR, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, BNP, BUN, 
uric acid, magnesium, creatinine, and creatine kinase (CK).  Line graphs include mean ± SE over 
time for both the observed values and for change from baseline. 
Due to the nature of urinalysis parameters, summaries of continuous statistics are not provided 
unless otherwise specified.  The one exception is the urine albumin to creatinine ratio (ACR) 
from the first morning void urine collection.  Qualitative lab results, including urinalysis, are 
included in the listings, but are not summarized.  Laboratory results that are above or below 
normal limits are flagged in the listings.   
Summaries of ACR (Section 6.5.7) will use the geometric mean with 95% confidence intervals 
instead of the arithmetic mean and will display ACR results in original units of mg/g.  Changes 
from baseline in ACR are reported as the post-baseline/baseline ratios and are summarized by 
geometric means with 95% confidence intervals at each time point.  Summaries of ACR will use 
the geometric mean instead of the arithmetic mean.  Presentations will display ACR results in the 
original units (mg/g).  Changes in ACR are calculated as the ratio of each visit to baseline.  
Similar ANCOVA analyses as described in this section will be performed for ACR ratio to 
baseline. 
Additionally, ACR is summarized by baseline ACR quartile.  Descriptive summaries at each 
visit include the standard deviation, geometric mean of ACR, as well as the geometric mean of % 
change from baseline.  Summaries of ACR exclude values within the Week 2 and Week 6 visit 
windows.   


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10.5.1.1. Natural log(ACR)/eGFR 
Mean ratios of natural log(ACR)/eGFR (Section 6.5.10) are summarized at each time point.  The 
ratio of natural log(ACR)/eGFR by analysis visit is summarized by arithmetic means. 
10.5.2. 
Categorical Summaries of Laboratory Results 
The number and percentage of patients by laboratory normality and abnormality categories at 
any time during the study (Normal, Low, High) are summarized by treatment, laboratory 
category (hematology, chemistry, and urinalysis), and laboratory test.  The worst abnormality 
values are defined as the maximum values while on study treatment, with the exception of 
magnesium and hemoglobin.  The worst abnormal values for magnesium and hemoglobin are 
defined as the minimum values while on study treatment. 
Shift tables summarizing (1) baseline to end of treatment, (2) worst on-treatment to Week 52 
(Year 1), and (3) worst on-treatment to Week 104 (Year 2), (4) worst on-treatment to worst off-
treatment at Week 52 or Week 104, and (5) baseline to worst on-treatment  are presented for lab 
parameters as appropriate. 
An initial set of parameters of specific interest (ALT, AST, ACR) are summarized using shift 
tables, though additional parameters may be added as appropriate. 
In addition, a summary table is provided for number and percentage of patients meeting a 
following pre-specified threshold level at any time during the study:  
x ACR > 3500 mg/g 
x Magnesium < 1.3 mEq/L (0.65 mmol/L) 
x BNP > 200 pg/mL 
10.5.2.1. Transaminases 
Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plots are generated for ALT and 
AST versus TBL.  
The number and percentage of patients meeting the following thresholds, which are consistent 
with FDA guidance, are summarized by the maximum dosage received: 
Table 9. Pre-Specified Threshold Levels for Transaminases 
Lab Parameter 
Threshold 
ALT, AST 
 
 3 × upper limit of normal (ULN) and < 5 × ULN 
 5 × ULN and < 10 × ULN 
 10 × ULN and < 20 × ULN 
 20 × ULN 
 5 × ULN for more than 2 weeks 
TBL 
 ULN and  1.5 × ULN 
> 1.5 × ULN and  2 × ULN 
> 2 × ULN 
ALT, /AST, TBL 
ALT or AST > 3×ULN and Total bilirubin > 1.5×ULN 


