Clinical trial NCT03918447
Conditions: Autosomal Dominant Polycystic Kidney ADPKD
Keywords: Bardoxolone Methyl RTA 402 Autosomal Dominant Polycystic Kidney Disease ADPKD
Sponsor: Biogen
Start date: 2019-05-29; Completion date: 2023-08-08
Enrollment: 667 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This international, multi-center, randomized, double-blind, placebo-controlled Phase 3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with ADPKD. Approximately 850 patients will be enrolled.

Detailed description:
This international, multi-center, randomized, double-blind, placebo-controlled Phase 3 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with ADPKD.

Patients will be randomized 1:1 to either bardoxolone methyl or placebo. 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. Patients will continue to receive study drug or placebo through Week 100 and will not receive study drug or placebo during a 12-week off-treatment period between Weeks 100 and 112.

Arms: arm 1: Patients randomized to receive bardoxolone methyl with a baseline ACR less than or equal to 300 mg/g will be titrated to a maximum dose of 20 mg. Patients will begin once-daily dosing with bardoxolone methyl capsules at 5 mg and will dose escalate to 10 mg at Week 2 and 20 mg at Week 4.

Patients will continue to receive study drug through Week 100, and will not receive study drug during a 12-week off-treatment period between Weeks 100 and 112. arm 2: Patients randomized to receive bardoxolone methyl with a baseline ACR greater than 300 mg/g will be titrated to a maximum dose of 30 mg. Patients will begin once-daily dosing with bardoxolone methyl capsules at 5 mg and will dose escalate to 10 mg at Week 2, 20 mg at Week 4 and 30 mg at Week 6.

Patients will continue to receive study drug through Week 100, and will not receive study drug during a 12-week off-treatment period between Weeks 100 and 112. arm 3: Patients randomized to placebo will remain on placebo capsules throughout the study, undergoing sham titration.

Patients will continue to receive placebo capsules through Week 100, and will not receive capsules during a 12-week off-treatment period between Weeks 100 and 112.
Interventions: intervention 1: Bardoxolone methyl oral capsule intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Bardoxolone methyl capsules dose escalated from 5 mg to a maximum of 20 or 30 mg, depending on baseline proteinuria status. intervention 2: Capsule containing an inert placebo

Protocol documents:
Prot_002.pdf: 
COVER PAGE 
Official Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in 
Patients with Autosomal Dominant Polycystic Kidney Disease  
NCT Number:  NCT03918447 
Document Date: 25 May 2022 


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SPONSOR APPROVAL AND SIGNATURE PAGE 
{See Appended Electronic Signature Page} 
 
 
 M.D. 
 
Date 
 
{See Appended Electronic Signature Page} 
 
 
 
Date 
 
{See Appended Electronic Signature Page} 
 
 
, M.S. 
 
Date 
 
 
{See Appended Electronic Signature Page} 
 
 
 M.S. 
 
Date 
 
 
 
 
{See Appended Electronic Signature Page} 
 
 
 M.D. 
 
Date 
 
 
 
 


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INVESTIGATOR’S AGREEMENT 
I have read the 402-C-1808 clinical study protocol and agree to conduct the study as outlined.  I 
have received and read the Investigator’s Brochure for bardoxolone methyl.  I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
Signature of Investigator 
 
 
 
 
Date 


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


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Product: 
Bardoxolone methyl 
Title of Study:  
A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal Dominant 
Polycystic Kidney Disease 
Study center(s): Up to 200 study centers 
Studied period: ~ 6 years  
Estimated date first patient enrolled: May 2019 
Estimated date last patient completed: November 2025 
The end of the study is defined as the last visit of the last patient. 
Phase of development:  
3 
Objectives:   
For patients with autosomal dominant polycystic kidney disease (ADPKD) enrolled in this study, the 
objectives to assess bardoxolone methyl relative to placebo are as follows: 
Primary: 
• 
To assess the off-treatment change from baseline in estimated glomerular filtration rate (eGFR) at 
Week 108. 
• 
To assess safety and tolerability. 
Secondary: 
• 
To assess the change from baseline in eGFR at Week 100. 
• 
 
• 
To assess the off-treatment change from baseline in eGFR at Week 112. 
• 
 
 
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Methodology:  
This international, multi-center, randomized, double-blind, placebo-controlled phase 3 trial will study the 
safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with ADPKD.  
Approximately 850 patients will be enrolled.   
Patients will be randomized 1:1 to either bardoxolone methyl or placebo.  Randomization will be 
stratified by eligibility eGFR category (30 to <60; ≥60 to 90), concomitant tolvaptan use (yes, no), and 
screening albumin to creatinine ratio (ACR; ≤300 mg/g, >300 mg/g).  Patients randomized to placebo will 
remain on placebo throughout the study, undergoing sham titration.  Patients with eGFR 60 to 
90 mL/min/1.73 m2 at screening should not comprise more than approximately 40% of enrolled patients.    
The maximum bardoxolone methyl dose will be determined by baseline proteinuria status.  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 assessed during treatment in-person at Week 1, 2, 4, 6, 8, 12, 24, 36, 48, 52, 64, 
76, 88, and 100 and by telephone contact on Day 3, 10, 21, 31, 38, and 45.  Patients will continue study 
drug treatment through Week 100.  Patients will also be assessed during follow-up in-person at 
Weeks 103, 104, 108, and 112.   


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Efficacy endpoints will be analyzed after all enrolled patients have completed the study and the database 
has been locked.  All enrolled patients are expected to remain on their blinded treatment assignment 
through Week 100 and to complete all scheduled assessments through Week 112.  
The conduct of the study, according to protocol specifications, was impacted by the COVID-19 
(Coronavirus Disease 2019) pandemic.  As a result, and as of Version 4 of the protocol, modifications 
intended to address access to and administration of study drug, and adherence to protocol-specified visits 
and laboratory assessments were implemented.  These modifications are described in Appendix 1 
(COVID-19 Mitigations), Appendix 2 (Use of Home Healthcare) and throughout the protocol. 
Number of patients (planned):  
Approximately 850 patients will be enrolled.   
Diagnosis and main criteria for inclusion: 
1. Male and female patients 12 ≤ age ≤ 70 upon study consent; 
2. Diagnosis of ADPKD: 
a. For adult (18 ≤ age ≤ 70) diagnosis of ADPKD by modified Pei-Ravine criteria:  
i. at least 3 cysts per kidney by sonography or at least 5 cysts by CT or MRI with 
family history of ADPKD; or  
ii. at least 10 cysts per kidney by any radiologic method and exclusion of other 
cystic kidney diseases if without family history;  
b.  For adolescent (12 ≤ age < 18) diagnosis of ADPKD by:  
i. 
the presence of family history and/or genetic diagnosis and the presence of at 
least 1 cyst of 0.5 cm on ultrasound or MRI; or 
ii. 
patients without a family history or genetic diagnosis must have at least 
10 bilateral renal cysts in total, and exclusion of other cystic kidney diseases. 
3. eGFR must: 
a. Have a percent difference ≤ 25% at screening (the values at Screen A and Screen B) and; 
b. Have an average (the values at Screen A and Screen B) ≥ 30 to ≤ 90 mL/min/1.73 m2 for 
patients 12 to 55 years or ≥ 30 to ≤ 44 mL/min/1.73 m2 for patients 56 to 70 years and; 
c. Support ADPKD disease progression (i.e., average yearly eGFR decline of 
≥ 2.0 mL/min/1.73 m2 for the past two years) for patients with either screening eGFR≥ 60 
to ≤ 90 mL/min/1.73 m2 or age 56 to 70 years (See Protocol Section 9.10.2) 
4. ACR ≤ 2500 mg/g at Screen B visit; 
5. Systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg at Screen A or 
Screen B visit after a period of rest. Patients receiving an angiotensin-converting enzyme (ACE) 
inhibitor and/or an angiotensin II receptor blocker (ARB)* must be on a stable dose for at least 
6 weeks prior to the Screen A visit; *see Protocol Section 9.1.7 
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), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤ the upper limit of normal (ULN); 
7. Able to swallow capsules; 


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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/assent document indicating that the 
patient has been informed of all pertinent aspects of the study prior to initiation of any protocol-
mandated procedures.  
10. Patients receiving an SGLT2 inhibitor must be on a stable dose for at least 4 weeks prior to the 
Screen A visit 
Major exclusion criteria: 
1. Prior exposure to bardoxolone methyl; 
2. Use of tolvaptan within 2 months prior to Screen A.  Initiation of concomitant tolvaptan use 
during the study is not permitted; 
3. History of administration of polycystic kidney disease-modifying agents (somatostatin analogues) 
within 2 months prior to the Screen A visit;   
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. Serum albumin < 3 g/dL at Screen A visit; 
7. History of intracranial aneurysms;  
8. Kidney or any other solid organ transplant recipient or a planned transplant during the study; 
9. Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during Screening; 
10. 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 III or IV; 
h. 
History of untreated atrial fibrillation; 
i. 
History of unstable arrhythmias; 
11. Systolic BP < 90 mm Hg at Screen A visit after a period of rest; 
12. BMI < 18.5 kg/m2 at the Screen A visit; 
13. History of malignancy within 5 years prior to Screen A visit, with the exception of localized skin 
or cervical carcinomas; 
14. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to 
randomization or anticipated need for immunosuppression during the study; 
15. Untreated or uncontrolled active bacterial, fungal, or viral infection; 
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17. 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;  
18. Women who are pregnant or breastfeeding; 
19. Known hypersensitivity to any component of the study drug;  
20. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at 
risk by trial enrollment; 
21. 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; 
22. Coronavirus disease 2019 (COVID-19) pneumonia, related acute kidney injury, or 
related hospitalization within 6 months prior to Day 1. 
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: Change from baseline in eGFR; 
  
Safety: Results of laboratory results (clinical chemistry, hematology, urinalysis, and microscopy), vital 
sign measurements, electrocardiogram (ECG) results, weight, 
, adverse events 
(AEs), and serious adverse events (SAEs).   
Statistical methods: 
Sample size:  
With 850 patients enrolled, the study will have approximately 80% power to detect a difference between 
the two treatment groups in change from baseline eGFR of 2.3 mL/min/1.73 m2.  The power calculation 
was based on a 2-sample t-test as an estimate for the planned ANCOVA analysis and assumes the 
following: 
• 
Overall two-sided Type I error rate of 0.05;  
• 
Standard deviation of change from baseline in eGFR of 12 mL/min/1.73 m2;  
• 
Analyses are based on the intent-to-treat (ITT) population; 
• 
Missing data will be imputed using multiple imputation. 
ANCOVA analysis expected to have approximately the same power as the t-test used for study planning.  
The method for maintaining strict control of the Type I error for the trial will be described in the 
statistical analysis plan (SAP).  Appropriate sensitivity analyses of the primary analysis will be specified 
in the SAP. 


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Schema for Study of Bardoxolone Methyl in Patients with ADPKD 
 
 
 


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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 
5.1.2.7. 
Impact on Adolescent Growth (Weight and Height) ..................................................28 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
6.1. 
Objectives ...................................................................................................................30 
6.1.1. 
Primary Objective .......................................................................................................30 
6.1.2. 
Secondary Objective ...................................................................................................30 
 
30 
6.2. 
Endpoints ....................................................................................................................31 
6.2.1. 
Primary Efficacy Endpoint .........................................................................................31 
6.2.2. 
Secondary Efficacy Endpoint .....................................................................................31 
 
31 
6.2.4. 
Safety Endpoints .........................................................................................................32 
7. 
INVESTIGATIONAL PLAN .....................................................................................33 
7.1. 
Overall Study Design ..................................................................................................33 
7.2. 
Number of Patients .....................................................................................................33 
7.3. 
Treatment Assignment and Dosing Rationale ............................................................34 
7.3.1. 
Adolescent Dosing Rationale .....................................................................................34 


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7.3.2. 
Dose Escalation Plan ..................................................................................................35 
7.3.3. 
Dose De-Escalation and Re-Escalation ......................................................................35 
7.3.4. 
Dose Interruption and Re-Challenge/Re-Initiation .....................................................35 
7.4. 
Criteria for Study Termination ...................................................................................35 
7.5. 
Schedule of Assessments ............................................................................................36 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................42 
8.1. 
Patient Inclusion Criteria ............................................................................................42 
8.2. 
Patient Exclusion Criteria ...........................................................................................43 
8.3. 
Screening, Treatment, and Off-Treatment Periods .....................................................44 
8.3.1. 
Screening Period .........................................................................................................44 
8.3.2. 
Treatment Period ........................................................................................................44 
8.3.3. 
Off-Treatment Period ..................................................................................................45 
8.4. 
Patient Re-Screening & Re-Testing ............................................................................46 
8.4.1. 
Re-Screening ...............................................................................................................46 
8.4.2. 
Re-Testing ...................................................................................................................46 
8.5. 
Patient Discontinuation and Termination ...................................................................46 
8.5.1. 
Study Drug Discontinuation Criteria ..........................................................................46 
8.5.2. 
Study Termination Criteria .........................................................................................47 
9. 
TREATMENT OF PATIENTS ..................................................................................49 
9.1. 
Select Management Guidelines ..................................................................................49 
9.1.1. 
Management of Fluid Status .......................................................................................49 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................49 
9.1.3. 
Management of Muscle Spasms .................................................................................51 
9.1.4. 
Weight Loss ................................................................................................................51 
9.1.5. 
Hypomagnesaemia ......................................................................................................51 
9.1.6. 
Management of Urinary Protein .................................................................................51 
9.1.7. 
Management of Blood Pressure ..................................................................................51 
9.1.8. 
Nausea .........................................................................................................................52 
9.1.9. 
End Stage Kidney Disease ..........................................................................................52 
9.1.10 
Monitoring Growth and Sexual Development in Adolescents ...................................52 
9.2. 
Description of Study Drug ..........................................................................................53 
9.3. 
Concomitant Medications ...........................................................................................54 
9.3.1. 
Excluded and Prohibited Medications ........................................................................54 


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9.3.1.1. 
Excluded Medications ................................................................................................54 
9.3.1.2. 
Prohibited Medications ...............................................................................................55 
9.3.2. 
Permitted Medications ................................................................................................55 
9.4. 
Treatment Compliance ................................................................................................56 
9.5. 
Randomization ............................................................................................................56 
9.6. 
Blinding ......................................................................................................................57 
9.6.1. 
Patient Unblinding ......................................................................................................57 
9.6.2. 
Unblinding for Regulatory Submission ......................................................................57 
9.6.3. 
Data Monitoring Committee .......................................................................................58 
9.7. 
Unscheduled Visits .....................................................................................................58 
9.8. 
Pregnancy ...................................................................................................................59 
9.8.1. 
Women of Childbearing Potential and Fertile Males .................................................59 
9.8.2. 
Methods of Birth Control............................................................................................59 
9.8.3. 
Suspected Pregnancy ..................................................................................................60 
9.9. 
Serious Toxicities .......................................................................................................61 
9.10. 
Study Procedures ........................................................................................................61 
9.10.1. 
Informed Consent and Assent .....................................................................................61 
9.10.2. 
Inclusion/Exclusion ....................................................................................................62 
9.10.3. 
Demographics and Baseline Disease Characteristics .................................................62 
9.10.4. 
Prior and Current Concomitant Medications ..............................................................62 
9.10.5. 
Medical History ..........................................................................................................63 
9.10.6. 
Height .........................................................................................................................63 
9.10.7. 
Weight and Body Mass Index (BMI) .........................................................................63 
9.10.8. 
Electrocardiograms (ECG) .........................................................................................64 
9.10.9. 
Echocardiogram ..........................................................................................................64 
9.10.10. 
Vital Sign Measurements ............................................................................................64 
9.10.11. 
Comprehensive Physical Examination & Targeted Physical Examination ................64 
9.10.12. 
Pregnancy Test ............................................................................................................65 
9.10.13. 
Study Drug Administration.........................................................................................65 
9.10.14. 
Study Drug Dispensation and Collection ...................................................................65 
9.10.15. 
Telephone Contact ......................................................................................................65 
9.10.16. 
Adverse Event Collection ...........................................................................................65 
9.10.17. 
Kidney Ultrasound ......................................................................................................66 


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9.10.18. 
Virus Serology ............................................................................................................66 
9.10.19. 
Clinical Chemistry ......................................................................................................66 
9.10.19.1. eGFR ...........................................................................................................................66 
9.10.20. 
N-Terminal Pro-Brain Natriuretic Peptide (NT-Pro BNP) and Brain 
Natriuretic Peptide (BNP) ...........................................................................................67 
9.10.21. 
Hemoglobin A1c .........................................................................................................67 
9.10.22. 
Hematology .................................................................................................................68 
9.10.23. 
Coagulation .................................................................................................................68 
9.10.24. 
Lipid Panel ..................................................................................................................68 
9.10.25. 
SARS-CoV-2 Antibody Testing .................................................................................68 
9.10.26. 
Urinalysis and Microscopy .........................................................................................68 
9.10.27. 
Urine Collection for Albumin to Creatinine Ratio (ACR) .........................................68 
 
69 
 
69 
 
69 
 
69 
9.10.32. 
Pharmacokinetic (PK) Blood Samples .......................................................................69 
9.10.33. 
Ambulatory Blood Pressure Monitoring ....................................................................70 
9.10.34 Tanner Staging ..................................................................................................................71 
9.11. 
Dose Management ......................................................................................................71 
9.11.1. 
Dose Escalation Period – Missed In-Person Visits .....................................................72 
9.11.2. 
Week 8 – 12 Visits – Missed In-Person Visits ...........................................................72 
9.11.3. 
Post-Week 12 Visits – Missed In-Person Visits .........................................................73 
9.11.4. 
Dose De-Escalation and Interruption for Missed Safety and Laboratory 
Assessments ................................................................................................................73 
9.11.5. 
Resuming Study Drug After COVID-19 Interruption ................................................73 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................74 
10.1. 
Study Drug ..................................................................................................................74 
10.2. 
Study Drug Packaging and Labeling ..........................................................................74 
10.3. 
Study Drug Storage .....................................................................................................74 
10.4. 
Study Drug Administration.........................................................................................75 
10.5. 
Study Drug Accountability .........................................................................................75 
10.6. 
Study Drug Handling and Disposal ............................................................................75 


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11. 
SAFETY ASSESSMENTS ........................................................................................76 
11.1. 
Safety Parameters .......................................................................................................76 
11.2. 
Adverse and Serious Adverse Events .........................................................................76 
11.2.1. 
Definition of Adverse Events .....................................................................................76 
11.2.1.1. 
Adverse Event .............................................................................................................76 
11.2.1.2. 
Serious Adverse Event ................................................................................................76 
11.3. 
Eliciting Adverse Event Information ..........................................................................77 
11.4. 
Assessment of Causality .............................................................................................77 
11.5. 
Assessment of Severity ...............................................................................................78 
11.6. 
Recording Adverse Events .........................................................................................78 
11.7. 
Reporting Serious Adverse Events .............................................................................79 
12. 
STATISTICS ..............................................................................................................81 
12.1. 
Sample Size ................................................................................................................81 
12.2. 
Study Variables ...........................................................................................................81 
12.2.1. 
Pharmacokinetic Variables .........................................................................................81 
12.2.2. 
Efficacy Variables ......................................................................................................81 
12.2.3. 
Safety Variables ..........................................................................................................81 
12.3. 
Statistical Analyses .....................................................................................................81 
12.3.1. 
Analysis of Efficacy ...................................................................................................82 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................83 
13.1. 
Study Monitoring ........................................................................................................83 
13.2. 
Audits and Inspections ................................................................................................83 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................84 
14.1. 
Quality Assurance .......................................................................................................84 
14.2. 
Financial Disclosure ...................................................................................................84 
14.3. 
Sponsor Obligations....................................................................................................84 
14.4. 
Investigator Documentation ........................................................................................84 
14.5. 
Clinical Study Insurance .............................................................................................85 
14.6. 
Use of Information ......................................................................................................85 
15. 
ETHICS ......................................................................................................................86 
15.1. 
Institutional Review Board (IRB) or Ethics Committee (EC) Review .......................86 
15.2. 
Ethical Conduct of the Study ......................................................................................86 
15.3. 
Written Informed Consent ..........................................................................................86 


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15.4. 
Confidentiality ............................................................................................................87 
15.5. 
Modification of the Protocol .......................................................................................87 
15.6. 
Protocol Deviations ....................................................................................................88 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................89 
16.1. 
Retention of Records ..................................................................................................89 
16.2. 
Case Report Forms .....................................................................................................89 
17. 
PUBLICATION POLICY ..........................................................................................90 
18. 
REFERENCES ...........................................................................................................91 
1. 
SITE OPERATIONS & PATIENT MANAGEMENT ..............................................92 
2. 
COVID-19 INFECTED PATIENTS AND STUDY DRUG USE .............................92 
3. 
STUDY DRUG ACCESS...........................................................................................93 
4. 
DOSE MANAGEMENT ............................................................................................93 
4.1 
Dose Escalation Period ...............................................................................................93 
4.2 
Week 8-12 Visits ........................................................................................................93 
4.3 
Post-Week 12 Visits ...................................................................................................93 
4.4 
Dose De-escalation and Interruption for Missed Safety and Laboratory 
Assessments ................................................................................................................93 
4.5 
Resuming or Dose-escalating Study Drug after Interruptions or Changes .................93 
5. 
DEVIATIONS ............................................................................................................93 
6. 
MONITORING ...........................................................................................................93 
APPENDIX 2. USE OF HOME HEALTHCARE .........................................................................94 
ATTACHMENT 1: GUIDANCE FOR DIRECT-TO-PATIENT SHIPPING OF RTA-
402 DRUG PRODUCT CAPSULES DURING THE CORONAVIRUS 
(COVID-19) PANDEMIC ..........................................................................................95 


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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 ............................................................................................37 
Table 5: 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................50 
Table 6: 
Bardoxolone Methyl Drug Product Information ........................................................54 
Table 7: 
Placebo Information ....................................................................................................54 
 
80 
 


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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 
ABPM 
Ambulatory Blood Pressure Monitoring 
ACE 
Angiotensin converting enzyme 
ACR 
Albumin to creatinine ratio 
ADPKD 
Autosomal Dominant Polycystic Kidney Disease 
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) 
 
 
CGMP 
Current Good Manufacturing Practices 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
Coronavirus Disease 2019 
CrCl 
Creatinine clearance 
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 


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Abbreviation or Specialist Term 
Explanation 
ESKD 
End stage kidney disease 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transpeptidase 
HbA1c 
Hemoglobin A1c 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
Hgb 
Hemoglobin 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
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 
MRI 
Magnetic resonance imaging 
MTLDD 
Maximally tolerated labeled daily dose 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
PBO 
Placebo  
 
 
 
 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic 
PT 
Prothrombin Time 
QTc 
Corrected QT interval 


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Abbreviation or Specialist Term 
Explanation 
RBC 
Red blood cell 
RNA 
Ribonucleic acid  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SGLT2i 
Sodium-glucose co-transporter 2 inhibitors 
T2D 
Type 2 diabetes  
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 