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Lab Parameter 
Threshold 
ALT or AST > 3×ULN and Total bilirubin > 2×ULN 
ALT, AST, TBL, 
INR 
> 3 × ULN and (TBL > 2 × ULN or INR > 1.5) 
ALP 
> 1.5 × ULN 
A summary table that includes frequencies and percentages of patients that meet any of the 
above criteria at any time during the study is provided.  A listing of subjects with abnormal ALT, 
AST, or TBL will also be provided. 
10.6. 
 Vital Signs 
Vital signs assessments include systolic blood pressure (SBP, mmHg) and diastolic blood 
pressure (DBP, mmHg), body temperature (°C), heart rate (HR, bpm), height (m), weight (kg), 
and BMI (kg/m2).  Vital signs are summarized at baseline and at each time point along with the 
change from baseline by treatment.  Boxplots and line graphs of change from baseline over time 
for blood pressure are plotted. 
10.6.1. 
Body Weight 
Body weight, as collected during each in-office visit, is summarized using descriptive statistics 
for observed results and change from baseline at time point.  In addition, number and percentage 
of patients experiencing a five pound (2.3 kilogram) or greater increase in weight are 
summarized by time point.  Boxplots and line graphs of change from baseline over time for 
weight are plotted. 
10.7. 
Physical Examination 
Physical exam results are listed. 
10.8. 
Electrocardiogram 
Electrocardiogram (ECG) data, such as clinical interpretation of ECGs, heart rate and interval 
assessments of PR, QRS, and QT are collected on the eCRF.  QTcF is calculated for analysis 
(Section 6.5.8).  Descriptive statistics for observed values and change from baseline at each time 
point are presented for these 12-lead ECG interval assessments.  In addition, number and 
percentage of patients with any abnormal values (i.e., above a pre-specified threshold) at any 
time during the study are summarized by time point and overall.  The pre-specified levels of 
ECG QTc thresholds are consistent with FDA guidance: 
Table 10. Pre-Specified Threshold Levels for ECG Parameters 
ECG 
Parameter 
Pre-Specified Level 
PR 
> 200 msec 
QTcF 
> 450 and  480 msec  
> 480 and  500 msec 
> 500 


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ECG 
Parameter 
Pre-Specified Level 
Change from baseline: >30 and  60 msec 
Change from baseline: > 60 msec 
Heart rate 
< 40 beats/min 
< 100 beats/min 
10.9. 
Visual Acuity 
Patients with normal visual acuity are those with 20/20 vision or less (e.g., 20/15. 20/10, etc.) in 
both eyes.  Findings from visual acuity examinations are listed.  Observed logMAR value and its 
change from baseline are summarized descriptively by time point.  In addition, shift tables are 
generated by treatment, visit, and normal versus abnormal visual acuity values.  
10.10. 
Audiology Assessment 
Findings from audiology assessments are listed.  The average pure-tone hearing threshold for 
each ear is measured using the automated pure tone test.  Patients with normal pure-tone hearing 
are those with pure tone audiometry (PTA) < 25 decibels in both HDUV $Q\ SDWLHQW ZLWK  25 
decibel hearing in either ear are considered to have audiology impairment.  The number and 
percentage of patients with normal or impaired hearing in at least one ear is summarized by time 
point.  In addition, number and percentage of patients within each of the following categories 
will be summarized at baseline, Week 48, and Week 100: 
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x PTA > 85 dB (profound hearing loss) 
  Descriptive statistics for observed values and change from baseline in hearing threshold for 
each ear (i.e., right and left) are presented. 
10.11. 
Pregnancy 
A listing is provided for serum and urine pregnancy results of all on-study pregnancies. 
 


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11. 
PHARMACOKINETICS 
Pharmacokinetic concentration and parameter data will be summarized descriptively.  A separate 
document contains details regarding other planned pharmacokinetic analyses. 


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12. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES 
12.1. 
Analysis of Key Secondary Endpoints 
The protocol defines the primary analysis for the key secondary endpoints as MMRM, using the 
same model as the primary endpoint analysis applied to the population of patients who 
completed treatment.  This SAP defines ANCOVA as the analysis method for key secondary 
endpoints using the ITT population.  The rationale for this change is that eGFR values following 
withdrawal of drug are testing a different biological hypothesis than eGFR values while 
receiving drug.  For this reason, it is likely that off-treatment eGFR values (i.e., Week 52 and 
Week 104) will have different variability and will not correlate in the same way as the on-
treatment eGFR repeated measures.  To guard against the risk of potential distributional 
differences for on-treatment as opposed to off-treatment data, the key secondary endpoints are 
analyzed using ANCOVA.   
Because of the above described change in planned analysis method, statistical power for the key 
secondary endpoints is now calculated from a 2-sample t-test.  As a result, the expected 
minimum detectable effect is changed from 2.2 (from the protocol based on analysis with 
MMRM and 50% power) to 2.9 (based on analysis with a 2-sample t-test and 50% power).   
12.2. 
Imputation of Missing Data for the Primary Endpoints 
This analysis plan specifies that missing data will not be imputed for the primary analysis of the 
primary endpoints (i.e., Week 48 and Week 100) with MMRM based on the assumption of 
MAR. (Section 8.5).  The protocol stated that missing data for the Week 48 analysis is imputed 
using Jump to Reference multiple imputation, based on available data collected from patients 
discontinuing from study treatment but continuing in the study.  The rationale for the change in 
imputation method is the assumption of data being missing at random.  A tipping point analysis 
and control-based imputation are included to assess the MAR assumption as part of a sensitivity 
analysis.   


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13. 
REFERENCES 
Guy, W. ECDEU Assessment Manual For Psychopharmacology, DHEW Publication No. ADM 
76–338, US Government Printing Office, Washington, DC, USA, 1976.   
KDIGO Practice Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and 
Management of Chronic Kidney Disease. Kidney Int  Suppl 2013;3;136-150.  
 

Prot_000.pdf: 
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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 – 22 APRIL 2019 
Protocol History 
Version 3.0 – 30 July 2018 
Version 2.0 – 03 August 2017 
Version 1.0 – 15 November 2016 
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 




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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 
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
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


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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 
Phase 3 cohort will be randomized 1:1 to either bardoxolone methyl or placebo and randomization will 


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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.  Adult patients (≥ 18 years of age) 
receiving bardoxolone methyl will start with once-daily dosing at 5 mg and will dose-escalate to 10 mg 
at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 6 (only if baseline ACR >300 mg/g) unless 
contraindicated clinically and approved by the medical monitor.  Patients under the age of 18 receiving 
bardoxolone methyl will start dosing at 5 mg every other day during the first week and begin once-
daily dosing with 5 mg during the second week of the study, and then continue with once-daily dosing 
following the same aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, and 6.  
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 12 ≤ 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


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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 (and assent form if
necessary) indicating that the patient (or a legally acceptable representative) has been informed
of all pertinent aspects of the study prior to initiation of any protocol-mandated procedures.
Major exclusion criteria: 
1.
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);


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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;
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


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•
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
•
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 
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 of the primary endpoint 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) after completing 48 weeks of treatment, 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 analysis of efficacy will use
an unstructured covariance structure, which is expected to have approximately the same 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.  Analysis methods for Year 2 endpoints will be similar to Year 1
endpoints.  Analysis of the Year 2 endpoints is independent of the Year 1 analysis of efficacy.