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5. 
INTRODUCTION 
Autosomal dominant polycystic kidney disease (ADPKD) is a multi-organ disorder that results in 
clusters of fluid-filled cysts in the kidneys and other organs leading to progressive enlargement 
and loss of organ function.  ADPKD is a genetic disorder caused by mutations in the PKD1 and 
PKD2 genes, which encode the proteins polycystin-1 and -2, respectively.  The PKD1 and PKD2 
mutations disrupt the function of these proteins within the cilia, forming fluid-filled cysts that 
progressively increase in size, leading to gross enlargement of the kidneys and distortion of the 
renal architecture.  The disease is the leading inheritable cause of kidney failure; the number of 
diagnosed patients in the United States is estimated to be between 100,000 and 200,000.   
Although cystogenesis is initiated by mutations in polycystin and other genes, inflammation 
plays a primary role in cyst growth and is associated with disease progression in ADPKD 
(Karihaloo, 2015).  Renal cyst formation and growth in ADPKD triggers a cascade of 
pathological inflammatory processes that, over prolonged periods, result in oxidative stress, 
mesangial matrix expansion, glomerulosclerosis and fibrosis, decreased surface area for 
filtration, and reduced kidney function.  Thus, the pathogenic role of inflammatory processes in 
ADPKD disease progression and declining renal function is similar to that of other forms of 
chronic kidney disease (CKD).   
Bardoxolone methyl activates molecular pathways that promote the resolution of inflammation 
by restoring mitochondrial function, reducing oxidative stress, and inhibiting reactive oxygen 
species (ROS)-mediated pro-inflammatory signaling.  Bardoxolone methyl binds to Kelch-like 
ECH-associated protein 1 (Keap1) and activates nuclear factor, erythroid 2-like 2 (Nrf2), a 
transcription factor that increases cellular antioxidant and detoxification enzymes and promotes 
normal mitochondrial function by making reducing equivalents available for adenosine 
triphosphate (ATP) production.  These anti-inflammatory and tissue-protective effects of 
bardoxolone methyl suppress multiple cellular processes that conspire to promote glomerular 
filtration rate (GFR) loss in ADPKD.  In vitro studies in renal cyst cell lines have shown that 
bardoxolone methyl significantly suppresses markers of inflammation (e.g., MCP-1) which are 
associated with cyst formation and growth.  Bardoxolone methyl also reverses endothelial 
dysfunction and pathogenic mesangial cell contraction, resulting in increased glomerular 
filtration surface area (Kf) and GFR.  Additionally, bardoxolone methyl inhibits activation of 
inflammatory and pro-fibrotic pathways that lead to structural remodeling and 
glomerulosclerosis.  As a result, bardoxolone methyl has been shown to reduce inflammation, 
improve renal function, and prevent injury, remodeling, and fibrosis in many animal models of 
renal injury and disease.      
Bardoxolone methyl has consistently improved parameters of renal function in multiple clinical 
studies in patients with 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 estimated glomerular filtration rate (eGFR) increases with bardoxolone methyl 
reflects its multiple protective and anti-inflammatory effects.  Early improvements in eGFR 
evident within the first 4 weeks of bardoxolone methyl treatment are likely attributed to the 
reversal of acute and dynamic inflammation-mediated processes such as endothelial dysfunction 


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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 may have disease-modifying effects in the 
kidney (e.g., reversal of mesangial expansion and interstitial fibrosis) that are beneficial and not 
deleterious.   
In summary, bardoxolone methyl has the potential to inhibit inflammation-mediated pathways 
that contribute to disease progression and GFR loss in ADPKD. Despite available therapies, 
patients with ADPKD have progressively declining kidney function, with average estimated 
glomerular filtration rate (eGFR) declines of 2.8 to 3.8 mL/min/1.73m2 per year (Torres, 2012; 
Boertien, 2013; Schrier, 2014; Torres, 2017).  Thus, 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 in patients with ADPKD.  
 
Although tolvaptan is approved for the treatment of ADPKD, there remains a significant need for 
additional treatment options for these patients, who still have progressive loss of kidney function 
despite approved therapies.  A placebo-controlled trial with bardoxolone methyl provides the 
best opportunity to determine the benefit-risk profile for bardoxolone methyl in ADPKD 
patients.  The use of a placebo comparator in the 402-C-1808 trial is justified because the known 
safety profile of tolvaptan, together with the known pharmacologic effects of bardoxolone 
methyl, would complicate regulatory agency recommendations for safety monitoring and 
medical management of patients in a double-blind trial.  Furthermore, it may interfere with the 
efficacy assessment in ADPKD patients.  For these reasons, Reata believes the use of a placebo 
comparator is justified.    
 
Treatment of patients with ADPKD disease progression is a significant unmet need. Adolescent 
patients with an average yearly eGFR decline of ≥ 2.0 mL/min/1.73 m2 for two years prior to 
study entry are at risk of developing ESKD earlier than other adolescent ADPKD patients. At 
present for adolescent ADPKD patients, there is no drug approved for CKD treatment. The 
current study will evaluate the efficacy and safety of bardoxolone methyl for treatment of CKD 
due to ADPKD.  
 
The study participation burden for patients including multiple study visits, laboratory tests and 
other required assessments may outweigh the risk of potential anticipated benefit of the study 
results. The Sponsor will undertake all reasonable measures to minimize the study burden and 
risk to the patients. This study will provide additional efficacy and safety information on the risk: 
benefit profile of bardoxolone methyl.  


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5.1. 
Clinical Experience with Bardoxolone Methyl 
Overall, bardoxolone methyl has been tested in multiple studies enrolling over 3,000 patients, 
and over 2,500 individuals have been exposed to bardoxolone methyl.     
5.1.1. 
Efficacy  
As seen in Table 3, improvements in renal function, including eGFR, creatinine clearance, and 
inulin clearance, have been observed with bardoxolone methyl treatment in multiple clinical 
studies, including those in CKD, cancer, and PH patients.  Bardoxolone methyl was originally 
considered for development in cancer patients, and in two Phase 1 studies, bardoxolone methyl 
was observed to reduce serum creatinine levels, corresponding to an increase in eGFR.  The 
reductions of serum creatinine levels and resultant increases in eGFR were time-dependent and 
manifested in a majority (82%) of the patients studied.  In subsequent studies that enrolled over 
2,700 patients with type 2 diabetes and CKD, bardoxolone methyl has been shown to 
consistently produce clinically and statistically significant improvements in eGFR that are 
durable for at least one year in treated patients.   
Study 402-C-0804 (“BEAM”) was a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, multi-dose, Phase 2b study designed to assess the efficacy and safety of 3 doses 
(25, 75, and 150 mg) of the crystalline formulation of bardoxolone methyl in patients with Stage 
3b-4 CKD (eGFR 20-45 mL/min/1.73 m2) and type 2 diabetes.  Analysis of the primary 
endpoint, the change in eGFR values from baseline at Week 24, demonstrated a clinically and 
statistically significant increase in eGFR relative both to the baseline value and to the change 
with placebo (p < 0.001) at each of the 3 tested dose levels (Pergola, 2011).  Mean eGFR 
increases were largely sustained through Week 52 and on average, patients treated with 
bardoxolone methyl experienced a net increase in eGFR of 7.4 ± 0.8 mL/min/1.73 m2 at 
Week 52 from a baseline of 32.4 mL/min/1.73 m2.   
Study 402-C-0903, titled "Bardoxolone Methyl Evaluation in Patients with Chronic Kidney 
Disease and Type 2 Diabetes: The Occurrence of Renal Events" (BEACON), was a Phase 3, 
randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study 
designed to compare the efficacy and safety of bardoxolone methyl to placebo in patients with 
Stage 4 CKD (eGFR 15 to 29 mL/min/1.73 m2) and Type 2 diabetes.  A total of 2185 patients 
were randomized 1:1 to once-daily administration of the amorphous SDD formulation of 
bardoxolone methyl (20 mg) or placebo.  The primary efficacy endpoint of the study was the 
time-to-first event in the composite endpoint defined as 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 
(−0.9 mL/min/1.73 m2, 95% CI −1.2 to −0.5 mL/min/1.73 m2), corresponding to a relative 
difference between groups of 6.4 mL/min/1.73 m2 (95% CI 5.9 to 6.9 mL/min/1.73 m2, p<0.001) 
(de Zeeuw, 2013).   
Patients in Study 402-C-0804 and 402-C-0903 also participated in a four-week withdrawal 
period following the treatment period.  In 402-C-0804, analysis of the change in eGFR from 
baseline to Week 56 for patients who received study drug for 52 weeks showed that a portion of 
the increase in eGFR is retained following withdrawal of therapy.  Patients treated with 75 and 


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150 mg of bardoxolone methyl for 52 weeks had eGFR increases from baseline of 4.0 and 
4.3 mL/min/1.73 m2, respectively, at Week 56.  Similar results were observed in BEACON for 
patients that received at least 48 weeks of treatment.  These data support that the longer-term 
protective and anti-inflammatory effects of bardoxolone methyl may reverse some of the 
structural remodeling processes in the kidney associated with declining renal function, resulting 
in sustained eGFR improvement after withdrawal of drug. 
Notably, Reata’s Asian development partner, Kyowa Kirin Co., Ltd, demonstrated that 
bardoxolone methyl treatment resulted in a significant improvement in measured GFR, as 
assessed by inulin clearance, in Japanese patients with CKD and type 2 diabetes.  Improvements 
in other measures of renal function, including BUN, uric acid, and phosphorus, have also been 
consistently observed, providing further evidence that observed changes in eGFR reflect true 
improvements in kidney function.  
Bardoxolone methyl was also shown to significantly increase eGFR in patients with CKD due to 
Alport syndrome after 12 weeks of treatment.  The increases in eGFR from baseline at Week 12 
were shown to be sustained through 48 weeks of treatment (10.4 mL/min/1.73 m2; n=25; 
p<0.0001) and partially retained four weeks after withdrawal of study drug (4.1 mL/min/1.73 m2; 
p<0.001).  The clinical activity of bardoxolone methyl in Alport syndrome and diabetic 
nephropathy, two diseases with distinct etiologies (type IV collagen defects versus 
hyperglycemia, respectively), suggests that the anti-inflammatory and anti-fibrotic effects of 
bardoxolone methyl target the common final pathways contributing to GFR loss in multiple 
forms of chronic kidney diseases.   
Most recently, bardoxolone methyl was studied in a Phase 2 trial (study 402-C-1702, PHOENIX, 
NCT03366337) in patients with four rare forms of CKD: genetically-confirmed autosomal 
dominant polycystic kidney disease (ADPKD), biopsy-confirmed IgA nephropathy (IgAN), 
diabetic nephropathy secondary to type 1 diabetes (T1D), or biopsy-confirmed focal segmental 
glomerulosclerosis (FSGS).  In the cohort of patients with ADPKD with PKD1 mutations, 
treatment with bardoxolone methyl significantly increased eGFR after treatment with 12 weeks 
(mean ± SE: 9.3 ± 1.4 mL/min/1.73 m2; n=31; p<0.0001).  The improvements were consistent, 
and 27 of the 28 (96%) patients with data at Week 12 had improvements from baseline in eGFR.  
The increases were observed across multiple subgroups including age, gender, baseline eGFR, 
and baseline albumin to creatinine ratio (ACR).  Historical eGFR data for 29 of the 31 patients 
showed that these patients’ kidney function was declining at an average annual rate of 4.8 
mL/min/1.73 m2 prior to study entry.  Therefore, the improvements in eGFR after 12 weeks of 
treatment with bardoxolone methyl represents a recovery of approximately two years of average 
eGFR loss in ADPKD patients.  Thus, the magnitude and durability of eGFR increases with 
bardoxolone methyl could provide a meaningful therapeutic benefit, even over the sole available 
therapy (tolvaptan) in ADPKD. 
 
 


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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 
Population 
# of 
Patients 
Treatment 
Duration 
∆eGFR 
(mL/min/1.73m2)a 
CKD Studies 
402-C-0801  
(Stratum 1) 
(open label) 
2a/ 
US 
Age ≥ 18, 
Diabetic nephropathy 
60 
28 days 
6.7 
(p<0.001) 
402-C-0801  
(Stratum 2) 
(open label) 
2b/ 
US 
Age ≥ 18, 
Diabetic nephropathy 
20 
56 days 
7.2 
(p<0.001) 
CrCl also sig. increased 
402-C-0804 
(BEAM) 
2/ 
US 
Age ≥ 18, 
T2D and CKD 
227 
52 weeks 
8.6 at WK52 
(p<0.001 vs PBO) 
402-C-0902 
2/ 
US 
Age ≥ 18, T2D and 
CKD 
131 
85 days 
6.5 
(p<0.001) 
402-C-0903 
(BEACON) 
3/ 
Global 
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 
Age ≥ 18, 
T2D and Stage 3b and 
Stage 4 CKD 
24 
56 days 
9.0 
(p<0.05) 
RTA402-005 
(TSUBAKI) 
2/ 
Japan 
Age ≥ 20,  
T2D and Stage 3 and  
4 CKD 
120 
16 weeks 
6.6 (inulin GFR) 
(p=0.008 vs PBO) 
402-C-1603 
2/US 
Age 12 to 65, 
Alport Syndrome 
30 
48 weeks 
10.4 (p<0.0001) 
402-C-1603 
(Year 1) 
3/Global 
Age 12 to 70,  
Alport Syndrome 
157 
48 weeks 
9.5 (p<0.001 vs PBO) 
402-C-1702 
2/US 
Age 18 to 70, 
ADPKD 
31 
12 weeks 
9.3 (p<0.0001) 
402-C-1702 
2/US 
Age 18 to 70, 
IgA Nephropathy 
26 
12 weeks 
8.0 (p<0.0001) 
402-C-1702 
2/US 
Age 18 to 70, 
T1D CKD 
28 
12 weeks 
5.5 (p=0.025) 
402-C-1702 
2/US 
FSGS 
18 
12 weeks 
7.8 (p=0.003) 
Non-CKD Studies 
402-C-0501 
1/ 
US 
Age ≥ 18, 
Advanced Solid Tumors 
or Lymphoid 
Malignancies 
47 
Median:  
56 days 
18.2 
(p<0.0001) 
402-C-0702 
1/2/ 
US 
Pancreatic Cancer 
34 
Median:  
56 days 
32.2 
(p=0.001) 
402-C-1302 
(LARIAT) 
2/ 
US 
Age 18 to 75 
PH (Baseline eGFR  
82 mL/min/1.73 m2) 
54b 
16 weeks 
14.7 
(p<0.001 vs PBO) 
a Unless noted, 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. 
b Number of patients enrolled in 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 patients, 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, and hepatotoxicity has not been 
observed.  In BEACON, fewer hepatobiliary SAEs were observed in the bardoxolone methyl 
arm than in the placebo arm.  The elevations begin immediately after initiation of treatment or an 
increase in dose; they peak approximately two to four weeks later.  In most patients, 
transaminase elevations were mild, but approximately 4% to 11% of patients experienced an 
elevation greater than 3X the upper limit normal (ULN).  The elevations resolved to levels less 
than the ULN in most patients with elevations, within two weeks after peak values while patients 
continued taking study drug.  Patients who experienced elevations to greater than 3X the ULN 
sometimes required additional time to resolve.  While some patients have had elevations to 


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above 3X the ULN, persistent elevations to above 3X the ULN have not been observed, and the 
elevations did not recur once resolved, unless caused by other factors. 
Bardoxolone methyl regulates gamma-glutamyl transpeptidase GGT, a known Nrf2 target gene 
protein.  In clinical studies, low level GGT elevations during treatment were common, mild, and 
typically lasted longer than alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) 
elevations.  Bilirubin levels in patients experiencing transaminase or GGT elevations due to 
treatment with bardoxolone methyl either remained at baseline levels or decreased.  The ALT, 
AST, and GGT elevations were generally self-limiting in patients who continued treatment with 
study drug.  
5.1.2.3. 
Muscle Spasms 
Muscle spasm was the most frequently reported AE in clinical trials of bardoxolone methyl in 
patients with CKD who also had type 2 diabetes.  The muscle spasms most often manifested in 
the first two months of treatment and resolved spontaneously or with empirical treatment.  They 
occurred mostly at night, in the lower extremities, and were generally mild to moderate in 
severity.  Muscle spasms have also been reported in bardoxolone methyl-treated PH patients but 
at lower incidences than that observed in prior CKD studies.  Moreover, the incidence of muscle 
spasms is similar to that observed in placebo-treated PH patients.  Muscle spasms may result 
from improved insulin sensitivity and glucose uptake in skeletal muscle cells.  Increases in 
glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp procedure, were 
observed in response to bardoxolone methyl in a defined subset of patients enrolled in a Phase 2a 
study.  To date, in those cases where serum creatinine kinase (CK) levels have been measured, 
no association has been observed between muscle spasms and elevated CK levels in patients 
treated with bardoxolone methyl.  Clinical signs and laboratory findings associated with the 
reports of muscle spasms have not been consistent with muscle toxicity.  Bardoxolone methyl 
patients showed no increase in prominent laboratory findings associated with muscle toxicity, 
such as increased levels of serum markers, including creatinine, lactate dehydrogenase (LDH), 
BUN, uric acid, phosphorus, and potassium, which were monitored weekly during the first two 
months of a prior study (402-C-0804) when muscle spasms were most frequently reported.  
Increases in the whole-body glucose disposal rate have been observed in mice treated with 
bardoxolone methyl, as well.  Increased glucose uptake was observed in isolated calf muscles of 
the mice, but not in white adipose tissue (Saha, 2010).   
5.1.2.4. 
Weight Loss 
Decreases in weight and reports of anorexia/decreased appetite have been observed following 
treatment with bardoxolone methyl in patients with CKD who also had type 2 diabetes.  In 
studies of these patients, 17% of bardoxolone methyl patients reported AEs of weight decrease or 
decreased appetite (irrespective of relationship to treatment).  Weight reduction was more 
pronounced in patients treated with bardoxolone methyl than in those given placebo. 
Weight loss of approximately one kilogram per month was observed, with patients of higher 
body-mass index at baseline losing more weight (in absolute terms) than those of normal or 
moderately-elevated body-mass index.     


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Bardoxolone methyl-treated PH patients have also had decreases in weight, with mean weight 
decreases of approximately 3 kg versus placebo at Week 16.  Weight loss in PH patients has not 
coincided with reports of decreased appetite or anorexia AEs. 
5.1.2.5. 
Hypomagnesaemia 
Hypomagnesaemia has not been commonly reported in PH patients to date but was reported as 
an AE for 15.5% of patients with CKD who also had type 2 diabetes who received bardoxolone 
methyl.  The AE of hypomagnesaemia (of any reported relationship to study drug) was more 
frequently reported in bardoxolone methyl-treated patients than in patients given placebo.  The 
investigators considered almost all reported events to be mild.  Additionally, patients treated with 
bardoxolone methyl had a greater decrease from baseline in serum magnesium levels than 
patients given placebo; the decrease was evident within 4 weeks and attenuated after 8 weeks of 
starting therapy.  In bardoxolone methyl clinical studies performed to date, a post-hoc analysis 
identified no correlation between hypomagnesaemia and either gastrointestinal AEs or cardiac 
AEs, including cardiac dysrhythmias and prolonged QTc.  The 24-hour urine collections from 
the BEACON ambulatory blood pressure monitoring sub-study showed no increase in urinary 
magnesium levels, indicating that renal loss of magnesium did not account for the reductions in 
serum magnesium observed with bardoxolone methyl treatment in CKD patients.  Notably, a 
thorough QT study that tested doses of bardoxolone methyl up to 80 mg, bardoxolone methyl 
showed no increase in the QT interval.  
5.1.2.6. 
Increases in Urinary Protein 
Increases in urinary albumin have been observed in some patients treated with bardoxolone 
methyl with CKD and type 2 diabetes.  The increases are likely due to bardoxolone methyl’s 
pharmacological modulation of tubular protein reabsorption and have not been associated with 
interstitial fibrosis or injury.  In preclinical studies, bardoxolone methyl has been shown to 
downregulate the primary proteins involved in protein reabsorption in the proximal tubules: the 
megalin-cubilin complex.  Moreover, the magnitude of observed eGFR increases with 
bardoxolone methyl treatment is thought to reduce the residence time of protein in the proximal 
tubules, thereby reducing protein reuptake and increasing urinary protein levels.  Therefore, 
increased eGFR, together with decreased megalin expression, is thought to result in decreased 
fractional 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. 
5.1.2.7. 
Impact on Adolescent Growth (Weight and Height)   
Impacts on weight and height gain were observed in bardoxolone methyl-treated adolescent 
patients (ages 12-17 years) with Alport syndrome (study 402-C-1603 CARDINAL) when 
compared to placebo-treated adolescent patients.  In this study, a total of 23 adolescents were 
enrolled, where 11 and 12 were randomized to bardoxolone methyl and placebo, respectively. 
In bardoxolone methyl treated adolescents, both weight and height at baseline were relatively 
higher than placebo treated adolescents. Bardoxolone methyl treated patients had a mean 
baseline weight of 65.50 kg (SD 10.193, median 63.90 kg, min/max 52.5/81.3 kg), while placebo 


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treated adolescents had a mean baseline weight of 57.79 kg (SD 16.020, median 59.80 kg, 
min/max 29.5/76.3 kg). A change from baseline using the last on treatment value available for 
weight showed a mean weight decrease of -1.41 kg (SD 5.260, median -2.30 kg, min/max -10.9 
to 6.8 kg) for bardoxolone methyl treated adolescents and a mean weight increase of +2.26 kg 
(SD 4.153, median +2.25 kg, min/max -5.7 to +8.2 kg) for placebo treated adolescents. 
Bardoxolone methyl treated adolescents at baseline had a mean height of 171.7 cm (SD 5.90, 
median 172.0 cm, min/max 165/183 cm), while placebo treated adolescents had a mean height of 
166.3 cm (SD 14.94, median 169.5 cm, min/max 136/186 cm).  A change from baseline using 
the last on treatment value available showed a mean height increase of +1.1 cm (SD 1.13, 
median +1.0 cm, min/max 0 to 3 cm) for bardoxolone methyl treated adolescents, compared with 
a mean height increase of +2.4cm (SD 3.65, median 0.6 cm, min/max -1 to +11cm) for placebo 
treated adolescents. 
Bardoxolone methyl treated adolescents at baseline had a mean BMI of 22.1 kg/m2 (SD 2.11, 
median 22.3 kg/m2, min/max 19/25 kg/m2), while placebo treated adolescents at baseline had a 
mean BMI of 20.5 kg/m2 (SD 3.63, median 20.3 kg/m2, min/max 16/26 kg/m2).  Overall, in 
bardoxolone methyl treated adolescents, BMI changes from baseline to last value on treatment 
showed a mean decrease of -0.5 kg/m2 (SD 1.40, median -0.8 kg/m2, min/max -3/+2 kg/m2), 
compared with a mean BMI increase in placebo treated adolescents of 0.3 kg/m2 (SD 1.15, 
median 0.3 kg/m2, min/max -2/+2 kg/m2).   
In Study 402-C-1603 phase 3, the number of adolescent subjects was relatively small; therefore, 
a firm conclusion cannot be derived. Overall, no other concerning differences in the safety 
profile were identified in patients 12 to < 18 years of age compared to adult patients randomized 
to receive bardoxolone methyl (total: n=77; adults: n=66) or to receive placebo (total: n=80; 
adults: 68). 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
The objectives are as follows: 
6.1.1. 
Primary Objective 
• To assess the off-treatment change from baseline in estimated glomerular filtration 
rate (eGFR) at Week 108. 
• To assess safety and tolerability. 
6.1.2. 
Secondary Objective 
• To assess the change from baseline in eGFR at Week 100. 
 