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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 ..................................................12 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5.
INTRODUCTION ......................................................................................................22 
5.1. 
Clinical Experience with Bardoxolone Methyl ..........................................................24 
5.1.1. 
Efficacy .......................................................................................................................24 
5.1.2. 
Safety and Tolerability ...............................................................................................27 
5.1.2.1. 
Fluid Overload ............................................................................................................27 
5.1.2.2. 
Transaminase and Gamma-glutamyl Transpeptidase (GGT) Elevations ...................27 
5.1.2.3. 
Muscle Spasms ...........................................................................................................28 
5.1.2.4. 
Weight Loss ................................................................................................................28 
5.1.2.5. 
Hypomagnesaemia ......................................................................................................29 
5.1.2.6. 
Increases in Urinary Protein .......................................................................................29 
6.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
6.1. 
Objectives ...................................................................................................................30 
6.1.1. 
Phase 2 ........................................................................................................................30 
6.1.1.1. 
Primary Objective .......................................................................................................30 
6.1.1.2. 
Secondary Objective ...................................................................................................30 
6.1.1.3. 
Exploratory Objective .................................................................................................30 
6.1.2. 
Phase 3 – Year 1 Objectives .......................................................................................30 
6.1.2.1. 
Primary Objectives .....................................................................................................30 
6.1.2.2. 
Key Secondary Objective ...........................................................................................30 
6.1.2.3. 
Exploratory Objectives ...............................................................................................30 
6.1.3. 
Phase 3 – Year 2 Objectives .......................................................................................31 
6.1.3.1. 
Primary Objectives .....................................................................................................31 
6.1.3.2. 
Secondary Objective ...................................................................................................31 
6.1.3.3. 
Exploratory Objectives ...............................................................................................31 
6.2. 
Endpoints ....................................................................................................................32 


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6.2.1. 
Phase 2 ........................................................................................................................32 
6.2.1.1. 
Primary Efficacy Endpoint .........................................................................................32 
6.2.1.2. 
Secondary Efficacy Endpoint .....................................................................................32 
6.2.1.3. 
Exploratory Efficacy Endpoint ...................................................................................32 
6.2.2. 
Phase 3 – Year 1 Endpoints ........................................................................................32 
6.2.2.1. 
Primary Efficacy Endpoint .........................................................................................32 
6.2.2.2. 
Key Secondary Efficacy Endpoint ..............................................................................32 
6.2.2.3. 
Exploratory Efficacy Endpoints .................................................................................32 
6.2.3. 
Phase 3 – Year 2 Endpoints ........................................................................................33 
6.2.3.1. 
Primary Efficacy Endpoint .........................................................................................33 
6.2.3.2. 
Secondary Efficacy Endpoint .....................................................................................33 
6.2.3.3. 
Exploratory Efficacy Endpoints .................................................................................33 
6.2.4. 
Safety Endpoints .........................................................................................................33 
7.
INVESTIGATIONAL PLAN .....................................................................................34 
7.1. 
Overall Study Design ..................................................................................................34 
7.2. 
Number of Patients .....................................................................................................35 
7.3. 
Treatment Assignment and Rationale .........................................................................35 
7.3.1. 
Dose Escalation ..........................................................................................................35 
7.3.2. 
Dose De-Escalation and Re-Escalation ......................................................................36 
7.4. 
Criteria for Study Termination ...................................................................................36 
7.5. 
Schedule of Assessments ............................................................................................36 
8.
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................40 
8.1. 
Patient Inclusion Criteria ............................................................................................40 
8.2. 
Patient Exclusion Criteria ...........................................................................................41 
8.3. 
Screening Period .........................................................................................................42 
8.4. 
Patient Re-Screening ..................................................................................................42 
8.5. 
Patient Discontinuation and Termination ...................................................................42 
8.5.1. 
Patient Study Drug Discontinuation Criteria ..............................................................42 
8.5.2. 
Patient Study Termination Criteria .............................................................................43 
9.
TREATMENT OF PATIENTS ..................................................................................44 
9.1. 
Select Management Guidelines ..................................................................................44 
9.1.1. 
Management of Fluid Status .......................................................................................44 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................45 