   
• 
  
• To assess the off-treatment change from baseline in eGFR at Week 112. 
• 
 
 
• 
 
 
• 
 
 
• 
 
. 
• 
 
 
• 
 
 
 
• 
 
 
− 
 
− 
− 
 
− 
 
• 
 
 
− 
  
− 
− 
 
− 
 


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• 
 
 
− 
 
− 
− 
 
− 
 
• 
 
 
− 
  
− 
− 
 
− 
 
6.2. 
Endpoints 
6.2.1. 
Primary Efficacy Endpoint 
• Off-treatment change from baseline in eGFR at Week 108. 
6.2.2. 
Secondary Efficacy Endpoint 
• Change from baseline in eGFR at Week 100. 
 
 
• 
 
• The off-treatment change from baseline in eGFR at Week 112. 
• 
 
 
• 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
• 
 
 
− 
 
− 
− 
 


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− 
 
• 
 
 
− 
 
− 
− 
 
− 
 
• 
 
 
− 
 
− 
− 
 
− 
 
• 
 
 
− 
 
− 
− 
 
− 
 
6.2.4. 
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, pediatric growth (height and weight), and sexual 
maturity using Tanner staging. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This international, multi-center, randomized, double-blind, placebo-controlled phase 3 trial will 
study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with 
ADPKD.  Approximately 850 patients will be enrolled.   
Patients will be randomized 1:1 to either bardoxolone methyl or placebo.  Randomization will be 
stratified by eligibility eGFR category (30 to <60; ≥60 to 90), concomitant tolvaptan use (yes, 
no), and screening ACR (≤300 mg/g, >300 mg/g).  Patients randomized to placebo will remain 
on placebo throughout the study, undergoing sham titration.  Patients with eGFR 60 to 
90 mL/min/1.73 m2 at screening should not comprise more than approximately 40% of enrolled 
patients. 
The maximum bardoxolone methyl dose will be determined by baseline proteinuria status.  
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, and 100 and by telephone contact on Days 3, 10, 21, 31, 
38, and 45.  Patients will continue study drug treatment through Week 100.  Patients will also be 
scheduled to be assessed at an in-person follow-up visit at Weeks 103, 104, 108, and 112 after 
the end of treatment, respectively.   
Efficacy endpoints will be analyzed after all enrolled patients have completed the study and the 
database has been locked.  All enrolled patients are expected to remain on their blinded treatment 
assignment through Week 100, and to complete all scheduled assessments through Week 112.   
The conduct of the study, according to protocol specifications, was impacted by the Coronavirus 
Disease 2019 (COVID-19) pandemic.  As a result, and as of Version 4 of the Protocol, 
modifications intended to address access to and administration of study drug, and adherence to 
protocol-specified visits and laboratory assessments were implemented.  These modifications are 
described in Appendix 1 (COVID-19 Mitigations), Appendix 2 (Use of Home Healthcare) and 
throughout the protocol. 
7.2. 
Number of Patients 
Approximately 850 patients will be enrolled.  


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7.3. 
Treatment Assignment and Dosing Rationale 
Patients will be randomized 1:1 to either bardoxolone methyl or placebo.  Randomization will be 
performed using an interactive web response system (IWRS).  Patients randomized to placebo 
will remain on placebo throughout the study but will follow sham titration to maintain the blind.   
The use of a placebo comparator is justified because the known safety profile of tolvaptan 
(approved for the treatment of ADPKD in adults with evidence of rapidly progressing disease) 
pertaining liver toxicity would interfere with known pharmacologic effects of bardoxolone 
methyl on aminotransferases increase without liver toxicity, and complicate safety monitoring 
and medical management of patients in a double-blind trial.  A placebo-controlled trial with 
bardoxolone methyl provides the best opportunity to determine the benefit-risk profile for 
bardoxolone methyl in ADPKD patients.  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.  The same dose 
titration regimen was used in a Phase 2 trial in adult ADPKD patients (study 402-C-1702).  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. 
Adolescent Dosing Rationale 
Adolescents (12 ≤ age < 18) will receive the same dosing regimen as adults. The maximum 
bardoxolone methyl dose will be determined by baseline proteinuria status.  Similar to the adult 
population, a dose de-escalation is permitted during the study if indicated clinically, and 
subsequent dose re-escalation is also permitted to meet the dosing objective of the highest 
tolerated dose.  
Although no adolescent (12 ≤ age < 18) patients with CKD due to ADPKD have been exposed to 
bardoxolone methyl, in Study 402-C-1603 (CARDINAL) phase 2/3 studies and an open-label 
extended access study in Alport syndrome (Study 402-C-1803, EAGLE), a total of 21 adolescent 
patients received bardoxolone methyl at a maximum dose of 20 mg for patients with baseline 
ACR ≤ 300 mg/g and a maximum dose of 30 mg for patients with baseline ACR > 300 mg/g. In 
CARDINAL phase 2/3 studies, the dose titration for adolescent patients was similar to adults, 
differing only during the first week, where adolescents administered study drug (at the 5 mg 
dose) every other day, while adults (also at the 5 mg dose) administered study drug daily. An 
overall safety/tolerability evaluation of adolescent patients from CARDINAL phase 2 
(open-label- n=2) and Phase 3 (double-blind placebo-controlled – n=11) showed the dosing 


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regimen was well tolerated and the adverse event profile in adolescent patients was similar to the 
adverse events profile observed in the adult patients. 
Additionally, a population pharmacokinetic (popPK) analysis was conducted for bardoxolone 
methyl using rich and sparse PK data from 8 clinical studies in healthy subjects and patients with 
Alport syndrome, PAH, T2DM CKD, ADPKD, and other rare CKDs (Study REAT-BARD-
PMX-1532).  The effects of intrinsic factors on bardoxolone methyl PK were evaluated in the 
popPK analysis and showed that no dose adjustments based on sex, age, body weight, race, or 
renal function are needed.   To further support dosing recommendations based on age, 
simulations using the popPK model were performed to assess the potential effects of age on 
bardoxolone methyl steady-state exposures.  Simulations were conducted following 20 mg QD 
and used individual posthoc PK parameter estimates for all patients and subjects in the popPK 
analysis dataset.  Model predictions demonstrate a lack of a clinically meaningful difference in 
exposures between patients and subjects <18 years of age and patients and subjects ≥18 years of 
age (ratio of median exposures: 0.93 to 1.11).    In addition, the systemic clearance of 
bardoxolone methyl was not affected by disease state in the popPK analysis.  Therefore, there are 
no differences in systemic exposure (AUC) expected between patients with ADPKD and patients 
with Alport syndrome.  The popPK model predicted mean steady-state AUC for patients 
receiving 30 mg QD (n=16) in Study 402-C-1702 (rare CKDs, including ADPKD) is 222 
ng*hr/ml (SD = 134 ng*hr/ml), and is similar to the popPK model predicted mean steady-state 
AUCs of 263 ng*hr/ml (SD = 135 ng*hr/ml) and 223 ng*hr/ml (SD = 155 ng*hr/ml) in Alport 
syndrome patients receiving 30 mg QD in the phase 2 (n=9) and  phase 3 (n-24) portions of 
Study 402-C-1603), respectively.   
In summary, there were no differences in adverse event profiles in adolescent and adult patients 
who received bardoxolone methyl in CARDINAL phase 2/3 studies, and a popPK analysis 
suggested there are no expected differences in systemic exposure (AUC) between ADPKD and 
Alport syndrome patients and no age dependent requirements for dose adjustments. Therefore, 
the same dosing regimen is proposed both for adolescent and adult ADPKD patients.   
7.3.2. 
Dose Escalation Plan  
Both adult and adolescent patients randomized to placebo will remain on placebo throughout the 
study, undergoing sham titration.  Both adult and adolescent 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.   
7.3.3. 
Dose De-Escalation and Re-Escalation 
For detailed instructions on dose management, refer to Section 9.11. 
7.3.4. 
Dose Interruption and Re-Challenge/Re-Initiation 
For detailed instructions on dose management, refer to Section 9.11. 
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 


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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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Dispense Study Drug 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
Collect Study Drug 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
Telephone Contact 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
Adverse Event Collection 
 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Kidney Ultrasoundj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry (incl. eGFR) k 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
BNP and NT-proBNP 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
Hemoglobin A1c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
Coagulation 
 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
Basic Lipid Panel 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis and Microscopy 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
Urine Collection for ACRl 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
Virus Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK Samplesn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 Antibody Test 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Ambulatory Blood Pressure Monitoringo 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tanner Stagingq 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 






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Abbreviations: ABPM = ambulatory blood pressure monitoring, ACR = albumin to creatinine ratio, ADPKD = autosomal dominant polycystic kidney disease, AE = adverse event, 
BNP = B-type natriuretic peptide, 
, , ECG = electrocardiogram, eGFR = estimated glomerular filtration rate,  
IRB/EC = institutional review board/ethics committee, IWRS = Interactive Web Response System, NT-proBNP = N-terminal pro-brain natriuretic peptide, 
 
, PK = pharmacokinetic, SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus 2, Wk = week, WOCBP = women of child-bearing potential 
 
a 
Total Screening period should not exceed 90 days. 
b Screen B visit should be at least 1 day after Screen A and no more than 30 days prior to Day 1. 
c 
Day 1 should be the day of randomization and administration of the first dose.  Where randomization in the IWRS must occur earlier than Day 1, the Day 1 visit must align with 
the administration of the first dose.  On Day 1, all procedures must 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 
e Height will be recorded in centimeters.  Adult patients (18 ≤ age ≤ 70 years at Screen A visit) will be measured at Screen A only.  Adolescent patients (12 ≤ age < 18 years at 
Screen A visit) will be measured at all specified timepoints. 
f 
An echocardiogram performed during screening or within 6 months prior to Day 1 may be used to determine eligibility. 
g Screen B vital sign measurements are needed only if re-assessing blood pressure for eligibility. 
h 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. 
i 
AE assessments on Day 1 should be performed following study drug administration. 
j 
Kidney ultrasound (historical or one obtained during screening) may be used to diagnose ADPKD for patients without a prior ADPKD diagnosis. 
k  eGFR will be calculated and appear on lab reports for Screen A and Screen B visits, eGFR will no longer be calculated for any visits after the Screening period. 
l 
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. 
 
 
 
n Patients must refrain from taking study drug prior to coming to the clinic for PK draws at Week 12 and Week 100. 
o Ambulatory Blood Pressure Monitoring (ABPM) is an optional sub-study for adult patients (18 ≤ age ≤ 70 years at Screen A) who enroll under protocol version 6.0 (or greater) 
and consent to the procedure prior to randomization. See Section 9.10.33 for details and timing on ABPM. ABPM will not be performed on adolescent patients (12 ≤ age < 18 
years at randomization 
p For patients who consent to the optional ABPM sub-study, the initial (baseline) 24-hour monitoring assessment must be done during the Screening period prior to Day 1.  See 
Section 9.10.33 for detailed information.  
q Adolescent patients (12 ≤ age < 18 years at Screen A visit) will be assessed by Tanner staging at all specified timepoints. 
r 
For adult patients who consent to the optional ABPM sub-study, the final 24-hour monitoring assessment occurs after Week 88 and prior to Week 100 (last dose).  For patients 
who discontinue study drug prior to Week 100, patients who consented to ABPM should have the assessment at End of Treatment if no ABPM was conducted in the four weeks 
prior to the date of last dose. 
s See Section 8.3.3 and Section 8.5.1 for details on the Off-Treatment Period.    
t 
Unless permitted in the protocol, all study activities, including assessments and sample collection, are expected to be completed on the same day (i.e., day of the visit). 


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
NOTE: Participating sites in Australia will only treat adult patients, defined as 18 years old or 
older at the time of consent. 
Diagnosis and main criteria for inclusion:  
1. Male and female patients 12 ≤ age ≤ 70 upon study consent; 
2. Diagnosis of ADPKD 
a. For adult (18 ≤ age ≤ 70 years) diagnosis of ADPKD by modified Pei-Ravine 
criteria:  
i. at least 3 cysts per kidney by sonography or at least 5 cysts by CT or 
MRI with family history of ADPKD or  
ii. at least 10 cysts per kidney by any radiologic method and exclusion of 
other cystic kidney diseases if without family history;   
b. For adolescent (12 ≤ age < 18 years) diagnosis of ADPKD by:  
i.  the presence of family history and/or genetic diagnosis and the 
presence of at least 1 cyst of 0.5 cm on ultrasound or MRI,   
ii.  patients without a family history or genetic diagnosis must have at 
least 10 bilateral renal cysts in total, and exclusion of other cystic 
kidney diseases; 
3. eGFR must: 
a. Have a percent difference ≤ 25% at screening (the values at Screen A and Screen 
B), and; 
b. Have an average (the values at Screen A and Screen B) ≥ 30 to ≤ 90 mL/min/1.73 m2 
for patients 12 to 55 years or ≥ 30 to ≤ 44 mL/min/1.73 m2 for patients 56 to 70 years, 
and; 
c. Support ADPKD disease progression (i.e., average yearly eGFR decline of 
≥ 2.0 mL/min/1.73 m2 for the past two years) for patients with either screening 
eGFR ≥ 60 to ≤ 90 mL/min/1.73 m2 or age 56 to 70 years (See Protocol 
Section 9.10.2) 
4. ACR ≤ 2500 mg/g at Screen B visit; 
5. Systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg at 
Screen A or Screen B visit after a period of rest.  Patients receiving an angiotensin-
converting enzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (T2T)* 
must be on a stable dose for at least 6 weeks prior to the Screen A visit; *see Protocol 
Section 9.1.7. 
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), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤ the upper limit of normal (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/assent document 
indicating that the patient has been informed of all pertinent aspects of the study prior 
to initiation of any protocol-mandated procedures.  
10. Patients receiving an SGLT2 inhibitor must be on a stable dose for at least 4 weeks 
prior to the Screen A visit; 
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. Use of tolvaptan within 2 months prior to Screen A.  Initiation of concomitant tolvaptan 
use during the study is not permitted; 
3. History of administration of polycystic kidney disease-modifying agents (somatostatin 
analogues) within 2 months prior to the Screen A visit;   
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. Serum albumin < 3 g/dL at Screen A visit; 
7. History of intracranial aneurysms;  
8. Kidney or any other solid organ transplant recipient or a planned transplant during the 
study; 
9. Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during 
Screening; 
10. 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 III or IV; 
h. History of untreated atrial fibrillation; 
i. History of unstable arrhythmias; 
11. Systolic BP < 90 mm Hg at Screen A visit after a period of rest; 


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12. BMI < 18.5 kg/m2 at the Screen A visit; 
13. History of malignancy within 5 years prior to Screen A visit, with the exception of 
localized skin or cervical carcinomas; 
14. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks 
prior to randomization or anticipated need for immunosuppression during the study; 
15. Untreated or uncontrolled active bacterial, fungal, or viral infection; 
16. Participation in other interventional clinical studies within 30 days prior to Day 1; 
17. 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;  
18. Women who are pregnant or breastfeeding; 
19. Known hypersensitivity to any component of the study drug;  
20. Any abnormal laboratory level that, in the opinion of the investigator, would put the 
patient at risk by trial enrollment; 
21. 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; 
22. Coronavirus disease 2019 (COVID-19) pneumonia, related acute kidney injury, or 
related hospitalization within 6 months prior to Day 1. 
8.3. 
Screening, Treatment, and Off-Treatment Periods 
8.3.1. 
Screening Period 
The screening period begins with the signing of the informed consent/assent form at the 
Screen A visit and ends at the start of the Day 1 visit. Where the signing of the informed 
consent/assent precedes the Screen A visit, the screening period is considered to begin at the 
Screen A visit.  The duration of the screening period must not exceed 90 days.  The Screen A 
procedures may be completed across multiple days.  Efforts should be made to ensure the 
Screen B visit is no more than 30 days prior to Day 1. 
Sites must not initiate screening of an adolescent who will become an adult prior to Day 1. If, 
prior to randomization, an adolescent patient who screened has become an adult, the patient must 
be screen-failed and rescreened, such that eligibility is assessed based on the adult eligibility 
parameters (ADPKD diagnosis and eGFR calculation). 
Where calculation of the screening eGFR average results in a decimal, basic rounding principles 
apply. For example, an average eGFR of 29.5 mL/min/1.73 m2 would round up to 30 
mL/min/1.73 m2. 
Eligibility should be confirmed prior to randomization of any patient in the IWRS.   
All screening procedures should be completed per the schedule of assessments in Table 4. 
8.3.2. 
Treatment Period 
The Treatment Period refers to the time from administration of the first dose (Day 1 visit) 
through administration of the last dose (Week 100 visit).  Administration of the first dose of 
study drug should occur in-clinic, at the Day 1 visit, after confirmation of eligibility and 


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randomization. Administration of the last dose of study drug should occur in-clinic, at the Week 
100 visit, following the collection of all lab and PK assessments. 
During the treatment period, sites should ensure proper documentation of any intentional 
interruptions in dosing, including the reason for and duration of the interruption.  Information 
regarding interruptions should be entered into the clinical database.   
A patient who discontinues study drug early has a shortened treatment period.  Regardless of 
when a patient’s treatment period ends, it is imperative that an off-treatment period follows study 
drug discontinuation.  See Section 8.3.3 for required assessments in the Off-Treatment Period. 
If a patient resumes study drug, the patient should resume the normal study schedule and follow 
instructions in Section 9.11 regarding dose interruption and re-challenge. 
All assessments during the Treatment Period should occur per the Schedule of Assessments, in 
Table 4. 
8.3.3. 
Off-Treatment Period 
The purpose of the Off-Treatment Period is to continue assessing patients for 12 weeks after 
patients have completed 100 weeks of study drug administration (or after the last dose of study 
drug if a patient discontinues study drug early).  The Off-Treatment Period visits are of critical 
significance to this study. Every effort should be made to obtain off-treatment assessments 
following any discontinuation of study drug, whether at the planned Week 100 timepoint or at an 
earlier timepoint during the study. 
For patients who remain on study drug through Week 100, the planned Off-Treatment Period 
begins the day after the Week 100 visit and continues through Week 112.  Patients must 
complete 7 visits during the Off-Treatment Period, as listed in Table 4, and as described below: 
• Week 103 visit (21 – 25 days from date of last dose) 
• Week 104 A & B visits (28 – 36 days from date of last dose) at least one day apart 
• Week 108 A & B visits (56 – 64 days from date of last dose) at least one day apart 
• Week 112 A & B visits (84 – 92 days from date of last dose) at least one day apart 
To the extent possible, sites should try to avoid bringing patients in very late in the window for a 
particular visit, and then very early in the window for the next timepoint. For example, a patient 
who completes Week 104 A & B visits 35 and 36 days after last dose, then completes Week 108 
A & B visits 56 and 57 days after last dose, would have Week 104 and Week 108 visits spaced 
only 20 days apart, rather than ~4 weeks apart.  Sites should attempt to achieve an approximate 
4-week interval between Weeks 100, 104, 108, and 112.     
For patients who discontinue study drug prior to Week 100, the patient should be assessed at the 
following timepoints, see Off Treatment Period in Table 4 for full list of assessments:  
• An End of Treatment visit as close as possible to the last dose 
• One visit 3 weeks after discontinuation (21 – 25 days from date of last dose) 
• Two visits 4 weeks after discontinuation (28 – 36 days from date of last dose) at least one 
day apart 
• Two visits 8 weeks after discontinuation (56 – 64 days from date of last dose) at least one 
day apart 


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• Two visits 12 weeks after discontinuation (84 – 92 days from date of last dose) at least 
one day apart 
 
For patients who discontinue study drug early, after the above Off-Treatment Period is 
completed, the patient will continue with all assessments through Week 112, except PKs and 
ABPM (if applicable).  See Section 8.5.1 for detail regarding the importance of continued 
follow-up for patients who discontinue study drug early. 
 
AEs should be reported until the Week 112 (B) study visit. .   
8.4. 
Patient Re-Screening & Re-Testing 
8.4.1. 
Re-Screening 
Patients may repeat Screening once to qualify for the study (re-screening must occur at least 
2 weeks after the screen fail).  In rare circumstances, a second re-screening may be appropriate; 
in these cases, the site must consult with the Medical Monitor for approval.  When a patient 
repeats screening, the patient is given a new patient number and re-screening procedures are 
completed under the new patient number.   
8.4.2. 
Re-Testing 
In rare situations, a specific screening test (e.g., BNP) may be repeated if the test value is 
inconsistent with the patient’s medical history and/or is considered by the investigator to be an 
anomaly.  Medical Monitor approval must be obtained prior to re-testing any of the eligibility 
parameters for a patient. 
8.5. 
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.  The term discontinuation generally refers to a permanent 
halt in study drug administration. 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 who 
interrupts study drug for 14 consecutive days or more must have approval from the Medical 
Monitor prior to resuming study drug.  
8.5.1. 
Study Drug Discontinuation Criteria 
Study drug discontinuation refers to a patient’s stopping administration of study drug 
permanently.  Reasons for study drug discontinuation may include the following: 
• Adverse event; 
• Death; 
• Lost to follow-up; 
• Physician decision; 
• Pregnancy; 


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• Protocol specified criterion met (Section 7.4, Section 9.1.1, Section 9.1.9, 
Section 9.3.1, Section 9.6.1, Section 9.8.3); 
• Withdrawal by patient; 
To maximize patient retention and minimize missing data, patients who discontinue study drug 
early are encouraged to remain active in the study and complete all future study visits and 
assessments, except PKs and ABPM, if applicable.   
For patients who discontinue treatment prior to Week 100, see Section 8.3.3 for the required off-
treatment assessments.  After the off-treatment assessments, the patient will continue with 
follow-up assessments through Week 112. The collection of laboratory data and vital status 
through Week 112 (B) is important for trial integrity, and data may be obtained through in-
person clinic visits or through home health visits. 
See Section 9.10.16 for Adverse Event Collection following study drug discontinuation.  
For patients who are unwilling to complete all future visits, the Week 108 visit is of paramount 
significance.  Collecting Week 108 data for all randomized patients is essential for trial integrity. 
For patients who discontinue study drug and are no longer willing to return for all scheduled 
study visits, a number of follow-up options are available and must be discussed with the patient 
thoroughly, including: 
• Participation in follow-up procedures specified in the protocol by an in-home visit, 
where feasible; 
• Reduced in-person visit schedule; 
• Telephone contact only; 
• Contact of alternative person(s) who has been designated in source records as being 
available to discuss the patient’s medical condition; 
• 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 following discontinuation of study drug.  The frequency and schedule of 
participation in follow-up procedures, whether in-clinic, by telephone, by in-home visit(s) or 
some other means, should be discussed and agreed to by patient and staff.  All efforts to prevent 
the patient from progressing to a “Lost to Follow-Up” status must be made. Any discussions 
about reduced follow-up options must be documented in the patient’s source file. 
Sites should strongly consider the use of home health care visits to maximize data collected from 
patients who become unwilling or unable to return for in-clinic visits.   
8.5.2. 
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: 
• Death; 
• Lost to follow-up; 


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• Withdrawal of consent by patient. 
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, as soon as possible, with 
patients who no longer wish to return for all scheduled in-person visits, patients who have failed 
to return for a scheduled visit, and patients who may be demonstrating an increasing risk of no 
longer communicating with the site.  Patients should not be considered lost to follow-up until the 
scheduled Week 112 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.  Unless the patient provides written withdrawal of consent or there is other 
written documentation by the investigator confirming the patient’s verbal intent to completely 
withdraw from the trial, patients should be followed for all protocol specified evaluations and 
assessments.  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.  Withdrawal of consent is a critical trial event and therefore should be 
approached with the same degree of importance and care as is used in initially obtaining 
informed consent or assent, if applicable.  The reasons for a patient’s intended withdrawal need 
to be completely understood, documented, and managed to protect the rights of the patient and 
the integrity of the trial.  Only patients who withdraw permission for all follow-up options 
outlined in Section 8.5.1 are considered to have completely withdrawn their consent to 
participate in the study. 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Select Management Guidelines 
The guidelines below 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 and rapid weight gain 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 to 
evaluate for any symptoms of fluid overload, and accordingly, request an unscheduled visit to 
assess signs and symptoms of congestive heart failure, heart failure, acute pulmonary edema, etc. 
identified through the telephone contact.  In addition, patients will be given a Sponsor-provided 
scale to use at home to collect and record weights daily during the study.  In the event the 
Sponsor-provided scale is temporarily unavailable (e.g., patient is traveling, replacement scale 
has not arrived to patient, etc.), patients may use any available scale.  Use of a scale other than 
the Sponsor-provided scale should be documented in the patient diary.  Patients who experience 
a weight increase of three pounds (1.4 kilograms) in a day or five pounds (2.3 kilograms) or 
greater increase within a week must have an unscheduled telephone contact immediately.  
Whether prompted by BNP elevations, sudden weight gain, or by the presence of clinical signs 
and symptoms the patient must be instructed to stop taking their study medication immediately 
and be medically evaluated by the investigator or a local physician within 1 to 2 days.   
Investigators are encouraged to consider starting or increasing doses of diuretics (thiazides, loop 
diuretics) early after recognition of edema.  This can be done concurrently with temporary 
discontinuation of the study drug.  Patients may not restart their study medication 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 must immediately assess symptoms of fluid overload and determine appropriate 
medical management, as necessary, including whether stopping drug administration is required.   
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) 
For only patients who enrolled under Version 2 of the protocol (only performed in the US at the 
beginning of the study) and are receiving tolvaptan (JYNARQUE), liver biochemistries (ALT, 
AST, and/or bilirubin levels) should be monitored according to the relevant package 
insert/REMS program for tolvaptan.   


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For all patients enrolled, nearly all instances of elevated transaminases due to bardoxolone 
methyl treatment are expected to be asymptomatic.  
Some patients may experience more rapid increases in ALT/AST values than others during the 
dose titration period.  Investigators may consider extending the time between each dose increase 
to manage ALT/AST elevations. 
If a patient’s transaminases are elevated, follow the instructions outlined in Table 5. 
Table 5: 
Management of Elevated Transaminase Levels (ALT and/or AST) 
ALT and/or AST 
Level(s) 
Interrupt 
Dose?  
Procedure 
> 8x ULN 
Yes 
➢ Discontinue study drug temporarily  
➢ Contact the Medical Monitor  
 
Study drug may be restarted with Sponsor approval after all 
the following criteria are met:  
• 
Ultrasound or MRI of the hepatobiliary tree*; 
• 
ALT and AST returned to ≤ ULN; 
• 
TBL is within normal range; 
• 
Other relevant labs (e.g., albumin, INR, PT) are within 
normal range; 
• 
No clinical signs or symptoms of liver injury are 
present. 
 
*Based on imaging results, if additional tests/studies are 
warranted, this should be discussed with the Medical 
Monitor.  
> 5x ULN for more than  
2 weeks 
> 3x ULN with 
appearance of fatigue, 
nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, 
and/or eosinophilia 
> 3x ULN and 
(TBL > 2X ULN or INR 
> 1.5) 
> 3x ULN 
No 
➢ Check transaminase levels (as well as TBL, GGT, ALP, 
and INR) within 48 to 72 hours 
Continue testing for ALT/AST every 72 to 96 hours until 
transaminase levels are below 3X the ULN for at least one 
week 
ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferase,  
GGT = gamma-glutamyl transpeptidase, INR = international normalized ratio, MRI = magnetic 
resonance imaging, PT = Prothrombin Time, TBL = total bilirubin, ULN = upper limit of normal  
 
Patients who meet the interruption criteria outlined above must restart study drug at the 5 mg 
dose level and dose titrate according to Section 7.3.3. 
 


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9.1.3. 
Management of Muscle Spasms 
Basic symptomatic relief is the first step in managing muscle spasm, including walking, adequate 
hydration, wearing socks, and stretching before bedtime. Assessment of levels of electrolytes 
such as magnesium, calcium, and potassium may indicate the need for replacement.  Serum 
vitamin D levels may be collected by the investigator, in the evaluation of muscle spasms.  If 
vitamin D levels are low, supplementation may be warranted.  Muscle relaxants may also help 
relieve symptoms. 
9.1.4. 
Weight Loss  
Adults - The investigator should evaluate a patient for unexplained weight loss of 7% or greater 
from the Day 1 weight. Ongoing assessments of other symptomology (for example: nausea, 
vomiting, abdominal pain or poor appetite) may be warranted to ensure the patient is receiving 
adequate nutrition and evaluate for other causes of weight loss. 
Adolescents - If weight loss of greater than 5% from the Day 1 weight is observed, the 
investigator should temporarily stop study drug, and evaluate the patient for any symptomology 
(for example: nausea, vomiting, abdominal pain or poor appetite) leading to weight loss, and/or 
other causes of weight loss.  The investigator should inform the Medical Monitor prior to 
stopping study drug, and the investigator and Medical Monitor should discuss management of 
the patient.  
9.1.5. 
Hypomagnesaemia 
In instances where a patient experiences hypomagnesaemia, defined as serum magnesium less 
than 1.3 mEq/L (0.65 mmol/L), consideration should be given for repletion of serum magnesium. 
9.1.6. 
Management of Urinary Protein 
Although increases in urinary protein with bardoxolone methyl have not been associated with 
renal injury or loss of kidney function, investigators should closely monitor patients if urinary 
albumin to creatinine ratios increase by more than 100% and exceed 1000 mg/g for proteinuria 
and should consult the Medical Monitor for appropriate measures.   
9.1.7. 
Management of Blood Pressure  
Investigators should attempt to maintain the blood pressure within the range recommended by 
the Kidney Disease Blood Pressure Working Group (KDIGO): ≤ 140 mm Hg systolic and 
≤ 90 mm Hg diastolic for patients with urine albumin to creatinine ratio (ACR) < 30 mg/g, and  
≤ 130 mm Hg systolic and ≤ 80 mmHg diastolic for patients with ACR > 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.  


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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 reasonable.   
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 (as calculated by the site, using the central lab-provided serum creatinine 
and the formulas provided in Section 9.10.18.1), 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 completed in-person or through a home health visit where in-person visits 
are not feasible, at least once every 4 weeks (± 2 weeks), until one of the following occurs: 
• Initiation of dialysis; 
• Receipt of transplant.   
Two off-treatment serum creatinine assessments should be collected 28 to 36 days after last dose, 
and prior to initiation of dialysis or receipt of transplant.  Upon initiation of dialysis, study drug 
should be interrupted.  Because laboratory and vital sign assessments can be affected by 
receiving dialysis, those safety assessments should not be performed concurrently while a patient 
is receiving dialysis.  Patients receiving dialysis should continue to be followed for vital status 
and SAEs by phone or in-person according to the protocol scheduled visits.  Dialysis not lasting 
at least 12 weeks will be considered acute dialysis, and patients should be considered for re-
initiation of study drug with Medical Monitor approval.  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 discontinued.   
Upon receipt of kidney transplant, study drug should be discontinued. 
Following 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 112 visit date.  See Section 8.5 for description of follow-up options following 
study drug discontinuation.  Initiation of dialysis (acute and/or maintenance) and receipt of 
kidney transplant due to end stage kidney disease should be considered important medical 
events, and as such recorded as SAEs.   
9.1.10 
Monitoring Growth and Sexual Development in Adolescents  
Growth and sexual development will be assessed through an evaluation of height, weight, and 
Tanner Staging. See the Study Reference Manual for details on the Tanner staging.  


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Body weight should be measured daily by patients/caregivers using a provided weighing scale. 
Weight and height will also be measured at all site visits, as outlined in Section 9.10.7.  Patients 
should be instructed to inform the site if there is an observed weight loss of more than 3 pounds 
(1.4kg) in between clinic visits (Section 9.1.1).  
The Medical Monitor will routinely evaluate both weight and height entered into the clinical 
database of adolescents and will inform the investigator to initiate further evaluation if there is a 
weight loss of ≥5% or lack of expected growth per growth charts. 
Sexual maturity will be assessed by the investigator using Tanner Staging. If any abnormal 
patterns of sexual maturity are identified on evaluation of Tanner Staging, the Medical Monitor 
should be notified for additional discussion.  
9.2. 
Description of Study Drug 
Bardoxolone methyl (RTA 402) drug product information is shown in Table 6. Information 
about the placebo is shown in Table 7. 


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Table 6: 
Bardoxolone Methyl Drug Product Information 
Description 
Bardoxolone methyl capsule (5 mg, 10 mg, 15 mg, 20 mg) 
Ingredients 
Bardoxolone methyl 
Methacrylic Acid – Ethyl Acrylate Copolymer (1:1), Type A  
Silicified Microcrystalline Cellulose  
Hydroxypropyl Methylcellulose  
Lactose Monohydrate 
Sodium Lauryl Sulfate 
Colloidal Silicon Dioxide 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide (capsule pigment) 
Route of Administration 
Oral 
Table 7: 
Placebo Information 
Descriptiona 
Placebo for bardoxolone methyl capsule (size #4, size #2, size #1, 
and size #0) 
Ingredients 
Silicified Microcrystalline Cellulose  
Lactose monohydrate 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide (capsule pigment) 
Route of Administration 
Oral 
a Placebo capsules are size matched to the corresponding active dose capsule 
9.3. 
Concomitant Medications 
9.3.1. 
Excluded and Prohibited Medications 
9.3.1.1. 
Excluded Medications 
Patients taking these medications or treatments will be ineligible for enrollment: 
• Tolvaptan (patients on tolvaptan who have already enrolled under Version 2 of the 
protocol may remain in the trial); 
• Somatostatin analogues 
• Any other investigational drug or device as part of an interventional study within 
30 days prior to Day 1; 
• Chronic (> 2 weeks) immunosuppressive therapy, or need for corticosteroids, including 
therapies such as glucocorticoids, oncologic preparations, and anti-TNFα agents [e.g., 
infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), 
etanercept (Enbrel®)] within 12 weeks prior to randomization.  Glucocorticoid intra-
articular injections, inhaled products, topical preparations, and nasal preparations are 
allowed. 


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If a patient takes an excluded medication during the study, the investigator should consult with 
the Medical Monitor immediately to discuss if there is need for study drug interruption or 
discontinuation.  
9.3.1.2. 
Prohibited Medications 
Concomitant use with strong and moderate CYP3A4 inhibitors is prohibited, switching to 
alternate allowed medication should be considered. If a strong or moderate CYP3A4 inhibitor is 
medically necessary, discuss with Medical Monitor.  Patients who are using these medications 
prior to screening should have a washout for at least 5-half-life’s or 30 days whichever is longer. 
Concomitant use with strong and moderate CYP3A4 inducers is prohibited, switching to 
alternate allowed medication should be considered. If a strong or moderate CYP3A4 inducers is 
medically necessary, discuss with the Medical Monitor. Patients who are using these medications 
prior to screening should have a washout for at least 5-half-life’s or 30 days whichever is longer. 
Concomitant use with chronic (> 2 weeks) immunosuppressive therapy (corticosteroids, 
including therapies such as glucocorticoids, oncologic preparations, and anti-TNFα agents [e.g., 
infliximab (Remicade®), adalimumab (Humira®), certolizumab pegol (Cimzia®), etanercept 
(Enbrel®)]) is prohibited.    
Concomitant use with tolvaptan, somatostatin analogues, and any other investigational drug or 
device is prohibited. Concomitant dosing with prohibited medications is not allowed and will not 
be approved by the Medical Monitor.  If a site becomes aware of a patient administering a 
prohibited medication, the Medical Monitor should be notified immediately to determine 
whether study drug should be permanently discontinued or whether an interruption is 
appropriate.   
To minimize missing data and to maintain study integrity, patients who must take prohibited 
medications during the study should continue follow-up visits, even after study drug 
discontinuation, unless directed otherwise by the Medical Monitor. Certain prohibited 
medications (e.g., tolvaptan) will warrant termination from the study, due to the potential for the 
concomitant medication to confound the interpretation of study data.   
Sites must avoid initiation of prohibited medications until all Off-Treatment assessments are 
completed (approximately 12 weeks following the patient’s last dose of study drug). 
If a patient permanently discontinues study drug and continues being followed in the study, the 
administration of a prohibited medication is no longer considered a protocol deviation after 12 
weeks following the patient’s last dose of study drug.  Beginning 12 weeks after the patient’s last 
dose, administration of a prohibited medication does not require input from the Medical Monitor.   
Importantly, the administration of any medications listed in this section should be recorded in the 
concomitant medication page of the EDC independent of the patient’s study drug status or 
duration since the patient’s last dose of study drug, in order to ensure accurate interpretation of 
safety and efficacy data.  
9.3.2. 
Permitted Medications 
Allowed concomitant medications include the following: 


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• Antibiotics, including (but not limited to) fluoroquinolones and trimethoprim-
sulfamethoxazole (if the antibiotic being prescribed is a moderate or strong CYP3A4 
inhibitor or inducer, see Section 9.3.1.2. 
• Daily multivitamins or recommended daily supplements; 
• Other medications intended to manage concurrent diseases, as authorized by the 
treating physician; 
• Statins (e.g., pravastatin or rosuvastatin), in the Czech Republic and globally; 
• Pain management: acetaminophen, and other adjuvant analgesics and opioids may be 
used as deemed appropriate by the investigator, in the Czech Republic and globally; 
• Oral, implantable, or injectable contraceptives ; 
• Glucocorticoid intra-articular injections, inhaled products, topical preparations, and 
nasal preparations.  
Patients taking medication chronically, including ACE inhibitors, ARBs, and SGLT2 inhibitors 
should be maintained on those same doses and dose schedules throughout the study period and 
should not have additions or changes made to their medications, unless medically indicated.   
The list presented above is meant to serve as a broad guideline and is not exhaustive. Drugs not 
listed here, but which are deemed medically necessary, may be used provided if they do not fall 
under the excluded medications described in Section 9.3.1.  Questions about permitted 
medications should be directed to the Medical Monitor.   
9.4. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to patients enrolled in the study in accordance with the protocol.  Patients should administer 
study drug exactly as instructed by the site. Non-compliance is defined as taking less than 80% 
or more than 110% of expected study medication during any evaluation period (visit to visit).  A 
lack of treatment compliance during any evaluation period (visit to visit) should be entered as a 
protocol deviation.   
Patients should record in the patient diary all administered and missed doses of study drug.  The 
reason for a missed dose should be recorded in the patient diary.  Missing dose includes 
inadvertent missed doses as well as study drug interruptions and discontinuations. Patients will 
be asked to return all unused study drug (study drug bottles and any unused capsules). The study 
drug must not be used for reasons other than that described in the protocol. 
9.5. 
Randomization 
An IWRS will be utilized to randomize patients 1:1 to bardoxolone methyl or placebo.  
Randomization will be stratified by eligibility eGFR category (30 to <60; ≥60 to 90), 
concomitant tolvaptan use (yes, no), and screening ACR (≤300 mg/g, >300 mg/g).  Eligibility 
eGFR is the average of Screening eGFR visits.   
Randomization should occur on Day 1, as a Day 1 study procedure.  Where this is not possible, 
due to logistical issues at the site, and randomization occurs prior to Day 1, this will result in a 


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protocol deviation.  When randomization occurs prior to Day 1, the site must confirm eligibility 
prior to randomizing the patient in the IWRS and again prior to dispensation of IP at the Day 1 
visit.  
9.6. 
Blinding 
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 throughout the trial.  To prevent potential bias, appropriate measures will be taken 
to ensure the blind is maintained for the patients and personnel.  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 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.  Following 
study drug discontinuation due to unblinding, patients should continue with study follow-up 
through their scheduled Week 112 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. 
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. 


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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 regular reviews through the last dose of the last 
patient enrolled.   
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 statistical group not associated 
with the DMC will be responsible for producing and finalizing the SAP and executing the 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 the study continue as is, be modified to 
protect patient safety, or be terminated for safety.  The DMC is not expected to make 
recommendations for the trial based specifically on the analysis of the primary endpoint.  
Investigators, not the DMC, will make intra-patient dose-escalation decisions.   
9.7. 
Unscheduled Visits 
Unscheduled visits may be performed at any time and for any reason, including those not 
specifically mentioned in this section, as deemed necessary by the investigator. 
Unscheduled visits conducted for the following reasons should include collection of AEs, 
clinical chemistry, BNP/NT-proBNP, hematology, concomitant medication collection, and vital 
signs: 
• Assessment of weight gain per Section 9.1.1;  
• Management of an AE or SAE; 
• Performance of additional laboratory tests for clinically abnormal laboratory test 
values or to confirm a possible pregnancy; 
• Dose re-escalation; 
• Dose de-escalation; 
• Resuming study drug following an extended interruption; 


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• eGFR ≤15.0 per Section 9.1.9; 
• Patient safety evaluation. 
Unscheduled visits conducted for the following reasons do not require additional assessments 
unless deemed necessary by the investigator: 
• Study drug dispensation; 
• Placement or return of ABPM monitor; 
• Any operational need that would require the patient to return to the site between 
scheduled visits. 
9.8. 
Pregnancy 
9.8.1. 
Women of Childbearing Potential and Fertile Males 
Women of childbearing potential (WOCBP) are those who have experienced menarche and are 
not surgically sterile (no history of bilateral tubal ligation, hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy), do not have fallopian inserts with confirmed blockage (e.g., x-ray, 
ultrasound), have not had reproductive potential terminated by radiation and are not 
postmenopausal (defined as no menses for at least 1 year without an alternative medical cause). 
For patients enrolled in United Kingdom, women with bilateral tubal ligation are considered as 
WOCBP and will be required to use other types of birth control measures specified in 
Section 9.8.2. 
Fertile males are those who have entered puberty or reached physical maturation (after puberty) 
and are not surgically sterile (no history of bilateral orchiectomy or vasectomy at least 6 months 
earlier with the appropriate post-procedure documentation of surgical success). 
Czech Republic Only: 
Women of childbearing potential (WOCBP) are those who have experienced menarche and are 
not surgically sterile (no history of bilateral tubal ligation, hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy), and are not postmenopausal (defined as no menses for at least 1 year 
without an alternative medical cause). 
Fertile males are those who have entered puberty or reached physical maturation (after puberty) 
and are not surgically sterile (no history of bilateral orchiectomy) 
9.8.2. 
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 methods are not 
allowed for patients at participating sites in Germany and Australia; 


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• Use of hormonal contraceptives (oral, parenteral, intravaginal, or transdermal) for at 
least 60 days prior to start of study drug administration; 
• Use of an intrauterine device; 
• Vasectomized partner (with vasectomy performed at least 6 months prior to screening 
with the appropriate post-procedure documentation of surgical success).  Partner must 
be the sole partner for that patient; 
• Abstain from sexual intercourse completely.  Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
During Screening, while taking study drug and until 30 days after the final dose of study 
medication is taken, fertile males who have female partners of childbearing potential must 
practice one of the following 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 and Australia: 
• Have had a vasectomy (with vasectomy performed at least 6 months prior to 
screening with the appropriate post-procedure documentation of surgical success) 
(not permitted in the United Kingdom) 
• Partner contraception methods; must be the sole partner for that patient: 
− Use of an intrauterine device; 
− Use of hormonal contraceptives (oral, parenteral, intravaginal or transdermal) for 
at least 60 days prior to start of study drug administration; 
− Surgically sterile partner (bilateral tubal ligation, hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy); fallopian inserts with confirmed 
blockage (e.g., x-ray, ultrasound) (not permitted in the Czech Republic); 
− Reproductive potential has been terminated by radiation (not permitted in the 
Czech Republic); 
− Postmenopausal (defined as no menses for at least 1 year) without an alternative 
medical cause. 
• Abstain from sexual intercourse completely.  Complete abstinence from heterosexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
9.8.3. 
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. 


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If a WOCBP or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If the serum pregnancy test 
confirms the pregnancy, the WOCBP patient must discontinue taking study drug.  The 
investigator must immediately report to the Medical Monitor a pregnancy associated with study 
drug exposure.  The early discontinuation protocol-required procedures outlined for End-of-
treatment and Follow-up visits must be performed on the patient.  
Pregnancy is not considered an AE; however, the investigator must follow a pregnant patient, or 
the pregnant female partner of a male patient (if she consents to be followed), and report follow-
up information regarding the course of the pregnancy, including perinatal and neonatal outcome.  
Infants resulting from such pregnancies should be followed for a minimum of 8 weeks.  Reata or 
designee may contact the investigator to request additional information throughout the course of 
the pregnancy. 
The following pregnancy outcomes must be considered SAEs and will require additional 
reporting in the eCRF and reported as a serious AE: 
• Congenital anomaly/birth defect; 
• Stillbirth; 
• Spontaneous miscarriage. 
9.9. 
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 study drug after an interruption will follow Section 9.11 for dose management and 
Table 4 for 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. 
A central laboratory should be used for all lab-based assessments.  For specific guidance on lab 
sample collection, processing, and shipment, please refer to the Laboratory Reference Manual. 
Every effort should be made to ensure all assessments are conducted at in-person visits.  In 
certain cases, and with prior sponsor approval, if a patient is unable or unwilling to come to the 
clinic for in-person assessments, the conduct of study procedures by home health nurses is 
permissible and should be considered as an alternative to a missed or skipped visit. 
9.10.1. 
Informed Consent and Assent 
Written informed consent (see Section 15.3) must be obtained from the patient before any 
study-related procedures are performed.  Re-consenting will be required when there is an update 
or change in the study procedures, safety information, or any other information that may affect 
the patient’s willingness to participate. 