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9.1.3. 
Management of Muscle Spasms .................................................................................45 
9.1.4. 
Weight Loss ................................................................................................................45 
9.1.5. 
Hypomagnesaemia ......................................................................................................45 
9.1.6. 
Management of Urinary Protein .................................................................................45 
9.1.7. 
Management of Blood Pressure ..................................................................................46 
9.1.8. 
Nausea .........................................................................................................................46 
9.1.9. 
End Stage Kidney Disease ..........................................................................................46 
9.2. 
Description of Study Drug ..........................................................................................47 
9.3. 
Concomitant Medications ...........................................................................................49 
9.3.1. 
Excluded Medications ................................................................................................49 
9.3.2. 
Permitted Medications ................................................................................................49 
9.4. 
Treatment Compliance ................................................................................................50 
9.5. 
Randomization ............................................................................................................50 
9.6. 
Blinding ......................................................................................................................50 
9.6.1. 
Patient Unblinding ......................................................................................................50 
9.6.2. 
Unblinding for Regulatory Submission ......................................................................51 
9.6.3. 
Data Monitoring Committee .......................................................................................51 
9.7. 
Unscheduled Visits .....................................................................................................51 
9.8. 
Pregnancy ...................................................................................................................52 
9.8.1. 
Women of Childbearing Potential ..............................................................................52 
9.8.2. 
Methods of Birth Control............................................................................................52 
9.8.3. 
Suspected Pregnancy ..................................................................................................53 
9.9. 
Serious Toxicities .......................................................................................................53 
9.10. 
Study Procedures ........................................................................................................53 
9.10.1. 
Informed Consent .......................................................................................................54 
9.10.2. 
Inclusion/Exclusion ....................................................................................................54 
9.10.3. 
Demographics and Baseline Disease Characteristics .................................................54 
9.10.4. 
Prior and Current Concomitant Medications ..............................................................54 
9.10.5. 
Medical History ..........................................................................................................54 
9.10.6. 
Height .........................................................................................................................54 
9.10.7. 
Weight and Body Mass Index (BMI) .........................................................................54 
9.10.8. 
Electrocardiograms (ECG) .........................................................................................55 
9.10.9. 
Echocardiogram ..........................................................................................................55 


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9.10.10. 
Vital Sign Measurements ............................................................................................55 
9.10.11. 
Physical Examination .................................................................................................55 
9.10.12. 
Pregnancy Test ............................................................................................................55 
9.10.13. 
Study Drug Administration.........................................................................................55 
9.10.14. 
Study Drug Dispensation and Collection ...................................................................56 
9.10.15. 
Telephone Contact ......................................................................................................56 
9.10.16. 
Adverse Event Collection ...........................................................................................56 
9.10.17. 
Genetic Testing ...........................................................................................................56 
9.10.18. 
Clinical Chemistry ......................................................................................................56 
9.10.18.1. eGFR ...........................................................................................................................57 
9.10.19. 
N-Terminal Pro-Brain Natriuretic Peptide (NT-Pro BNP) and Brain
Natriuretic Peptide (BNP) ...........................................................................................57 
9.10.20. 
Insulin-Like Growth Factor-1 (IGF-1) and Serum Ketones .......................................57 
9.10.21. 
Hemoglobin A1c .........................................................................................................58 
9.10.22. 
Hematology .................................................................................................................58 
9.10.23. 
Urinalysis and Microscopy .........................................................................................58 
9.10.24. 
Urine Collection for Albumin to Creatinine Ratio (ACR) .........................................58 
9.10.25. 
Visual Acuity ..............................................................................................................58 
9.10.26. 
Audiology Assessment ...............................................................................................58 
9.10.27. 
Patient Global Impression of Change .........................................................................58 
9.10.28. 
Clinical Global Impression-Improvement ..................................................................59 
9.10.29. 
Virus Serology ............................................................................................................59 
9.10.30. 
Pharmacokinetic (PK) Blood Samples .......................................................................59 
10.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................60 
10.1. 
Study Drug ..................................................................................................................60 
10.2. 
Study Drug Packaging and Labeling ..........................................................................60 
10.3. 
Study Drug Storage .....................................................................................................60 
10.4. 
Study Drug Administration.........................................................................................60 
10.5. 
Study Drug Accountability .........................................................................................61 
10.6. 
Study Drug Handling and Disposal ............................................................................61 
11.
SAFETY ASSESSMENTS ........................................................................................62 
11.1. 
Safety Parameters .......................................................................................................62 
11.2. 
Adverse and Serious Adverse Events .........................................................................62 