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For adolescent patients, informed consent will be obtained from the parent(s) or legal guardian in 
accordance with regional laws or regulations. In addition, dependent upon the patient’s age and 
IRBs, IEC, and/or local requirements, assent of the patient must also be obtained. Adolescent 
patients may be asked to personally sign and date either a separately designed, written assent 
form, or the written informed consent. 
Patients who chose to participate in the Ambulatory Blood Pressure Monitoring sub-study will 
need to provide written informed consent prior to performing any assessments associated with 
ABPM. 
Patients who chose to participate in blood and urine biobanking collection will need to provide 
written informed consent prior to performing any assessment associated with the specimen 
collection. 
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. 
Inclusion 2b, which references genetic diagnosis, may be satisfied by either PKD1 and/or PKD2 
gene mutation. 
Inclusion 3c must show disease progression using average yearly eGFR decline of 
≥ 2.0 mL/min/1.73 m2 from the past two years. If a patient has limited historical eGFR values 
from the past two years, the investigator must discuss the patient’s eligibility with the Medical 
Monitor. 
Historical eGFRs used to determine eligibility must be well documented in the patient’s source.   
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.  Prior and concomitant medications (i.e., medications that the 
patient is taking or has taken within 30 days prior to Day 1) will be reviewed as indicated in 
Table 4.  All medications will be recorded through the Week 112 visit as indicated in Table 4. 
For patients who remain on study drug, the administration of any medications should be recorded 
in the concomitant medication page of the EDC through Week 112,  
For patients who discontinue study drug early and continue to be followed in the study, all 
concomitant medications should be recorded for 12 weeks following the patient’s last dose of 
study drug.  Beyond 12 weeks after the patient’s last dose, only those medications that are 
relevant to the clinical condition including kidney disease or that may have a potential impact on 


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kidney function must be recorded in the concomitant medication page of the EDC.  Unscheduled 
phone visits may be used, as necessary, to ensure accurate collection of concomitant medications 
of interest.    
Importantly, the administration of any medications listed in Section 9.3.1.2 (Prohibited 
Medications) should be recorded in the concomitant medication page of the EDC independent of 
the patient’s study drug status or duration since the patient’s last dose of study drug, in order to 
ensure accurate interpretation of safety and efficacy data.  
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 includes the collection of historical serum 
creatinine values for the purpose of calculating historical eGFR values. Where possible, sites 
should obtain historical lab reports from the patient, and enter into the EDC approximately one 
historical value per year, for the prior 5 years.  Medical history will be recorded as indicated in 
Table 4.   
9.10.6. 
Height 
Height should be measured without footwear or prosthetics using a wall-mounted stadiometer if 
performed in-clinic.  For adult patients (18 ≤ age ≤ 70 years at Screen A visit), height is 
measured at Screen A.  Adolescent patients (12 ≤ age < 18 years at Screen A visit), height is 
measured at the timepoints specified in Table 4,when in clinic visits are not possible, home 
health nurses should be used (see Appendix 2). 
Height should be recorded in centimeters, and where height is measured in inches, the following 
formula should be used to convert inches to centimeters: 
Height (in inches) × 2.54 = Height (in centimeters) 
Any conversions of units should be documented in the source documents. 
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. In the 
event the Sponsor-provided scale is temporarily unavailable (e.g., patient is traveling, 
replacement scale has not arrived to patient, etc.), patients may use any available scale. Weights 
recorded in patient diaries will not be entered in the eCRF.  Weights should be taken at 
approximately the same time each day and recorded in a patient diary.  During study, weights 
will be recorded daily.  Missing more than 20% of expected weight records in the patient diary 
during any evaluation period (visit to visit) is considered as non-compliance, which should be 
reported as a deviation.  Patients will be instructed to stop administering study drug and contact 
the investigator if their daily weight increases per the criteria outlined in Section 9.1.1.  Patients 
will be provided instructions within the Informed Consent Form and/or Assent Form to help 
ensure consistent weight collection throughout the study.  
Weight should be recorded in kilograms, and where weight is measured in pounds, the following 
formula should be used to convert pounds to kilograms: 


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Weight (in pounds) ÷ 2.205 = Weight (in kilograms) 
Any conversions of units should be documented in the source documents. 
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.  The 
echocardiogram may be performed during the Screening Period, or an historical echocardiogram 
may be used if it was performed within 6 months prior to Day 1. 
9.10.10. 
Vital Sign Measurements 
Vital sign measurements include the patient’s pulse rate (beats/minute taken for at least 
15 seconds), respiration rate, blood pressure, and body temperature.  Vital sign measurements 
should be taken as indicated in Table 4.   
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.  For specific guidance related to blood pressure measurement, 
please see the Study Reference Manual.  
9.10.11. 
Comprehensive Physical Examination & Targeted Physical Examination 
Physical examinations must be performed by a physician, physician assistant, or registered nurse 
practitioner. 
A comprehensive physical examination must be performed as indicated in Table 4 and as 
documented within the medical record.  The comprehensive physical 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 addressed in medical history, (i.e., findings should be attributable to a 
diagnosis recorded in 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. 
Targeted physical examinations are symptom-directed examinations and involve the organ 
system(s) associated with the symptoms exhibited or reported. Targeted physical examinations 
are to be performed at visits indicated in Table 4.  If the investigator observes no symptoms that 
warrant further examination, the investigator may forego a more detailed physical examination, 
and the targeted physical examination may be considered complete. 


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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.  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. 
See Section 9.8.3 for a description of procedures to be followed in case of pregnancy.   
9.10.13. 
Study Drug Administration 
For dose levels up to 20 mg, patients should self-administer one capsule orally once a day 
beginning on Day 1 (in clinic) through the end of the Treatment Period, as indicated in Table 4.  
Patients who dose escalate to 30 mg should administer two capsules orally once a day. Each dose 
of study drug should be administered at approximately the same time each day.  Study drug 
administration should be recorded in a patient diary through Week 100.     
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. 
Refer to Section 9.4 and 9.11 for treatment compliance and detail in dose management.  
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 the appropriate number of treatment kits at each timepoint: Day 1, 
Week 2, Week 4, Week 6, Week 8, Week 12, Week 24, Week 36, Week 48, Week 52 (B), 
Week 64, Week 76, and Week 88.  If the patient is provided more than one kit, only one 
treatment kit should be opened at a time.  Dispensed treatment kits from each visit (including 
unscheduled visits) should be returned to the site for collection as indicated in Table 4 or at the 
subsequent visit.   
If the appropriate number of treatment kits (e.g., a 3-month supply) cannot be dispensed as 
outlined in Table 4, a partial supply may be provided to the patient.  The remainder may be 
provided separately to the patient.  Every effort should be made to avoid interruptions in dosing.   
9.10.15. 
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 sites may 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 


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concomitant medication regimens (including prescription drugs, over-the-counter medications, 
vitamins, herbal products, and minerals).  Responses must be documented in the source 
documents.   
AEs should be reported from the time of the first dose until the Week 112 (B) visit as indicated 
in Table 4.   
For patients who discontinue study drug early (prior to Week 100) and continue to be followed in 
the study, all AEs should be recorded for 12 weeks following the patient’s last dose of study 
drug.  Beyond 12 weeks after the patient’s last dose, only those AEs that are relevant to the 
clinical condition including kidney disease, may have an impact on kidney function, or may 
impact the interpretation of safety or efficacy data must be recorded in the AE log within the 
EDC.  Unscheduled phone visits may be used, as necessary, to ensure accurate collection of AEs 
of interest.    
AEs that are related to study procedures should be recorded in the AE log within the EDC 
independent of the patient’s study drug status or duration since the patient’s last dose of study 
drug.   
See Section 11 for more detail regarding adverse events. 
9.10.17. 
Kidney Ultrasound 
Kidney ultrasound (historical or an ultrasound performed at Screen A) may be used to diagnose 
ADPKD.  Patients with prior diagnosis of ADPKD will not have a kidney ultrasound performed 
as part of the study but must provide documentation of ADPKD diagnosis for eligibility.  
9.10.18. 
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. 
9.10.19. 
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.   
9.10.19.1. eGFR 
The equation used to calculate eGFR for each patient (CKD-EPI or Bedside-Schwartz) is based 
on the patient’s age at the time of consent/assent (generally the Screen A visit).  For Adults (≥ 18 
years ≥ 70 years) eGFR will be calculated by a central laboratory at the Screen A and Screen B 
visits using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: 
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] 


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For Adolescents (≥12 and < 18 years ): 
• eGFR will be calculated by a central laboratory at the Screen A and Screen B visits using 
the Bedside Schwartz equation: 
eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Scr 
 
Where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scr/κ or 1 and max indicates the 
maximum of Scr/κ or 1.  Age indicates age at time of lab collection. 
 
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 
 
In the absence of any clinically significant event or other medical conditions, the investigator 
should consider re-testing eGFR if the most recent value is significantly different from the prior 
value.  
9.10.20. 
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 the 
Central 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 the Central Laboratory 
Manual provided to the investigator.   


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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. 
Coagulation  
Samples will be collected for the following coagulation assessments as indicated in Table 4: 
Prothrombin Time (PT) and International Normalized Ratio (INR). The coagulation assessments 
were added to the schedule of assessments through a protocol amendment.  Sites should collect 
these samples from patients once the central laboratory kits and database enable collection.  Until 
such time the site can collect this test, failure to collect it is not considered a protocol deviation.   
9.10.24. 
Lipid Panel 
Samples will be collected for the following lipid assessments as indicated in Table 4: Total 
Cholesterol, Low-Density Lipoprotein (LDL), High-Density Lipoprotein (HDL), and 
Triglycerides. 
The lipid panel was added to the schedule of assessments through a protocol amendment.  Sites 
should collect these samples from patients once the central laboratory kits and database enable 
collection.  Until such time the site can collect this test, failure to collect it is not considered a 
protocol deviation.   
9.10.25. 
SARS-CoV-2 Antibody Testing 
Samples will be collected for SARS-CoV-2 antibody testing as indicated in Table 4. 
The SARS-CoV-2 antibody testing was added to the schedule of assessments through a protocol 
amendment.  Sites should collect these samples from patients once the central laboratory kits and 
database enable collection.  Until such time the site can collect this test, failure to collect it is not 
considered a protocol deviation.  
9.10.26. 
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). 
9.10.27. 
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. 


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9.10.32. 
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 provide the time of their last two doses of study drug.   
PK blood sample collection instructions should be referenced in the Central Laboratory Manual.   
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. 
Patients who have discontinued study drug should not complete PK procedures 
Week 12 PK 
If sites or patients are unable to perform the required PK assessments at the Week 12 visit, these 
PK assessments may be collected at Week 24, Week 36, or Week 48.   


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Patients must refrain from taking study drug prior to coming to the clinic for the Week 12 visit, 
as patients will administer study drug in-clinic as instructed by the site.  Patients must provide 
the time and date of the two most recent doses of study drug, prior to the blood samples being 
collected.   
Sites should obtain the 0-hour (pre-dose) PK sample, then instruct the patient to administer study 
drug.  Blood samples for PK analysis should then be drawn at 2 and 4 hours post dose 
administration.   
Week 100 PK  
Patients must be instructed to refrain from taking study drug prior to coming to the clinic for the 
Week 100 visit, as patients will administer study drug in-clinic as instructed by the site.  Patients 
must provide the time and date of the two most recent doses of study drug, prior to the blood 
samples being collected.   
Patients will have blood drawn at a single timepoint (i.e., pre-dose) for PK analysis at this visit. 
Sites should obtain the 0-hour (pre-dose) PK sample, then instruct the patient to administer the 
final dose of study drug in-clinic. 
Week 103, Week 104 (B), and Week 108 (B) PK 
These PK assessments occur during the Off Treatment Period, so no study drug administration is 
associated with these assessments. 
Patients will have blood drawn at a single timepoint for PK analysis at this visit. 
9.10.33. 
Ambulatory Blood Pressure Monitoring 
For adult patients, Ambulatory Blood Pressure Monitoring (ABPM) is an optional sub-study 
conducted at the timepoints specified in Table 4. To participate, patients must have a baseline 
ABPM assessment.  The baseline assessment must occur during the screening period, ideally 
2-3 days prior to Day 1. The additional assessments occur at the following time points: Week 12, 
Week 48, and between Weeks 88 and 100 (prior to the patient’s last dose of study drug), as 
defined in Table 4. 
Participation in the ABPM sub-study is optional; however, patients should be encouraged to 
participate, and use of home health visits is strongly encouraged to minimize the burden on the 
patient and to maximize participation.  
To ensure a sufficient volume of ABPM data, the Sponsor may halt enrollment of patients not 
participating in the ABPM sub-study.  Participation will be monitored closely as overall 
enrollment progresses, and the Sponsor will update sites on progress toward achieving sufficient 
ABPM participation.  
A Sponsor-provided device will be placed on the patient by the study team, and the patient must 
wear the device for approximately 24 hours.   
Upon completion of the 24-hour period, the site will collect the device from the patient and 
ABPM data will be sent to the central vendor to determine if the 24-hour recording passes the 
validity criteria.  The criteria used to define a valid ABPM session for sites to determine the need 
for a repeat 24-hour session, if possible, are: 


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• At least 70% of planned inflations are successful during the overall recording session; 
• At least 18 hours of analyzable data, and; 
• Not more than two consecutive hours of missing data. 
For detailed instructions regarding ABPM refer to the study reference manual.   
The addition of ABPM to the schedule of assessments occurred through a protocol amendment, 
and site and patient participation will be offered, once available. 
9.10.34 Tanner Staging 
Gender appropriate Tanner staging will be performed on all patients who enroll in the study as 
adolescents.  Tanner staging should be performed at Day 1, Week 52 (B), and Week 108 (B), as 
outlined in Table 4, to monitor and assess sexual maturity.  All assessments must be performed 
even if a patient reaches 18 years of age while participating in the study.  Tanner staging may be 
performed only by a physician (specifically, the principal investigator or sub-investigator).  For 
further guidance and to access the Tanner Staging see the Study Reference Manual. 
9.11. 
Dose Management 
DOSE ESCALATION 
Both adult and adolescent patients randomized to placebo will remain on placebo throughout the 
study, undergoing sham titration. Both adult and adolescent patients receiving study drug 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 escalation may need to proceed more slowly if the patient experiences early elevations in 
ALT/AST over ULN, e.g. at Week 2 (see Section 9.1.2) or if the patient misses visits (see 
Section during the Dose Escalation Period .  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 1, 2, 4, or 
6 with the Medical Monitor.  In cases where dose escalation is delayed or not achieved, the 
investigator should consider dose escalation to goal dose at any time throughout the dosing 
period. 
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 the dose and must be documented.  After dose de-
escalation, patients must return for an unscheduled office visit within 4 weeks (± 3 days) to 
perform the assessments detailed in Section 9.7. 
If a patient’s dose has been reduced, dose re-escalation back to a higher dose is permitted to meet 
the dosing objective.  However, patients who dose re-escalate must have a telephone call 1 week 
after dose re-escalation and an unscheduled office visit 2 weeks (± 3 days) after dose re-
escalation to perform assessments detailed in Section 9.7. 


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INTERRUPTION OF STUDY DRUG 
In addition to dose de-escalation and re-escalation, the study drug administration can be 
interrupted, if clinically indicated. The term interruption generally refers to a temporary halt of 
study drug administration. All efforts should be made to resume study drug at any point during 
the treatment period following interruption, upon consultation with the Medical Monitor.  If 
there are any questions regarding study drug interruption, please consult the Medical Monitor. 
RESUMING STUDY DRUG 
Any patient who interrupts study drug for 14 consecutive days or more must have approval from 
the Medical Monitor prior to resuming study drug. 
When a patient resumes study drug, after an extended interruption (e.g., more than 14 days), the 
site should discuss the appropriate starting dose and visit frequency with the Medical Monitor.  
The duration of the interruption and the reason for interruption should be taken into 
consideration when determining how to safely resume study drug.  Following an extended 
interruption, when the investigator deems it is safe for the patient to return to the site for an in-
person visit, the investigator should conduct an evaluation to determine whether the patient is 
still eligible to receive study drug and to determine the appropriate dose, in consultation with the 
Medical Monitor.  This should include a confirmation that the patient’s circumstances have not 
changed in a manner that would prohibit administration of the study drug (e.g., the patient is now 
taking an excluded medication).  Once the investigator determines study drug administration is 
appropriate, dosing may proceed.   
Patients must have a telephone call 1 week after resuming and an unscheduled office visit 2 
weeks (± 3 days) after resuming study drug to perform assessments detailed in Section 9.7. 
For additional guidance on resuming drug following a positive COVID-19 test, see 
Section 9.11.5  
9.11.1. 
Dose Escalation Period – Missed In-Person Visits 
The first 8 weeks of the trial require intense safety monitoring of patients as they progress 
through the dose-escalation period of the study.  When in-person visits are not be feasible, due to 
COVID-19 or any other reason, patients who are in the dose escalation period of the study 
should remain on their current study drug dose. The dose at the last in-person visit, if not the goal 
dose, will be considered the maximum dose until completion of dose-escalation can be safely 
resumed (See Section 9.11.5).  
Protocol specified in-clinic follow-up visits, for safety/tolerability, must be completed where 
possible.  Required assessments for patients who are unable to have an in-person visit are 
described in Appendix 2. 
9.11.2. 
Week 8 – 12 Visits – Missed In-Person Visits 
Patients in the maintenance period of the trial who have completed dose escalation and who have 
not reached the Week 12 time point must be assessed at Week 12 by conducting an in-person 
visit, per protocol.  Patients who are unable to return to the clinic/site for a scheduled Week 12 
follow-up visit should remain on their current study drug dose and have remote assessments 


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completed to evaluate assess safety/tolerability.  These remote assessments may be conducted as 
described in Appendix 2. 
9.11.3. 
Post-Week 12 Visits – Missed In-Person Visits 
Patients who have completed dose escalation and who have completed the Week 12 Visit must 
be assessed at their next scheduled visits (as outlined in Table 4).  Patients who will be unable to 
return to the clinic/site for scheduled follow-up visits should remain on their current study drug 
dose and complete remote assessments to evaluate safety/tolerability until in-clinic visits can be 
resumed (see Section 9.11.5).  These remote assessments may be conducted as described in 
Appendix 2. 
If no in-clinic visit can be completed and remote assessments/laboratory samples cannot be 
collected within a reasonable time, based on the investigator’s discretion, the investigator should 
consider whether de-escalation may be appropriate.   
9.11.4. 
Dose De-Escalation and Interruption for Missed Safety and Laboratory 
Assessments 
From Protocol Version 7.0 forward, this text was removed, and language was placed within 
Section 9.11. 
9.11.5. 
Resuming Study Drug After COVID-19 Interruption 
Patients who interrupt study drug due to a positive COVID-19 test may resume study drug 
without an in-clinic visit, at the investigator’s discretion, if COVID-19 symptoms are mild, and if 
the duration of interruption did not exceed 14 days. 
Study drug may be resumed when the patient no longer presents an active infection (defined as 
resolution of symptoms or a negative SARS-CoV-2 test), as assessed by the Investigator and/or 
the patient’s physician(s). If COVID-19 symptoms persist (e.g., loss of taste or smell), the patient 
should be encouraged to repeat SARS-CoV-2 testing in order to minimize the duration of study 
drug interruption. 
For more information related to study drug management and COVID-19 see Appendix 1, 
Section 4.5. 
 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 5 mg (size #4), 10 mg (size #2), 15 mg (size #1), and 20 mg 
(size #0) may be used in this study.  The 30 mg dose will be given as two 15 mg capsules.  
Placebo capsules will have matching capsule sizes to have the same appearance as the active 
doses. 
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied as either individual bottles (5, 10, 20 mg dose) or in tamper-
evident kits containing two high-density polyethylene (HDPE) bottles (30 mg dose as 2 x 15 mg 
capsules).  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, 10 mg, 15 mg, or 20 mg strength 
bardoxolone methyl or the matching placebo capsules.  Each bottle will also contain desiccant 
insert(s) that must not be ingested.  Labeling on each kit bottle will contain at minimum the 
following information: 
• Medication ID number; 
• Protocol 402-C-1808; 
• Caution Statement: New Drug – Limited by Federal Law to Investigational Use.  
Keep out of reach of children; 
• Control or lot number; 
• Store at 15° – 25°C (59° – 77°F); 
• Reata Pharmaceuticals, Inc., Irving, TX. 
When applicable, a double-panel label will be presented on the treatment kit carton containing 
this and other information.  Additionally, labeling, in the relevant local languages for study drug 
use and distribution in the EU shall adhere to current Eudralex, Volume 4 Annex 13 guidance 
and requirements.   
In the event the investigational product is not packaged as intended or may not adhere to Current 
Good Manufacturing Practices (CGMP), a complaint should be filed with the Sponsor, ideally 
through the site’s CRA. Guidance on filing study drug complaints is available in the Study 
Reference Manual, and attention should be given to ensure the patient number is not submitted 
within the complaint documentation. 
10.3. 
Study Drug Storage 
The stability of the drug product has been and is currently being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location with room 
temperature conditions of 15° - 25°C (59° - 77°F).   
If the investigational product is stored outside of the designated conditions, a temperature 
excursion notification should be submitted to the Sponsor for review and approval for use of the 


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affected study drug. Guidance on filing temperature excursions is available in the Study 
Reference Manual. 
10.4. 
Study Drug Administration 
Please refer to Section 9.10.13 for details on study drug administration.  It is the responsibility of 
the investigator or designee to provide clear instructions to the patient regarding the number and 
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 through Week 100 unless: 
(1) the patient has been otherwise instructed by the investigator or (2) the patient has been 
formally discontinued from study treatment.    
10.5. 
Study Drug Accountability 
Study drug bottles and any unused capsules should be returned to the study staff for eventual 
disposition by the Sponsor.  The investigator or designee will maintain a record of all study drug 
received, dispensed, and returned.  The number of capsules returned at each visit will be 
recorded by the site for each bottle in the kit.  The site will make these records available for 
Sponsor or designee review. 
10.6. 
Study Drug Handling and Disposal 
At any time during the conduct of the study, the Sponsor or its designee will direct the site 
regarding the final disposition of study drug. No study drug shall be destroyed by the clinical site 
unless agreed upon in writing by the Sponsor.  Documentation of study drug disposition will be 
retained with the investigator.  Refer to the IP Handling Manual for detailed instructions on study 
drug handling and disposal.  


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11. 
SAFETY ASSESSMENTS 
11.1. 
Safety Parameters 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all safety assessments.  Safety 
parameters include vital sign measurements, ECG results, AEs, SAEs, weight, and laboratory 
test results.  
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Event 
An AE is defined as any untoward medical occurrence in a patient regardless of its causal 
relationship to study drug.  An AE can be any unfavorable and unintended sign (including any 
clinically significant abnormal laboratory test result), symptom, or disease temporally associated 
with the use of the study drug, whether it is considered to be study-drug related.  Included in this 
definition are any newly occurring events or previous conditions that have increased in severity 
or frequency since the administration of study drug. 
All AEs that are observed or reported by the patient during the study (from administration of the 
first dose until the Week 112 (B) study visit as indicated in Table 4) must be reported, regardless 
of their relationship to study drug or their clinical significance.  
For patients who discontinue study drug early (prior to Week 100) and continue to be followed in 
the study, all AEs should be recorded for 12 weeks following the patient’s last dose of study 
drug. Beyond 12 weeks after the patient’s last dose, only those AEs that are relevant to the 
clinical condition including kidney disease, may have an impact on kidney function, or may 
impact the interpretation of safety or efficacy data must be reported.  
AEs that are related to study procedures should be reported independent of the patient’s study 
drug status or duration since the patient’s last dose of study drug. SAEs, if considered related to 
study drug, can be reported at any time during the study duration.  
11.2.1.2. Serious Adverse Event 
An SAE is any AE occurring at any dose and regardless of causality that: 
• Results in death; 
• Is life-threatening; 
• Requires 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.  


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The term "life-threatening" refers to an event in which the patient was at immediate risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
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 Week 112 (B) 
study 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 Week 112 (B)  study visit indicated in Table 4), including events 
resulting from protocol-associated procedures as defined in relevant legislation, and regardless of 
their relationship to study drug or their clinical significance.  For patients who discontinue study 
drug early, SAEs should be reported through 12 weeks following the date of last dose of study 
drug.  SAEs, if considered related to study drug, should be reported at any time during the study.  
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. 
For information on ESKD related SAEs see section 9.1.9.  
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 
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Unlikely Related: This relationship suggests that the temporal sequence of the event with study 
drug administration makes a causal relationship improbable and/or other factors also provide 
plausible explanations. 
Possibly Related: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence from the time 
of study drug administration, and/or, follows a known response pattern to the study drug, but 
could have been produced by other factors. 
Probably Related: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
Definitely Related: This relationship suggests that a definite causal relationship exists between 
the drug administration and the AE, and other conditions (e.g., concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
For regulatory reporting purposes, an adverse event is considered to be related when the 
causality evaluation is either “Definitely Related, Probably Related, or Possibly Related.”  An 
adverse event is considered to be not related when the causality evaluation is either “Unlikely 
Related or Not Related.” 
11.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities 
Severe: Symptoms causing inability to perform usual social and functional activities  
11.6. 
Recording Adverse Events 
All conditions present prior to the administration of the first dose of study drug (Day 1) should 
be documented as medical history.  After the first dose, documentation of AEs shall continue 
until the Week 112 (B) study visit, as indicated in Table 4, regardless of their relationship to 
study drug or their clinical significance. For patients who discontinue study drug early (prior to 
Week 100) and continue to be followed in the study, all AEs should be recorded for 12 weeks 
following the patient’s last dose of study drug.  Beyond 12 weeks after the patient’s last dose, 
only those AEs that are relevant to the clinical condition including kidney disease, may have an 
impact on kidney function, or may impact the interpretation of safety or efficacy data must be 
reported.  
AEs that are related to study procedures should be reported independent of the patient’s study 
drug status or duration since the patient’s last dose of study drug.  


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Information to be collected includes type of event, date of onset, date of resolution, investigator-
specified assessment of severity and relationship to study drug, seriousness, as well as any action 
taken.  
For guidance on how to handle AEs that change in severity (e.g., worsening or improving), see 
the eCRF Completion Guidelines. All drug-related (possibly, probably, or definitely related, see 
Section 11.4) AEs and clinically significant abnormal laboratory test results reported or observed 
during the study must be followed to resolution (either return to baseline, within normal limits, 
or stabilization).  All non-drug related AEs or clinically significant abnormal laboratory test 
results will be followed through the Week 112 (B) study visit or for 12 weeks following the last 
dose for patients who discontinue study drug early.  
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 
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 or email the completed SAE form 
 
 within 24 hours of awareness. 
 


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: 
 
 
E-mail: 
 
For questions regarding SAE reporting, contact your study manager, medical monitor, 
 
. 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. 
Within 24 hours of receipt of new information, the updated follow-up SAE form, along with any 
supporting documentation (e.g., patient discharge summary or autopsy reports), should be faxed 
or emailed 
. 
The Sponsor or designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible but no later than 
7 calendar days after the initial receipt of the information.  Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency.  For other 
SAEs that do not meet the fatal or life-threatening unexpected criteria but are reported to be 
associated with the use of the study drug, Reata or designee will notify the appropriate regulatory 
agencies in writing within the timeframe established by those regulatory agencies.  Reata or 
designee will provide copies of any reports to regulatory agencies regarding serious and 
unexpected SAEs to the investigators for review and submission to their 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 
With 850 patients enrolled, the study will have approximately 80% power to detect a difference 
between the two treatment groups in change from baseline eGFR of 2.3 mL/min/1.73 m2.  The 
power calculation was based on a 2-sample t-test as an estimate for the planned ANCOVA 
analysis and assumes the following: 
• Overall two-sided Type I error rate total of 0.05; 
• Standard deviation of change from baseline in eGFR of 12 mL/min/1.73 m2;  
• Analyses are based on the intent-to-treat (ITT) population; 
• Missing data will be imputed using multiple imputation. 
ANCOVA analysis is expected to have approximately the same power as the t-test used for study 
planning.  The method for maintaining strict control of the Type I error for the trial will be 
described in the statistical analysis plan (SAP).  Appropriate sensitivity analyses of the primary 
analysis will be specified in the SAP. 
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,
 
 endpoints.  
 
  
12.2.3. 
Safety Variables 
The safety variables include results of laboratory testing, vital sign measurements, ECG results, 
height, 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 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.  


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12.3.1. 
Analysis of Efficacy 
The ITT population, which includes all patients randomized within each cohort, will be used as 
the population for assessment of the efficacy endpoints.  This includes patients on tolvaptan who 
have already enrolled under Version 2 of the protocol. 
Analysis of covariance (ANCOVA) will be used to analyze the primary efficacy endpoints of 
change from baseline in off-treatment eGFR.  The model will include change from baseline in 
eGFR as the dependent variable, treatment group as fixed effect, and baseline eGFR as a 
continuous covariate.  Other covariates may be specified in the SAP.  The off-treatment 
endpoints assess the preserved drug benefit relative to placebo following withdrawal of 
treatment; therefore, analyses of these endpoints do not include eGFR values collected during 
treatment.    Sensitivity analyses, including a tipping point analysis, will be performed to assess 
the impact of missing data.   


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
The study monitor, as a representative of the Sponsor, is obligated to follow the study conduct 
closely.  In doing so, the monitor will visit the principal investigator and study facilities 
periodically and will maintain necessary telephone and letter contact.  The monitor will maintain 
current knowledge of the study activity of the investigator and his/her staff through observation, 
review of study records and source documentation, and discussion of the conduct of the study 
with the investigators and staff. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Council for Harmonisation for Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guideline E6(R2): Good Clinical 
Practice: Consolidated Guideline and current standard operating procedures. 
Each investigator is expected to make a reasonable effort to accommodate the monitor when 
monitoring visits are necessary and to be available during the site visit.  Furthermore, the 
monitor should be provided direct access to source data and documents for trial-related 
monitoring and internet during the visit. 
In case that study sites are closed for any visitors and monitors over a certain period of time 
during the COVID-19 pandemic, a risk-based approach to monitoring will be taken, focusing on 
certain sites, certain data points and certain processes that are critical to ensure the rights, safety 
and well-being of trial participants and the integrity of the trial (and trial data).  The results of 
adjusted monitoring/review measures and their impact will be reported to the Sponsor in 
monitoring reports and in the clinical study report, where applicable.  Adjusting monitoring 
activities may include a combination of on-site and off-site monitoring, where permitted by local 
regulations.  Remote source data verification may also be taken into consideration, where 
permitted by local regulations. 
13.2. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/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/study drug 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 (and assent, if applicable), samples of 
site advertisements for recruitment for this study, and any other written information 
regarding this study that is to be provided to the patient or legal guardians; 
• A Form FDA 1572 or equivalent statement of investigator, fully executed, and all 
updates on a new fully executed Form FDA 1572; 
• Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
are accurate and current; 
• Completed financial disclosure forms (Section 14.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 


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


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15. 
ETHICS 
15.1. 
Institutional Review Board (IRB) or Ethics Committee (EC) Review 
The protocol and the proposed informed consent form (and assent, if applicable) 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 (and assent, if appliable) 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 
Council for Harmonisation for Technical Requirements for Pharmaceuticals for Human Use 
(ICH) for Guidance for Industry on Good Clinical Practice (GCP) ICH E6(R2) 
[https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/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, in compliance with Title 21 of US CFR Part 50, 
will be obtained from each patient before the patient enters the study.  For sites outside of the 
United States, the signed consent will be obtained in accord with local regulations, ICH E6 (R2), 
and principles of the Declaration of Helsinki.  An informed consent template may be provided by 
the Sponsor or designee to the investigators.  The consent must be reviewed by the Sponsor or 
designee before IRB/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. 
For adolescent patients, informed consent will be obtained from the parent(s) or legal guardian in 
accordance with regional laws or regulations. In addition, dependent upon the patient’s age and 
IRBs, IEC, and/or local legal requirements, assent of the patient must also be obtained. 
Adolescent patients may be asked to personally sign and date either a separately designed, 
written assent form, or the written informed consent. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/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 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments.  The FDA or other applicable regulatory agencies must be notified of protocol 
amendments.  The changes will become effective only after approval of the Sponsor, the 
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. 


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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 site personnel and the responsible 
monitor during monitoring visits, and those observations will be communicated to the 
investigator.  Protocol deviations will be reviewed and any that are a serious breach of GCP 
and/or the protocol will be reported to the relevant regulatory agency, as required.  Protocol 
waivers are not allowed for sites in the United Kingdom, and protocol waivers will not be 
granted by the Sponsor in any participating countries. 
If there is an immediate hazard to a patient the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/EC approval.  The Sponsor and IRB/EC must be 
notified of the deviation.  
Deviations will be reported, evaluated, and discussed according to the Protocol Deviation Plan 
and in the final study report. 
All protocol deviations due to the impacts of COVID-19 will be identified and documented 
accordingly by the site and the Sponsor.  When visits are completed remotely (due to COVID-19 
or other reasons), sites should ensure the completion of at least those assessments listed in 
APPENDIX 2. Where these study procedures are completed remotely, any additional study 
procedures that cannot be completed will be noted as missing and will not be considered as a 
protocol deviation.  The failure to complete the minimally required procedures outlined in 0, will 
be considered a protocol deviation.    


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Retention of Records 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).  Records will be retained for at least 2 years after the last marketing application 
submission or 2 years after formal discontinuation of the clinical development of the 
investigational product, or for the duration required by local regulations, whichever is longer.  If 
the investigator withdraws from the responsibility of keeping the study records, custody must be 
transferred to a person willing to accept the responsibility.  The Sponsor must be notified in 
writing if a custodial change occurs.  
16.2. 
Case Report Forms 
All case report form data will be entered in paper or electronic forms at the investigational site.  
A 21 CFR Part 11 compliant 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 
Boertien WE, Meijer E, Li J, et al., Relationship of copeptin, a surrogate marker for arginine 
vasopressin, with change in total kidney volume and GFR decline in autosomal dominant 
polycystic kidney disease: results from the CRISP cohort. Am J Kidney Dis. 2013 ;61 :420-9. 
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. 
Karihaloo A.  Role of inflammation in polycystic kidney disease.  Li X ed.  Polycystic Kidney 
Disease [Internet]. Brisbane (AU): Codon Publications;2015:Chapter 14. 
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. 
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. 
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. 
Schrier RW, Abebe KZ, Perrone RD, et al., Blood pressure in early autosomal dominant 
polycystic kidney disease. N Engl J Med. 2014;371:2255-66. 
Torres VE, Chapman AB, Devuyst O, et al., Tolvaptan in patients with autosomal dominant 
polycystic kidney disease.  N Engl J Med. 2012;367:2407-18 
Torres VE, Chapman AB, Devuyst O, et al., Tolvaptan in later-stage autosomal dominant 
polycystic kidney disease.  N Engl J Med. 2017;377:1930-1942. 
Marshall WA and Tanner JM. Variations in Pattern of Pubertal Changes in Girls. 1969;44:291- 
303.


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APPENDIX 1.  COVID-19 MITIGATIONS 
This appendix outlines the mitigation strategies adopted to protect the health of participants in 
the study, while maintaining compliance with good clinical practice (GCP) and minimizing the 
risk to trial integrity during the COVID-19 (Coronavirus Disease 2019) pandemic.   
The mitigations will be in place as long as COVID-19 has an impact on trial conduct.  
All measures/mitigations undertaken will be done in accordance with the applicable regional and 
national guidelines of the health authorities (for example, the Guidance on the Management of 
Clinical Trials During the COVID-19 (Coronavirus) Pandemic by the European Medicines 
Agency [EMA] and the FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency). 
COVID-19 impacts to the conduct of study assessments and data collection are noted within the 
clinical database. 
1. 
SITE OPERATIONS & PATIENT MANAGEMENT 
If study sites close or restrict access to study teams during the COVID-19 pandemic, study teams 
must maintain open lines of communication with active study participants.  Additionally, the 
Sponsor is to be regularly updated on changes to the site’s status regarding closures, access 
limitations, contact information or other important information.  Sites are encouraged to provide 
alternate contact information to their patients and the Sponsor.  Updates may be sent to the 
Sponsor study team (COVID19@reatapharma.com). 
2. 
COVID-19 INFECTED PATIENTS AND STUDY DRUG USE 
If a patient enrolled in the study tests positive for Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2), study drug must be temporarily discontinued.  The Sponsor must 
be notified immediately for additional guidance. 
Study drug may be resumed when the patient no longer presents an active infection (defined as 
resolution of symptoms or a negative SARS-CoV-2 test), as assessed by the Investigator and/or 
the patient’s physician(s). If COVID-19 symptoms persist (e.g., loss of taste or smell), the patient 
should be encouraged to repeat SARS-CoV-2 testing in order to minimize the duration of study 
drug interruption. 
Patients who interrupt study drug due to a positive COVID-19 test may resume study drug 
without an in-clinic visit, at the investigator’s discretion, if COVID-19 symptoms are mild, and if 
the duration of interruption did not exceed 14 days. 
The maximum duration of treatment interruption due to COVID-19 infection must be determined 
based on the patient’s symptoms and the investigator’s discretion.  Instructions for how to 
resume study drug (i.e., appropriate dose for restarting and appropriate visit schedule) are 
contained in Section 9.11.  
Additional instructions on resuming study drug are provided in Section 9.11.5 


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3. 
STUDY DRUG ACCESS 
In order to maintain dosing continuity during the COVID-19 pandemic, study drug may be 
shipped from the sites to patients using couriered tracking services, when a patient is not able or 
willing to travel to the study site.  Drug will not be shipped directly from the Sponsor to patients.  
Stability information for study drug shipments is contained in the “Guidance for Direct-to-
Patient Shipping of RTA-402 Drug Product Capsules during the Coronavirus (COVID-19) 
Pandemic” (Attachment 1).  For shipments anticipated to exceed a 48-hour transit time, sites will 
be supplied with temperature monitors upon request.  When a shipment exceeds this transit time, 
the Sponsor should be notified immediately via the COVID-19 Investigational Product 
Temperature Excursion form.  The Sponsor will assess whether the product is fit for use.  During 
this assessment period, the patient should be informed to not take the study drug until further 
notice from the site.  Study drug dispensation should be recorded in the appropriate drug 
accountability logs and all study drug receipts of delivery should be filed in the Investigative Site 
File.    
4. DOSE MANAGEMENT 
4.1 
Dose Escalation Period 
Refer to Section 9.11.1. 
4.2 
Week 8-12 Visits 
Refer to Section 9.11.2 
4.3 
Post-Week 12 Visits 
Refer to Section 9.11.3  
4.4 
Dose De-escalation and Interruption for Missed Safety and Laboratory 
Assessments 
Refer to Section 9.11.4.  
4.5 
Resuming or Dose-escalating Study Drug after Interruptions or 
Changes 
Refer to Section 9.11.5. 
5. DEVIATIONS  
Refer to Section 15.6. 
6. MONITORING  
Refer to Section 13.1. 


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APPENDIX 2. USE OF HOME HEALTHCARE 
For continued patient safety oversight, patients should continue with protocol-specified visits.  
Where inadvisable for the patient to be seen for an in-person clinic visit or if a patient is 
unwilling to come to the clinic, alternate visit completion methods should be considered, such as 
by phone, telemedicine, home health visits and/or local laboratory monitoring of safety labs.  
Visits conducted over the phone (or via telemedicine, if available), at a minimum should include 
the following assessments: 
• Adverse-event assessment 
• Prior and concomitant medication assessment 
In-home visits at a minimum should include the following assessments: 
• Safety labs (may also be done by local laboratories)  
− Clinical chemistry (including eGFR) 
− BNP and NT-proBNP 
− Hematology 
− Urinalysis and microscopy / Urine collection for ACR 
− Urine pregnancy test for WOCBP 
• Vital signs  
• Weight at home 
• Adverse event assessment 
• Prior and concomitant medication assessment 
• Height  


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ATTACHMENT 1: GUIDANCE FOR DIRECT-TO-PATIENT SHIPPING 
OF RTA-402 DRUG PRODUCT CAPSULES DURING THE 
CORONAVIRUS (COVID-19) PANDEMIC 
  




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AMENDMENT CHANGE SUMMARY DOCUMENT 
 
CLINICAL STUDY PROTOCOL 402-C-1808 
Study Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal 
Dominant Polycystic Kidney Disease (FALCON) 
 
Protocol History 
Version 7.0 – 25 May 2022 
Version 6.0 – 04 February 2022 
Version 5.1 Czech Republic – 30 March 2021 
Version 5.1 United Kingdom – 30 March 2021 
Version 5.1 Germany – 30 March 2021 
Version 5.0 – 25 February 2021 
Version 4.1 Czech Republic – 28 August 2020 
Version 4.1 United Kingdom – 25 June 2020 
Version 4.1 Germany – 25 June 2020 
Version 4.0 – 25 June 2020 
Version 3.1 United Kingdom – 09 January 2020 
Version 3.1 Germany – 19 December 2019 
Version 3.1 Czech Republic – 18 November 2019 
Version 3.0 – 16 July 2019 
Version 2.0 – 04 March 2019 
Version 1.0 – 12 December 2018 
 
CONFIDENTIALITY STATEMENT 
 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc. Any unauthorized use or disclosure 
of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 


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Reata Confidential 
 
 
SUMMARY OF CHANGES 
 
The following document outlines the changes made to Version 6 to produce the text of Version 7. Additionally, the following points are 
provided: 
• 
New text added is underscored; deleted text is designated by strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not 
described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the new version of the protocol. 




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2. Synopsis: 
Diagnosis and main 
criteria for inclusion  
10. Patients receiving an SGLT2 inhibitor must be on a stable dose for at least 4 weeks prior to the 
Screen A visit 
Added language, since 
SGLT2 inhibitors are 
used in treatment of 
CKD and will have 
direct impact on eGFR. 
It is important to have 
subject on a stable dose 
prior and during the 
study. 
6.2.4. 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. pediatric growth (height and weight), and sexual maturity using Tanner staging. 
Added based on health 
authority feedback 
seeking confirmation of 
adequate measures to 
monitor safety of, and 
minimize risk to, the 
adolescent population in 
the study. 
7.3.2. Dose 
Escalation Plan 
Patients Both adult and adolescent patients randomized to placebo will remain on placebo throughout the 
study, undergoing sham titration.  Patients Both adult and adolescent 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 escalation may need to proceed more slowly if the patient experiences early elevations in ALT/AST 
over ULN, e.g. at Week 2 (see Section 9.1.2).  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 1, 2, 4, or 6 with the Medical 
Monitor.  In cases where dose escalation is delayed or not achieved, the investigator should consider dose 
escalation to goal dose at any time throughout the dosing period 
Clarification added to 
specify both adults and 
adolescents will follow 
the same dose 
escalation plan.  
 
Relocated and 
consolidated all dose 
management text to 
Section 9.11 (Dose 
Management). 
7.3.3 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 the dose and must be documented.  After dose de escalation, patients must return for an 
unscheduled office visit within 4 weeks (± 3 days) to perform the assessments detailed in Section 9.7. 
Relocated and 
consolidated all dose 
management text to 
Section 9.11 (Dose 
Management). 


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If a patient’s dose has been reduced, dose re escalation back to a higher dose is permitted to meet the dosing 
objective.  However, patients who dose re escalate must have a telephone call 1 week after dose re
escalation and an unscheduled office visit 2 weeks (± 3 days) after dose re escalation to perform 
assessments detailed in Section 9.7. 
For detailed instructions on dose management, refer to Section 9.11. 
7.3.4. Dose 
Interruption and Re-
Challenge/ Re-
Initiation  
In addition to dose de escalation and re escalation, the study drug administration can be interrupted, if 
clinically indicated. The term interruption generally refers to a temporary halt of study drug administration. 
All efforts should be made to re challenge the study drug at any point during the treatment period following 
interruption, upon consultation with the Medical Monitor.  If there are any questions regarding study drug 
interruption, please consult the Medical Monitor. 
When a patient resumes or re challenges study drug, after an extended interruption (e.g., more than several 
weeks), the site should discuss the appropriate starting dose and visit frequency with the Medical Monitor.  
The duration of the interruption and the reason for interruption should be taken into consideration when 
determining how to safely resume or re challenge study drug.   
For detailed instructions on dose management, refer to Section 9.11. 
Relocated and 
consolidated all dose 
management text to 
Section 9.11 (Dose 
Management). 
7.5. Schedule of 
Assessments 
Table 4: Schedule of 
Assessments  
 
Week 5 (Phone) Day 38 ±32 Days 
Visit window 
inadvertently changed 
to ±3 Days between 
protocol V5.0 to V6.0. 
Corrected back to ±2 
Days.   
7.5. Schedule of 
Assessments 
Table 4: Schedule of 
Assessments  
 
Tanner Staging: Day 1, Week 52(B), Week 108(B) 
Added new Tanner 
Staging Assessment at 
specific timepoints to 
monitor the growth and 
sexual development of 
adolescents.  
7.5. Schedule of 
Assessments 
Table 4: Schedule of 
Assessments  
 
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 
Pregnancy tests are 
required at all visits, as 
outlined in Table 4.  
Language was removed 
to avoid potential 
confusion due to use of 
the word “should.”   