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11.2.1. 
Definition of Adverse Events .....................................................................................62 
11.2.1.1. 
Adverse Event .............................................................................................................62 
11.2.1.2. 
Serious Adverse Event ................................................................................................62 
11.3. 
Eliciting Adverse Event Information ..........................................................................63 
11.4. 
Assessment of Causality .............................................................................................63 
11.5. 
Assessment of Severity ...............................................................................................64 
11.6. 
Recording Adverse Events .........................................................................................64 
11.7. 
Reporting Serious Adverse Events .............................................................................65 
12.
STATISTICS ..............................................................................................................67 
12.1. 
Sample Size ................................................................................................................67 
12.2. 
Study Variables ...........................................................................................................68 
12.2.1. 
Pharmacokinetic Variables .........................................................................................68 
12.2.2. 
Efficacy Variables ......................................................................................................68 
12.2.3. 
Safety Variables ..........................................................................................................68 
12.3. 
Statistical Analyses .....................................................................................................68 
12.3.1. 
Primary Analysis of Efficacy ......................................................................................68 
13.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................70 
13.1. 
Study Monitoring ........................................................................................................70 
13.2. 
Audits and Inspections ................................................................................................70 
14.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................71 
14.1. 
Quality Assurance .......................................................................................................71 
14.2. 
Financial Disclosure ...................................................................................................71 
14.3. 
Sponsor Obligations....................................................................................................71 
14.4. 
Investigator Documentation ........................................................................................71 
14.5. 
Clinical Study Insurance .............................................................................................72 
14.6. 
Use of Information ......................................................................................................72 
15.
ETHICS ......................................................................................................................73 
15.1. 
Institutional Review Board (IRB) or Ethics Committee (EC) Review .......................73 
15.2. 
Ethical Conduct of the Study ......................................................................................73 
15.3. 
Written Informed Consent ..........................................................................................73 
15.4. 
Confidentiality ............................................................................................................74 
15.5. 
Modification of the Protocol .......................................................................................74 
15.6. 
Protocol Deviations ....................................................................................................75 


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16.
DATA HANDLING AND RECORDKEEPING .......................................................76 
16.1. 
Retention of Records ..................................................................................................76 
16.2. 
Case Report Forms .....................................................................................................76 
17.
PUBLICATION POLICY ..........................................................................................77 
18.
REFERENCES ...........................................................................................................78 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................19 
Table 3: 
Cross-Study Comparison of Increases in eGFR, Inulin Clearance, and 
Creatinine Clearance with Bardoxolone Methyl Treatment .......................................26 
Table 4: 
Schedule of Assessments ............................................................................................37 
Table 5: 
Bardoxolone Methyl Drug Product Information ........................................................48 
Table 6: 
Placebo Information ....................................................................................................49 
Table 7: 
SAE Reporting Contact Information ..........................................................................65 