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8.1 Patient Inclusion 
Criteria 
3. eGFR must: 
a. Have a percent difference ≤ 25% at screening (the values at Screen A and Screen B), and; 
b. Have an average (the values at Screen A and Screen B) ≥ 30 to ≤ 90 mL/min/1.73 m2 for patients 12
55 years or ≥ 30 to ≤ 44 mL/min/1.73 m2 for patients 56 to 70 years, and; 
c. Support ADPKD disease progression (i.e., average yearly eGFR decline of ≥ 2.0 mL/min/1.73 m2 
for 2 consecutive the past two years) for patients with either screening eGFR ≥ 60 to 
≤ 90 mL/min/1.73 m2 or age 56 to 70 years (See Protocol Section 9.10.2) 
Clarification that 
disease progression is 
assessed based on the 
past two years.  
8.1 Patient Inclusion 
Criteria 
10. Patients receiving an SGLT2 inhibitor must be on a stable dose for at least 4 weeks prior to the 
Screen A visit; 
Added language, since 
SGLT2 inhibitors are 
used in treatment of 
CKD and will have 
direct impact on eGFR. 
It is important to have 
subject on a stable dose 
prior and during the 
study. 
8.3.1. Screening 
Period  
The screening period begins with the signing of the informed consent/assent form at the Screen A visit and 
ends at the start of the Day 1 visit. Where the signing of the informed consent/assent precedes the Screen A 
visit, the screening period is considered to begin at the Screen A visit.  The duration of the screening period 
must not exceed 90 days.  The Screen A procedures may be completed across multiple days.  Efforts should 
be made to ensure the Screen B visit is no more than 30 days prior to Day 1. 
Sites must not initiate screening of an adolescent who will become an adult prior to Day 1. If, at the time of 
prior to randomization, a an adolescent patient is who screened has become an adult, the patient must be 
screen-failed and rescreened, such that eligibility must be is assessed based on the adult eligibility 
parameters (ADPKD diagnosis and eGFR calculation). 
Clarified that the 
Screening period begins 
at the Screen A visit, 
even when the ICF is 
signed prior.   
Refined instructions to 
sites regarding patients 
who transition from 
adolescent to adult 
during screening.   
8.3.3. Off-Treatment 
Period  
AEs should be reported for 30 days following until the patient’s last dose of Week 112 (B) study drug visit. Because endpoint data 
are being collected 
through 12 weeks 
following the last dose 
of drug, the AE 
collection period was 
extended.   
8.5. Patient 
Discontinuation and 
Termination  
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 who discontinues interrupts study drug for 14 consecutive 
days or more must have approval from the Medical Monitor prior to resuming treatment with study drug. 
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8.5.1. Study Drug 
Discontinuation 
Criteria  
For patients who discontinue treatment prior to Week 100, see Section 8.3.3 for the required off-treatment 
assessments.  After the off-treatment assessments, the patient will continue with follow-up assessments 
through Week 112. The collection of laboratory data and vital status through Week 112 (B) is important for 
trial integrity, and data may be obtained through in-person clinic visits or through home health visits. 
See Section 9.10.16 for Adverse Event Collection following study drug discontinuation. 
Added language to 
emphasize the 
importance of 
continuing follow up 
through Week 112 for 
patients who 
discontinue drug early.   
9.1.2. Management 
of Elevated 
Transaminase Levels 
(ALT and/ or AST)  
Patients restarting who meet the interruption criteria outlined above must restart study drug should start at 
the 5 mg dose level and dose titrate according to Section 7.3.3. 
The hepatobiliary tree must be assessed by ultrasound or magnetic resonance imaging (MRI) for patients 
who meet temporary discontinuation criteria. Based on imaging results, if additional tests/studies are 
warranted, this should be discussed with the Medical Monitor. 
Clarified that 5mg 
restarting dose must be 
used when interruption 
criteria are met.  
 
Removed redundant 
instruction regarding 
visualization of 
hepatobiliary tree.  
9.1.4. Weight Loss  Adults - The investigator should evaluate a patient for unexplained weight loss of 7% or greater from the 
Day 1 weight.   Ongoing assessments of other symptomology (for example: nausea, vomiting, abdominal 
pain or poor appetite) may be warranted to ensure the patient is receiving adequate nutrition and 
consideration of evaluate for other etiologies causes of weight loss may be warranted for patients receiving 
bardoxolone methyl.  
Adolescents - If weight loss of greater than 5% from the Day 1 weight is observed, the investigator should 
temporarily stop study drug, and evaluate the patient for any symptomology (for example: nausea, 
vomiting, abdominal pain or poor appetite) leading to weight loss, and/or other causes of weight loss.  The 
investigator should inform the Medical Monitor prior to stopping study drug, and the investigator and 
Medical Monitor should discuss management of the patient. 
Language was added to 
clarify assessment of 
symptomology related 
to weight loss and 
specify criteria for 
interruption of IP in 
adolescents with a >5% 
drop in weight from the 
Day 1 measurement.  
9.1.9. End Stage 
Kidney Disease  
For patients with eGFR ≤ 15.0 mL/min/1.73 m2, (as calculated by the site, using the central lab-provided 
serum creatinine and the formulas provided in Section 9.10.18.1), 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).   
Language added to 
guide sites on how 
eGFR should be 
calculated in the 
absence of values being 
present on lab reports.   
9.1.10. Monitoring 
Growth and Sexual 
Development in 
Adolescents 
Growth and sexual development will be assessed through an evaluation of height, weight, and Tanner 
Staging. See the Study Reference Manual for details on the Tanner staging.  
Body weight should be measured daily by patients/caregivers using a provided weighing scale. Weight and 
height will also be measured at all site visits, as outlined in Section 9.10.7.  Patients should be instructed to 
inform the site if there is an observed weight loss of more than 3 pounds (1.4kg) in between clinic visits 
(Section 9.1.1).  
Added based on health 
authority feedback 
seeking confirmation of 
adequate measures to 
monitor safety of, and 
minimize risk to, the 
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The Medical Monitor will routinely evaluate both weight and height entered into the clinical database of 
adolescents and will inform the investigator to initiate further evaluation if there is a weight loss of ≥5% or 
lack of expected growth per growth charts. 
Sexual maturity will be assessed by the investigator using Tanner Staging. If any abnormal patterns of 
sexual maturity are identified on evaluation of Tanner Staging, the Medical Monitor should be notified for 
additional discussion.  
the study. 
9.3.1.2. Prohibited 
Medications  
ChronicConcomitant use with 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®)] within 12 weeks prior to randomization.  Glucocorticoid intra articular injections, inhaled 
products, topical preparations, and nasal preparations are allowed.®)])  is prohibited.    
Patients who Concomitant use with tolvaptan, somatostatin analogues, and any other investigational drug or 
device is prohibited. Concomitant dosing with prohibited medications is not allowed and will not be 
approved by the Medical Monitor.  If a site becomes aware of a patient administering a prohibited 
medication, the Medical Monitor should be notified immediately to determine whether study drug should be 
permanently discontinued or whether an interruption is appropriate.    
To minimize missing data and to maintain study integrity, patients who must take prohibited medications 
during the study should not discontinue study drug solely on this basis. 
Consultation with the Medical Monitor should occur prior to Continue follow-up visits, even after study 
drug discontinuation, or withdrawing a patient ,  unless directed otherwise by the Medical Monitor. Certain 
prohibited medications (e.g., tolvaptan) will warrant termination from the study, due to the potential for the 
concomitant medication to confound the interpretation of study data.    
Sites must avoid initiation of prohibited medications until all Off-Treatment assessments are completed 
(approximately 12 weeks following the patient’s last dose of study drug). 
If a patient permanently discontinues study drug and continues being followed in the study, the 
administration of a prohibited medication is no longer considered a protocol deviation after 12 weeks 
following the patient’s last dose of study drug.  Beginning 12 weeks after the patient’s last dose, 
administration of a prohibited medication does not require input from the Medical Monitor.   
Importantly, the administration of any medications listed in this section should be recorded in the 
concomitant medication page of the EDC independent of the patient’s study drug status or duration since 
the patient’s last dose of study drug, in order to ensure accurate interpretation of safety and efficacy data. 
Added language and 
additional instruction on 
how to handle 
administration of 
prohibited medications 
in patients who have 
stopped study drug, and 
who continue to be 
followed in the trial.   
 
Added requirement for 
Medical Monitor input 
when a prohibited 
medication is used or is 
anticipated.   
 
Use of tolvaptan in a 
patient who has stopped 
study drug will warrant 
termination from the 
study, due to 
confounding effects on 
data interpretation. 
9.3.2. Permitted 
Medications  
Allowed concomitant medications include the following: 
•  Antibiotics, including (but not limited to) fluoroquinolones and trimethoprim-sulfamethoxazole (if the 
antibiotic being prescribed is a moderate or strong CYP3A4 inhibitor or inducer, see Section 9.3.1.29.3.10); 
• Daily multivitamins or recommended daily supplements; 
• Other medications intended to manage concurrent diseases, as authorized by the treating physician; 
Country specific 
language was 
inadvertently removed 
between protocol V5.0 
to V6.0.  Language has 
been added to V7. 


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• Statins (e.g., pravastatin or rosuvastatin), in the Czech Republic and globally; 
• Pain management: acetaminophen, and other adjuvant analgesics and opioids may be used as deemed 
appropriate by the investigator, in the Czech Republic and globally; 
• Oral, implantable, or injectable contraceptives; 
• Glucocorticoid intra-articular injections, inhaled products, topical preparations, and nasal preparations. 
9.3.2. Permitted 
Medications 
Patients taking medication chronically, including ACE inhibitors and, ARBs, and SGLT2 inhibitors should 
be maintained on those same doses and dose schedules throughout the study period and should not have 
additions or changes made to their medications, unless medically indicated.   
Updated to reference 
SLGT2i  
9.4. Treatment 
Compliance  
A lack of treatment compliance during any evaluation period (visit to visit) should be entered as a protocol 
deviation.   
Patients should record in the patient diary all administered and missed doses of study drug.  The reason for 
a missed dose should be recorded in the patient diary.  A missed Missing dose includes drug holidays and 
temporary inadvertent missed doses as well as study drug interruptions and discontinuations. Patients will 
be asked to return all unused study drug (study drug bottles and any unused capsules). The study drug must 
not be used for reasons other than that described in the protocol. 
Language added to 
define “missed doses” 
to minimize ambiguity 
in interpretation 
9.7. Unscheduled 
Visits  
Unscheduled visits conducted for the following reasons should include collection of AEs, clinical 
chemistry, BNP/NT-proBNP, hematology, concomitant medication collection, and vital signs: 
• 
Resuming study drug following an extended interruption; 
Clarified that 
unscheduled visits may 
be conducted to resume 
study drug following an 
interruption  
9.8.1. Women of 
Childbearing 
Potential and Fertile 
Males  
Czech Republic Only: 
Women of childbearing potential (WOCBP) are those who have experienced menarche and are not 
surgically sterile (no history of bilateral tubal ligation, hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy), and are not postmenopausal (defined as no menses for at least 1 year without an alternative 
medical cause). 
Fertile males are those who have entered puberty or reached physical maturation (after puberty) and are not 
surgically sterile (no history of bilateral orchiectomy) 
Country specific 
language was 
inadvertently excluded.  
Language has been 
added to V7. 
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 methods are not allowed for patients at 
participating sites in Germany and Australia; 
Country specific 
language was 
inadvertently excluded.  
Language has been 
added to V7. 


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9.8.2. Methods of 
Birth Control 
During Screening, while taking study drug and until 30 days after the final dose of study medication is 
taken, fertile males who have female partners of childbearing potential must practice one of the following 
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 and Australia: 
• 
Have had a vasectomy (with vasectomy performed at least 6 months prior to screening with the 
appropriate post-procedure documentation of surgical success) (not permitted in the United 
Kingdom) 
• 
Partner contraception methods; must be the sole partner for that patient: 
− 
Use of an intrauterine device; 
− 
Use of hormonal contraceptives (oral, parenteral, intravaginal or transdermal) for at least 60 
days prior to start of study drug administration; 
− 
Surgically sterile partner (bilateral tubal ligation, hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy); fallopian inserts with confirmed blockage (e.g., x-ray, ultrasound) 
(not permitted in the Czech Republic); 
− 
Reproductive potential has been terminated by radiation (not permitted in the Czech 
Republic); 
Country specific 
language was 
inadvertently excluded.  
Language has been 
added to V7. 
9.10.2. Inclusion/ 
Exclusion  
Inclusion 3c must show disease progression using average yearly eGFR decline of ≥ 2.0 mL/min/1.73 m2 
from the last past two consecutive years. If a patient has limited historical eGFR values from the past two 
years, the investigator must discuss the patient’s eligibility with the Medical Monitor. 
Clarification that 
disease progression is 
assessed based on the 
past two years. 
9.10.4. Prior and 
Current Concomitant 
Medications  
All medications will be recorded through the Week 112 visit as indicated in Table 4. 
For patients who remain on study drug, the administration of any medications should be recorded in the 
concomitant medication page of the EDC through Week 112,  
For patients who discontinue study drug early and continue to be followed in the study, all concomitant 
medications should be recorded for 12 weeks following the patient’s last dose of study drug.  Beyond 12 
weeks after the patient’s last dose, only those medications that are relevant to the clinical condition 
including kidney disease or that may have a potential impact on kidney function must be recorded in the 
concomitant medication page of the EDC.  Unscheduled phone visits may be used, as necessary, to ensure 
accurate collection of concomitant medications of interest. 
Language revised to 
ensure consistent data 
collection related to 
concomitant medication 
and prohibited 
medication use to aid in 
safety data review and 
efficacy analysis. 
 
 


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Importantly, the administration of any medications listed in Section 9.3.1.2 (Prohibited Medications) should 
be recorded in the concomitant medication page of the EDC independent of the patient’s study drug status 
or duration since the patient’s last dose of study drug, in order to ensure accurate interpretation of safety and
efficacy data.  
9.10.6. Height  
Height should be measured without footwear or prosthetics using a wall-mounted stadiometer if performed 
in-clinic.  For adult patients (18 ≤ age ≤ 70 years at Screen A visit), height is measured at Screen A.  
Adolescent patients (12 ≤ age < 18 years at Screen A visit), height is measured at the timepoints specified in 
Table 4, when in clinic visits are not possible, home health nurses should be used (see Appendix 2). 
Language added to 
define timing and 
methods of height 
collection.  
9.10.7. Weight and 
Body Mass Index 
(BMI) 
In the event the Sponsor-provided scale is temporarily unavailable (e.g., patient is traveling, replacement 
scale has not arrived to patient, etc.), patients may use any available scale. 
Missing more than 20% of expected weight records in the patient diary during any evaluation period (visit 
to visit) is considered as non-compliance, which should be reported as a deviation.   
Language added to 
define what will be 
considered as subject 
non-compliance 
regarding missed at 
home weights.  
9.10.11. 
Comprehensive 
Physical 
Examination & 
Targeted Physical 
Examination 
A comprehensive physical examination Physical examinations must be performed by a physician, physician 
assistant, or registered nurse practitioner. 
A comprehensive physical examination must be performed as indicated in Table 4 and as documented 
within the medical record.   
Table 4.  If the investigator observes no symptoms that warrant further examination, the investigator may 
forego a more detailed physical examination, and the targeted physical examination may be considered 
complete. 
Clarification added to 
ensure targeted physical 
exams are performed, as 
indicated in Table 4, 
and more detailed 
physical exams are 
conducted when 
needed. 
 
9.10.13 Study Drug 
Administration  
Refer to Section 9.4 and 9.11 for treatment compliance and detail in dose management. 
Language added to 
guide sites to the 
treatment compliance 
and dose management 
sections.   
9.10.16. Adverse 
Event Collection  
AEs should be reported from the time of the first dose until the Week 112 (B) visit as indicated in Table 4.   
For patients who discontinue study drug early (prior to Week 100) and continue to be followed in the study, 
all AEs should be recorded for 12 weeks following the patient’s last dose of study drug.  Beyond 12 weeks 
after the patient’s last dose, only those AEs that are relevant to the clinical condition including kidney 
disease, may have an impact on kidney function, or may impact the interpretation of safety or efficacy data 
must be recorded in the AE log within the EDC.  Unscheduled phone visits may be used, as necessary, to 
ensure accurate collection of AEs of interest.    
AEs that are related to study procedures should be recorded in the AE log within the EDC independent of 
the patient’s study drug status or duration since the patient’s last dose of study drug.  
Clarification on the 
duration of AE 
reporting.  Extended AE 
reporting period from 
30 days following the 
last dose to 12 weeks 
following the last dose 
of drug, due to the 
collection of endpoint 
data through that period. 




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9.11. Dose 
Management 
INTERRUPTION OF STUDY DRUG 
In addition to dose de-escalation and re-escalation, the study drug administration can be interrupted, if 
clinically indicated. The term interruption generally refers to a temporary halt of study drug administration. 
All efforts should be made to resume study drug at any point during the treatment period following 
interruption, upon consultation with the Medical Monitor.  If there are any questions regarding study drug 
interruption, please consult the Medical Monitor. 
Relocated and 
consolidated all dose 
management text to 
Section 9.11 (Dose 
Management). 
9.11. Dose 
Management 
RESUMING STUDY DRUG 
Any patient who interrupts study drug for 14 consecutive days or more must have approval from the 
Medical Monitor prior to resuming study drug. 
When a patient resumes study drug, after an extended interruption (e.g., more than 14 days), the site should 
discuss the appropriate starting dose and visit frequency with the Medical Monitor.  The duration of the 
interruption and the reason for interruption should be taken into consideration when determining how to 
safely resume study drug.  Following an extended interruption, when the investigator deems it is safe for the 
patient to return to the site for an in-person visit, the investigator should conduct an evaluation to determine 
whether the patient is still eligible to receive study drug and to determine the appropriate dose, in 
consultation with the Medical Monitor.  This should include a confirmation that the patient’s circumstances 
have not changed in a manner that would prohibit administration of the study drug (e.g., the patient is now 
taking an excluded medication).  Once the investigator determines study drug administration is appropriate, 
dosing may proceed.   
Patients must have a telephone call 1 week after resuming and an unscheduled office visit 2 weeks (± 3 
days) after resuming study drug to perform assessments detailed in Section 9.7. 
For additional guidance on resuming drug following a positive COVID-19 test, see Section 9.11.5. 
Relocated and 
consolidated all dose 
management text to 
Section 9.11 (Dose 
Management). 
9.11.3. Post- Week 
12 Visits – Missed 
In-Person Visits  
If no in-clinic visit can be completed and remote assessments/laboratory samples cannot be collected within 
a reasonable time, based on the investigator’s discretion, the investigator should consider whether de-
escalation may be appropriate.   
Language added to 
defer to investigator’s 
clinical judgement 
regarding dose de-
escalation in the event 
of a missed visit.  
9.11.4. Dose De-
Escalation and 
Interruption for 
Missed Safety and 
Laboratory 
Assessments 
If no in clinic visit is completed and remote assessments/laboratory samples cannot be collected within the 
per protocol allowed time window for that visit, the study drug dose must be de escalated to the previous 
dose within 6 days of the protocol visit window.  For patients on 5 mg, the lowest dose, the dose may be 
maintained, and no de escalation is required.  All efforts should then be made to collect laboratory samples.  
However, if laboratory samples cannot be collected within 14 days from the date of dose de escalation (for 
visits through Week 12) and within 28 days (for visits beyond Week 12), 5 mg study drug must be 
continued until safety lab values can be evaluated and it is deemed appropriate to dose escalate.  Section 
9.11.5 describes the procedure for resuming and dose escalating study drug following drug interruption. 
Language was moved 
from section 9.11.4 to 
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From Protocol Version 7.0 forward, this text was removed, and language was placed within Section 9.11. 
9.11.5. Resuming or 
Dose Escalating 
Study Drug After 
COVID-19 
Interruption or 
Changes  
Patients who interrupt study drug due to a positive COVID-19 test may resume study drug without an in-
clinic visit, at the investigator’s discretion, of if COVID-19 symptoms are mild, and if the duration of 
interruption did not exceed 14 days. 
When the investigator deems it is safe for the patient to return to the site for an in person visit, the 
investigator should conduct an evaluation to determine whether the patient is still eligible to receive study 
drug and to determine the appropriate dose.  This should include a confirmation that the reason for 
interruption was not a per protocol specified reason and that the patient’s circumstances have not changed 
in a manner that would prohibit administration of the investigational 
Study drug may be resumed when the patient no longer presents an active infection (defined as resolution of 
symptoms or a negative SARS-CoV-2 test), as assessed by the Investigator and/or the patient’s 
physician(s). If COVID-19 symptoms persist (e.g., loss of taste or smell), the patient should be encouraged 
to repeat SARS-CoV-2 testing in order to minimize the duration of study drug interruption. 
For more information related to study drug management and COVID-19 see Appendix 1, Section 4.5. 
Once the investigator determines study drug administration is appropriate, dosing may proceed as 
recommended in the table below. 
Study Drug Status 
Dosing Recommendation 
Study drug temporarily discontinued for any reason (e.g., 
COVID 19, delays in obtaining safety lab, AEs) 
Resume study drug at last administered 
dose 
Study drug dose not escalated as required per COVID 19 
mitigation plan 
Continue last administered dose; consider 
escalating dose, if appropriate 
Study drug de escalated for any reason (e.g., due to delays 
in obtaining safety labs, AEs) 
Continue last administered dose; consider 
escalating dose, if appropriate 
If the patient is not at the target dose, dose escalation to a higher dose is permitted.  Patients who dose 
escalate must have a telephone call 1 week after dose escalation and an office visit (or unscheduled visit, if 
necessary) 2 weeks (± 3 days) after dose escalation to collect clinical chemistry, BNP, and NT proBNP.  
Clarified that drug may 
be resumed without an 
in-clinic visit, if the 
interruption is not > 14 
days in duration.   
 
Relocated instruction on 
resuming study drug to 
main Section 9.11 
(Dose Management). 
 
 
 
Relocated text from 
COVID Appendix to 
this section.  
 
 
 
 
Relocated and 
consolidated dosing 
management 
instructions, and 
removed redundant text 
within the protocol. 