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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 
7.22 
(p<0.001) 
CrCl also sig. 
increased 
402-C-0804
(BEAM)
2/ 
US 
Multicenter, 
Double-Blinded, 
Randomized, 
Placebo-Controlled 
Age >=18, 
T2D and CKD 
227 
52 weeks 
8.6 at WK52 
(p<0.001 vs PBO) 
402-C-0902 
2/
US 
Multicenter, Open-
Label, Randomized, 
Parallel-Group, 
Dose-Ranging 
Age >=18, T2D 
and CKD 
131 
85 days 
6.52 
(p<0.001) 
402-C-0903
(BEACON)
3/ 
Global 
Multinational, 
Multicenter, 
Randomized, 
Double-Blinded, 
Placebo-Controlled 
Age >=18, 
T2D and Stage 4 
CKD 
2185 
Median: 
7 months with 
522 patients 
through Week 
48 
6.4 
(p<0.001 vs PBO) 
CrCl also 
significantly 
increased 
402-C-1102 
1/US
Multi-Dose, 
Multicenter, Open-
Label 
Age>=18, 
T2D and Stage 
3b and 4 CKD 
24 
56 days 
9.0 
(p<0.05) 
RTA402-005 
(TSUBAKI) 
2/ 
Japan 
Randomized, 
Double-Blinded, 
Placebo-Controlled 
Age >=20,  
T2D and Stage 3 
and 4 CKD 
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 
18.22 
(p<0.0001) 
402-C-0702 
1/2/
US 
Double-Blinded, 
Randomized 
Pancreatic 
Cancer 
34 
Median: 
56 days 
32.22 
(p=0.001) 
402-C-1302
(LARIAT)
2/ 
US 
Randomized, 
Double-Blinded, 
Placebo-Controlled 
Age 18 to 75 
PH (Baseline 
eGFR 82 
mL/min/ 
1.73 m2) 
54c 
16 weeks 
14.7 
(p<0.001 vs PBO) 
1 Unless noted, data are differences between mean eGFR changes from baseline for bardoxolone methyl versus 
placebo groups and p-values calculated comparing the difference in means between bardoxolone methyl and 
placebo groups. 
2 Data are mean eGFR changes from baseline for bardoxolone methyl patients and p-values are calculated from two-
sided paired t-tests comparing eGFR change to 0. 
3 Number of patients enrolled Cohorts 1 and 2. 


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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.  Adult 
patients (≥ 18 years of age) receiving bardoxolone methyl will start with once-daily dosing at 
5 mg and will dose-escalate to 10 mg at Week 2, to 20 mg at Week 4, and then to 30 mg at Week 
6 (only if baseline ACR >300 mg/g) unless contraindicated clinically and approved by the 
medical monitor.  Patients under the age of 18 receiving bardoxolone methyl will start dosing at 
5 mg every other day during the first week and begin once-daily dosing with 5 mg during the 
second week of the study, and then continue with once-daily dosing following the same 
aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4, and 6.  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 


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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. 
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.  Adult patients (>18 years of age) 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.  Patients
under the age of 18 will receive 5 mg every other day during the first week and begin once-daily
dosing with 5 mg during the second week of the study, and then continue with once-daily dosing
following the same aforementioned dose-titration scheme based on baseline ACR at Weeks 2, 4,
and 6.  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.


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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. 
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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1 Total Screening period should not exceed 6 months.
2 Screen B visit should be no more than 30 days prior to Day 1.
3 Day 1 is the day of administration of the first dose.  On Day 1, all procedures should be performed before study drug administration. 
4 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.
5 An echocardiogram performed at the Screen A visit or within 6 months prior to Day 1 may be used to determine eligibility. 
6 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.  
7  AE assessments on Day 1 should be performed following study drug administration.
8 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.
9 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.
10 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 12 ≤ 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 (and assent form
if necessary) indicating that the patient (or a legally acceptable representative) has been
informed of all pertinent aspects of the study prior to initiation of any 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 of consent, 
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 drug with medical monitor approval.  


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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. 


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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 
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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]);
•
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,
diaphragm [always use with spermicidal jelly/cream]);


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•
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. 
For pediatric patients, informed consent will be obtained from the parent(s) or legal guardian in 
accordance with regional laws or regulations.  In addition, dependent upon the patient’s age and 
IRBs, IEC, and/or local requirements, assent of the patient may also need to be obtained.  
Pediatric patients may be asked to personally sign and date either a separately designed, written 
assent form, or the written informed consent. 
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 


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within the Informed Consent Form to help ensure consistent weight collection throughout the 
study.  
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 under the age of 18 should self-administer one capsule from each bottle included in the 
study drug kit orally every other day for the first week after randomization, and begin dosing 
once a day on Day 7 through the end of the study, as indicated in Table 4.  Adult patients 
(≥ 18 years of age) 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 


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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. 
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, 


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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. 
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 equation used to calculate eGFR for each patient throughout the study will be based on the 
patient’s age on the date of consent.  For patients consented at age 18 years and older, 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] 
For patients consented at age 12 to 17, the Bedside Schwartz equation will be used: 
eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Scr 
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scr/κ or 1 and max indicates the 
maximum of Scr/κ or 1. 
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.   


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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, 
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.   


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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. 
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 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, fully executed, and all updates on a new fully executed Form
FDA 1572;
•
Curricula vitae for the principal investigator and each sub-investigator listed on Form
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.
The curricula vitae must have been signed and dated by the principal investigators
and sub-investigators within 2 years before study start-up to indicate the documents
are accurate and current;


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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 (and assent form if necessary) 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) [https://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Efficac 
y/E6/E6 R2
Step 4 2016 1109.pdf] and the principles of the Declaration of Helsinki 
[https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-
research-involving-human-subjects/].  The principal investigator must conduct all aspects of this 
study in accordance with all national, state, and local laws or regulations. 
15.3. 
Written Informed Consent 
Because the study will be conducted under a United States Investigational New Drug 
Application, a signed informed consent form (or assent form if necessary), in compliance with 
Title 21 of US CFR Part 50, will be obtained from each patient before the patient enters the 
study.  For sites outside of the United States, the signed consent will be obtained in accord with 
local regulations, ICH E6 (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 (or assent as required) to participate in the study by signing the 
informed consent form (or assent form, if necessary).  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.  For pediatric patients, 
informed consent will be obtained from the parent(s) or legal guardian in accordance with 
regional laws or regulations.  In addition, dependent upon the patient’s age and IRBs, IEC, 
and/or local legal requirements, assent of the patient may also need to be obtained.  Pediatric 
patients may be asked to personally sign and date either a separately designed, written assent 
form, or the written informed consent. 
Informed consent and assent, if necessary, 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 (and assent, if necessary) 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 and/or 
assent form as necessary (signed copy to be provided per applicable law) to the patient and/or 
legal guardian.  The original form will be maintained in the patient’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/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 


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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 
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. 
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.
REFERENCES
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de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 
chronic kidney disease.  N Engl J Med 2013;369:2492-503. 
Ding Y, Stidham RD, Bumeister R, et al. The synthetic triterpenoid, RTA 405, increases the 
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Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci USA 2005;102:4584-9. 
Ferguson DA, Wigley WC, Heiss E. Bardoxolone methyl (BARD) improves markers of 
endothelial function in cultured cells.  Poster American Society of Nephrology (ASN) 2010. 
Gross O, Licht C, Anders HJ, et al. Early angiotensin converting enzyme inhibition in Alport 
syndrome delays renal failure and improves life expectancy.  Kidney Int 2012;81:494-501. 
Gross O, Perin L, Deltas C. Alport syndrome from bench to bedside: the potential of current 
treatment beyond RAAS-blockade and the horizon of future therapies. Nephrol Dial Transplant 
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Jedlicka J, Soleiman A, Draganovici D, et al. Interstitial inflammation in Alport syndrome.  
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Jiang T, Tian F, Zheng H, et al. Nrf2 suppresses lupus nephritis through inhibition of oxidative 
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Kashtan CE, Ding J, Gregory M, et al. Clinical practice guidelines for the treatment of Alport 
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Ped Nephrol 2013;28:5-11. 
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 
Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney 
Disease. Kidney Int Suppl  2012;2:337–414. 
Krügel J, Rubel D, Gross O: Alport Syndrome – Recent insights in basic and clinical research. 
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Lee D-F, Kuo H-P, Liu M, et al. KEAP1 E3 ligase-mediated downregulation of NF-kB signaling 
by targeting IKKß.  Molecular Cell 2009;36:131-40. 
Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmune inflammation, enhanced 
lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the 
antioxidant-activated transcription factor Nrf2.  Am J Pathol 2006;168:1960-74. 
Osburn WO & Kensler TW. Nrf2 signaling: An adaptive response pathway for protection against 
environmental toxic insults.  Mutat Res 2008;669:31-9. 


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