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Amendment to Version 7.0 – Study Protocol 402-C-1808 
 
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Reata Confidential 
Unscheduled visits due to dose escalation should also include assessments detailed in Section 9.7 of the 
protocol.  Once the target dose has been reached and 2 week follow up completed, the Schedule of 
Assessments may be resumed. 
11.2.1.1. Adverse 
Event  
All AEs that are observed or reported by the patient during the study (from administration of the first dose 
until 30 days following administration of the last dose of Week 112 (B) study drug) visit as indicated in 
Table 4Table 4) must be reported, regardless of their relationship to study drug or their clinical significance. 
For patients who discontinue study drug early (prior to Week 100) and continue to be followed in the study, 
all AEs should be recorded for 12 weeks following the patient’s last dose of study drug. Beyond 12 weeks 
after the patient’s last dose, only those AEs that are relevant to the clinical condition including kidney 
disease, may have an impact on kidney function, or may impact the interpretation of safety or efficacy data 
must be reported.  
AEs that are related to study procedures should be reported independent of the patient’s study drug status or 
duration since the patient’s last dose of study drug. SAEs, if considered related to study drug, can be 
reported at any time during the study duration. In addition, as noted in Section 11.2.1.2, death, initiation of 
dialysis, or transplant should be reported through Week 112, on the appropriate eCRF.   
Clarification on the 
duration of AE 
reporting.  Extended AE 
reporting period from 
30 days following the 
last dose to 12 weeks 
following the last dose 
of drug, due to the 
collection of endpoint 
data through that period.
11.2.1.2. Serious 
Adverse Event  
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 Week 112 (B) study 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 Week 112 (B)  study 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.  For patients who discontinue study drug early, SAEs should be 
reported through 30 days12 weeks following the date of last dose of study drug.  SAEs, if considered 
related to study drug, should be reported at any time during the study.  In addition, death, initiation of 
dialysis, or transplant should be reported through Week 112, on the appropriate eCRF.  (see Section 11.7). 
For information on ESKD related SAEs see section 9.1.9.  
Clarification on the 
duration of AE 
reporting.  Extended AE 
reporting period from 
30 days following the 
last dose to 12 weeks 
following the last dose 
of drug, due to the 
collection of endpoint 
data through that period.
11.6. Reporting 
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 
Week 112 (B) study follow up visit, as indicated in Table 4, regardless of the their relationship of the AE to 
study drug or their clinical significance. For patients who discontinue study drug early (prior to Week 100) 
and continue to be followed in the study, all AEs should be recorded for 12 weeks following the patient’s 
last dose of study drug.  Beyond 12 weeks after the patient’s last dose, only those AEs that are relevant to 
the clinical condition including kidney disease, may have an impact on kidney function, or may impact the 
interpretation of safety or efficacy data must be reported.  
Clarification on the 
duration of AE 
reporting.  Extended AE 
reporting period from 
30 days following the 
last dose to 12 weeks 
following the last dose 
of drug, due to the 
collection of endpoint 
data through that period.


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Amendment to Version 7.0 – Study Protocol 402-C-1808 
 
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Reata Confidential 
AEs that are related to study procedures should be reported independent of the patient’s study drug status or 
duration since the patient’s last dose of study drug.  
11.6. Reporting 
Adverse Events 
For guidance on how to handle AEs that change in severity (e.g., worsening or improving), see the eCRF 
Completion Guidelines. All drug-related (possibly, probably, or definitely related, see Section 11.4) AEs 
and clinically significant abnormal laboratory test results reported or observed during the study must be 
followed to resolution (either return to baseline, within normal limits, or stabilization).  All other non-drug 
related AEs or clinically significant abnormal laboratory test results will be followed through the 30 days 
after Week 112 (B) study visit or for 12 weeks following the last dose of for patients who discontinue study 
drug early.  
Extended AE reporting 
period from 30 days 
following the last dose 
to 12 weeks following 
the last dose of drug, 
due to the collection of 
endpoint data through 
that period..   
18. References  
Marshall WA and Tanner JM. Variations in Pattern of Pubertal Changes in Girls. 1969;44:291- 
303. 
Reference added  
Appendix 1. 
COVID-19 
Mitigations  
2. COVID-19 
Infected Patients and 
Study Drug Use  
Patients who interrupt study drug due to a positive COVID-19 test may resume study drug without an in-
clinic visit, at the investigator’s discretion, if COVID-19 symptoms are mild, and if the duration of 
interruption did not exceed 14 days. 
The maximum duration of treatment interruption due to COVID-19 infection must be determined based on 
the patient’s symptoms and the investigator’s discretion.  Instructions for how to resume study drug (i.e., 
appropriate dose for restarting and appropriate visit schedule) are contained in Section 9.11.  
Additional instructions on resuming study drug are provided in Section 9.11. 
Added based on health 
authority feedback 
seeking definition of the 
maximum treatment 
interruption due to 
COVID-19 infection 
and time limit in which 
the patient must meet 
with the investigator 
after treatment is 
resumed. 
Appendix 1. 
COVID-19 
Mitigations 
4. Study Visits  
 
4. Study Visits  
For continued patient safety oversight, patients should continue with protocol specified visits.  Where 
inadvisable for the patient to be seen for an in person clinic visit or if a patient is unwilling to come to the 
clinic, alternate visit completion methods should be considered, such as by phone, telemedicine, home 
health visits and/or local laboratory monitoring of safety labs.  
Visits conducted over the phone (or via telemedicine, if available), at a minimum should include the 
following assessments: 
• 
Adverse event assessment 
• 
Prior and concomitant medication assessment 
In home visits at a minimum should include the following assessments: 
• 
Safety labs (may also be done by local laboratories)  
Relocated the “Study 
Visit” section from 
Appendix 1 to 
Appendix 2. Home 
healthcare can be used 
for reasons outside of 
COVID-19, therefore 
removed from the 
COVID-19 Appendix.  


Reata Pharmaceuticals, Inc. 
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Reata Confidential 
 
Clinical chemistry (including eGFR) 
 
BNP and NT proBNP 
 
Hematology 
 
Urinalysis and microscopy / Urine collection for ACR 
 
Urine pregnancy test for WOCBP 
• 
Vital signs  
• 
Weight at home 
• 
Adverse event assessment 
• 
Prior and concomitant medication assessment 
Appendix 2. Use of 
Home Healthcare 
For continued patient safety oversight, patients should continue with protocol-specified visits.  Where 
inadvisable for the patient to be seen for an in-person clinic visit or if a patient is unwilling to come to the 
clinic, alternate visit completion methods should be considered, such as by phone, telemedicine, home 
health visits and/or local laboratory monitoring of safety labs.  
Visits conducted over the phone (or via telemedicine, if available), at a minimum should include the 
following assessments: 
• 
Adverse-event assessment 
• 
Prior and concomitant medication assessment 
In-home visits at a minimum should include the following assessments: 
• 
Safety labs (may also be done by local laboratories)  
− 
Clinical chemistry (including eGFR) 
− 
BNP and NT-proBNP 
− 
Hematology 
− 
Urinalysis and microscopy / Urine collection for ACR 
− 
Urine pregnancy test for WOCBP 
• 
Vital signs  
• 
Weight at home 
• 
Adverse event assessment 
Created a new 
Appendix specific to the 
use of home healthcare. 
Home healthcare can be 
used for reasons outside 
of COVID-19, therefore 
removed from the 
COVID-19 Appendix. 


Reata Pharmaceuticals, Inc. 
Amendment to Version 7.0 – Study Protocol 402-C-1808 
 
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Reata Confidential 
• 
Prior and concomitant medication assessment 
• 
Height 
 


Reata Pharmaceuticals, Inc. 
Amendment to Version 6.0 – Study Protocol 402-C-1808 
 
 
 
 
Page 1 of 50 
 
Version 6.0 
 
Reata Confidential 
 
 
 
AMENDMENT CHANGE SUMMARY DOCUMENT  
CLINICAL STUDY PROTOCOL 402-C-1808 
Study Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal  
Dominant Polycystic Kidney Disease (FALCON) 
Protocol History 
Version 6.0 – 04 February 2022  
Version 5.1 – 30 March 2021 
Version 5.1 United Kingdom – 30 March 2021 
Version 5.1 Germany – 30 March 2021 
Version 5.0 – 25 February 2021 
Version 4.1 Czech Republic – 28 August 2020 
Version 4.1 United Kingdom – 25 June 2020 
Version 4.1 Germany – 25 June 2020 
Version 4.0 – 25 June 2020 
Version 3.1 United Kingdom – 09 January 2020 
Version 3.1 Germany – 19 December 2019 
Version 3.1 Czech Republic – 18 November 2019 
Version 3.0 – 16 July 2019 
Version 2.0 – 04 March 2019 
Version 1.0 – 12 December 2018 
 
CONFIDENTIALITY STATEMENT 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc.  Any unauthorized use or disclosure 
of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 


Reata Pharmaceuticals, Inc. 
Amendment to Version 6.0 – Study Protocol 402-C-1808 
 
 
 
 
Page 2 of 50 
 
Version 6.0 
 
Reata Confidential 
 
SUMMARY OF CHANGES 
The following document outlines the changes made to Version 5 to produce the text of Version 6.  Additionally, the following points are 
provided: 
• 
New text added is underscored; deleted text is designated by strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not 
described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the new version of the protocol. 




































Reata Pharmaceuticals, Inc. 
Amendment to Version 6.0 – Study Protocol 402-C-1808 
 
 
 
 
Page 20 of 50 
 
Version 6.0 
 
Reata Confidential 
 8.3. Screening, 
Treatment, and Off-
treatment Periods 
8.3 Screening, Treatment, and Off-Treatment Periods 
The screening period must not exceed 3 months. The Screen B visit should be no more should be than 
30 days prior to Day 1. 
8.3.1. Screening Period 
The screening period begins with the signing of the informed consent/assent at the Screen A visit and 
ends at the start of the Day 1 visit.  The duration of the screening period must not exceed 90 days 3 
months.  The Screen A procedures may be completed across multiple days.  Efforts should be made to 
ensure the Screen B visit should be is no more than 30 days prior to Day 1.  
Sites must not initiate screening of an adolescent who will become an adult prior to Day 1.  If, at the time 
of randomization, a patient is an adult, eligibility must be assessed based on the adult eligibility 
parameters (ADPKD diagnosis and eGFR calculation). 
Where calculation of the screening eGFR average results in a decimal, basic rounding principles apply. 
For example, an average eGFR of 29.5 mL/min/1.73 m2 would round up to 30 mL/min/1.73 m2. 
Eligibility should be confirmed prior to randomization of any patient in the IWRS.   
All screening procedures should be completed per the schedule of assessments in Table 4. 
8.3.2 Treatment Period 
 
The Treatment Period refers to the time from administration of the first dose (Day 1 visit) through 
administration of the last dose (Week 100 visit).  Administration of the first dose of study drug should 
occur in-clinic, at the Day 1 visit, after confirmation of eligibility and randomization. Administration of the 
last dose of study drug should occur in-clinic, at the Week 100 visit, following the collection of all lab and 
PK assessments. 
During the treatment period, sites should ensure proper documentation of any intentional interruptions in 
dosing, including the reason for and duration of the interruption.  Information regarding interruptions 
should be entered into the clinical database.   
A patient who discontinues study drug early has a shortened treatment period.  Regardless of when a 
patient’s treatment period ends, it is imperative that an off-treatment period follows study drug 
discontinuation.  See Section 8.3.3 for required assessments in the Off-Treatment Period. 
Added general guidance 
regarding each period 
of the study (Screening, 
Treatment, Off-
Treatment).   
 
Screening Period:  
Added language to 
avoid adolescent 
patients screening for 
the study, if the patient 
will become and adult 
prior to Day 1.   
 
Added guidance on 
calculation of average 
eGFR, and how 
decimals should be 
handled, for eligibility 
determination.   
 
Treatment Period:  
Added general 
guidance.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 






Reata Pharmaceuticals, Inc. 
Amendment to Version 6.0 – Study Protocol 402-C-1808 
 
 
 
 
Page 23 of 50 
 
Version 6.0 
 
Reata Confidential 
8.5.1. 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 (Section 7.4, Section 9.1.1, Section 9.1.9, Section 9.3.1, 
Section 9.6.1, and Section 9.8.3); 
• Withdrawal by subjectpatient; 
To maximize patient retention and minimize missing data, patients who are permanently discontinued 
discontinue from study drug should still early are encouraged to remain active in the study and complete 
all future study visits and assessment, except PKs and ABPM, if applicable.  
 
For patients who discontinue treatment prior to Week 100, see Section 8.3.3 for the required off-
treatment assessments.  After the off-treatment assessments, the patient will continue with study follow-
up, completing all study visits and undergoing all scheduled study assessments through Week 104 112.  
 
For patients who are unwilling to complete all future visit, the Week 108 visit is of laboratory paramount 
significance.  Collecting Week 108 data and vital status (including ESKD status) through Week 104 is 
important for all randomized patients is essential for trial integrity and data may be obtained through in
person clinic visits or through home health visits.  AEs and SAEs should be collected for 30 days 
following the date of last dose. 
For patient 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 and must be discussed with the patient 
thoroughly, including: 
• 
Participation in follow-up procedures specified in the protocol by an in-home visit, where 
feasible; 
• 
Reduced in-person visit schedule; 
• 
Telephone contact only; 
• 
Contact of alternative person(s) who has been designated in source records as being available 
to discuss the patient’s medical condition; 
 
Off-treatment period is 
extended to 12 weeks, 
added language to have 
same off-treatment 
visits for subjects who 
discontinue. Added 
additional language 
around visit for clarity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






Reata Pharmaceuticals, Inc. 
Amendment to Version 6.0 – Study Protocol 402-C-1808 
 
 
 
 
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Version 6.0 
 
Reata Confidential 
9.1.2. Management 
of Elevated 
Transaminase 
Levels (ALT and/or 
AST) 
For only patients who enrolled under Version 2 of the protocol (only performed in the US at the 
beginning of the study) and are receiving tolvaptan (JYNARQUE), liver biochemistries (ALT, AST, 
and/or bilirubin levels) should be monitored according to the relevant package insert/REMS program 
for tolvaptan.   
 
For all patients enrolled, nearly all instances of elevated transaminases due to bardoxolone methyl 
treatment are expected to be asymptomatic.  
 
Some patients may experience more rapid increases in ALT/AST values than others during the dose 
titration period.  Investigators may consider extending the time between each dose increase from two 
weeks to four weeks to manage ALT/AST elevations. 
 
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 > 3X ULN. 
Repeat testing every 72 to 96 hours until transaminase levels are below 3X the ULN for at least one 
week.  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 by a home health nurse using a central lab kit, or at a 
local lab and sent to the investigator and medical monitor for review.   
 
Discontinue study drug administration temporarily and contact the medical monitor to discuss 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 study drug may be restarted with the Sponsor’s approval after the following criteria are fulfilled: 
• 
Ultrasound of the hepatobiliary tree; 
• 
ALT and AST returned to < ULN; 
• 
TBL is within normal range; 
• 
Other relevant labs (e.g., albumin, INR, PT) are within normal range; 
Updated to clarify that 
version 2 of the 
protocol was only 
performed in the US. 
 
Updated information 
into a table format for 
clarity and 
understanding. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Reata Pharmaceuticals, Inc. 
Amendment to Version 6.0 – Study Protocol 402-C-1808 
 
 
 
 
Page 27 of 50 
 
Version 6.0 
 
Reata Confidential 
No clinical signs or symptoms of liver injury are present. If a patient’s transaminases are elevated, follow 
the instructions outlined in Table 5. 
 
Table 5: Management of Elevated Transaminase Levels (ALT and/or AST) 
 
ALT and/or AST Level(s) 
Dose 
Interruption 
(yes/no) 
Procedure 
> 8x ULN 
Yes 
 Discontinue study drug temporarily  
 Contact the Medical Monitor  
The study drug may be restarted with Sponsor 
approval after all the following criteria are met:  
• Ultrasound or MRI of the hepatobiliary tree*; 
• ALT and AST returned to ≤ ULN; 
• TBL is within normal range; 
• Other relevant labs (e.g., albumin, INR, PT) 
are within normal range; 
• No clinical signs or symptoms of liver injury 
are present. 
*Based on imaging results, if additional 
tests/studies are warranted, this should be 
discussed with the Medical Monitor.  
> 5x ULN for more than 2 weeks 
> 3x ULN with the appearance of 
fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia 
> 3x ULN and 
(TBL > 2X ULN or INR > 1.5) 
> 3x ULN 
No 
 Check transaminase levels (as well as TBL, 
GGT, alkaline phosphatase (ALP), and 
International Normalized Ratio (INR)) 
within 48 to 72 hours 
Continue testing for ALT/AST every 72 to 96 
hours until transaminase levels are below 3X 
the ULN for at least one week 
 
Patients restarting study drug should start at the 5 mg dose level and dose titrate according to  
Section 7.3.23. 
 
Language was modified 
to align with clinical 
practices in the study. 
















































Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
Version 5.0 
Page 1 of 26 
Confidential 
AMENDMENT CHANGE DOCUMENT 
CLINICAL STUDY PROTOCOL 402-C-1808 
Study Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal Dominant 
Polycystic Kidney Disease 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc. Any unauthorized use 
or disclosure of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 
Protocol History 
Version 01 
Version 02 
Version 03 
Version 04 
12 December 2018 
4 March 2019 
16 July 2019 
25 June 2020 
Version 05 
25 February 2021 


Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
 
 
Version 5.0 
Page 2 of 26 
Confidential 
 
SUMMARY OF CHANGES 
 
The following document outlines the changes that have been made to Version 4 to produce the text of Version 5. Additionally, the 
following points are provided: 
• 
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not 
described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the new version of the protocol. 
























Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
 
 
 
Version 5.0 
Page 14 of 26 
Confidential 
 
Section 9.1.2 
Management 
of Elevated 
Transaminase 
Levels (ALT 
and/or AST) 
Repeat testing every 72 to 96 hours until transaminase levels are below 3X the ULN 
for at least one week.  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 by a 
home health nurse using a central lab kit, or at a local lab and sent to the investigator 
and medical monitor for review (by approval from the medical monitor). 
Discontinue study drug administration temporarily and contact the medical monitor to discuss 
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 study drug may be restarted with the Sponsor’s approval after the following criteria are 
fulfilled: 
• 
Ultrasound of the hepatobiliary tree; 
• 
ALT and AST returned to < ULN; 
• 
TBL is within normal range; 
• 
Other relevant labs (e.g., albumin, INR, PT) are within normal range; 
• 
No clinical signs or symptoms of liver injury are present. 
Patients restarting study drug should start at the 5 mg dose level and dose titrate according to 
Section 7.3.2. 
The hepatobiliary tree must be visualized (e.g., ultrasound, magnetic resonance 
imaging [MRI]) and assessed if a patient meeting above discontinuation criteria 
discontinues taking study drug secondary to elevated transaminase levels.  Additional 
tests/studies may be warranted depending on the clinical presentation 
Updated information 
and clarification for 
discontinuation of 
study drug due to 
transaminase 
elevation 


























Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
 
 
 
 
Version 04 
Page 1 of 24 
Confidential 
 
 
AMENDMENT CHANGE DOCUMENT 
CLINICAL STUDY PROTOCOL 402-C-1808 
Study Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal Dominant Polycystic Kidney 
Disease 
 
Protocol History 
Version 01 
Version 02 
Version 03 
Version 04 
12 December 2018 
4 March 2019 
16 July 2019 
25 June 2020 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc.  Any unauthorized use or disclosure 
of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 
 


Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
Version 04 
Page 2 of 24 
Confidential 
SUMMARY OF CHANGES 
The following document outlines the changes that have been made to Version 3 to produce the text of Version 4.  Additionally, the following 
points are provided: 
•
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough.
•
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not
described.
•
Grammatical corrections and minor editorial changes are not described.
•
Section numbers refer to the numbers in the new version of the protocol.








































Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
 
 
 
 
Version 04 
Page 22 of 24 
Confidential 
 
Section 12.1 
Sample Size 
With 300 patients enrolled, the study will have approximately 80% power to detect a difference 
between the two treatment groups in change from baseline in eGFR of 3.12.2 mL/min/1.73 m2 at 
Week 48.  The power calculation, which was based on mixed model repeated measures (MMRM)a 
2-sample t-test as an estimate for the planned ANCOVA analysis, and assumes the following: 
• 
9 repeated measurements (Weeks 1, 2, 4, 6, 8, 12, 24, 36, and 48);  
• 
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 are based on the intent to treat (ITT) population; 
• 
No imputation for missing data since all patients are included in MMRM 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. 
Analysis of covariance (ANCOVA) will be used for analysis of the off treatment endpoints 
(i.e., Week 52 and Week 104).  Using a two sample t test to estimate power for the ANCOVA 
analysis, the study will have approximately 80% power to detect a difference between the two 
treatment groups in change from baseline in eGFR of 2.6 mL/min/1.73 m2.  The power calculation 
assumes the following: 
• 
Overall two-sided Type I error rate total of 0.05; 0.025 allocated to primary endpoint 
and 0.025 allocated to the key secondary endpoint; 
• 
Two-sided Type I error rate of 0.05; 
• 
Proportion of patients with missing off-treatment data not to exceed 15%; 
• 
Standard deviation of change from baseline in eGFR of 8 mL/min/1.73 m2;  
• 
Analyses are based on the intent-to-treat (ITT) population; 
• 
Missing data are not imputed (sensitivity analyses, including a tipping point analysis, 
will be performed to assess the impact of missing data).using multiple imputation; 
Removed the 
power calculation 
for on-treatment 
endpoints.  The 
study has 
approximately 
80% power to 
detect an off-
treatment 
difference 
between the 
treatment groups 
of 3.1, which 
allows for up to 
15% of patients 
with missing off-
treatment data.  
The power 
calculation 
assumes that the 
overall two-sided 
Type I error rate is 
split between the 
primary and key 
secondary 
endpoint and that 
missing data is not 
imputed. 






Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
_____ 
Version 03 
Page 1 of 9 
Confidential 
AMENDMENT CHANGE DOCUMENT 
CLINICAL STUDY PROTOCOL 402-C-1808 
Study Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal Dominant Polycystic Kidney 
Disease 
Protocol History 
Version 01 
Version 02 
Version 03 
12 December 2018 
4 March 2019 
16 July 2019 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc.  Any unauthorized use or disclosure 
of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 


 
 
 
Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
 
_____ 
 
 
Version 03 
Page 2 of 9 
Confidential 
 
SUMMARY OF CHANGES 
 
The following document outlines the changes that have been made to Version 2 to produce the text of Version 3.  Additionally, the following 
points are provided: 
 
• 
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not 
described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the new version of the protocol. 
 
 
















 
 
 
Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
 
 
 
 
Version 02 
Page 1 of 13 
Confidential 
 
 
AMENDMENT CHANGE DOCUMENT 
CLINICAL STUDY PROTOCOL 402-C-1808 
Study Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal Dominant Polycystic Kidney 
Disease 
 
Protocol History 
Version 01 
Version 02 
12 December 2018 
4 March 2019 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary property of Reata Pharmaceuticals, Inc.  Any unauthorized use or disclosure 
of such information without the prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 
 


 
 
 
Reata Pharmaceuticals, Inc. 
Amendment – Study Protocol 402-C-1808 
 
 
 
 
Version 02 
Page 2 of 13 
Confidential 
 
SUMMARY OF CHANGES 
 
The following document outlines the changes that have been made to Version 1 to produce the text of Version 2.  Additionally, the following 
points are provided: 
 
• 
New text that is added is marked with an underscore; text that has been deleted is marked with a strikethrough. 
• 
The changes made in the body of the protocol are reflected in the synopsis; the corresponding changes made in the synopsis are not 
described. 
• 
Grammatical corrections and minor editorial changes are not described. 
• 
Section numbers refer to the numbers in the new version of the protocol. 
 
 























SAP_003.pdf: 
COVER PAGE 
Official Title: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in 
Patients with Autosomal Dominant Polycystic Kidney Disease  
NCT Number:  NCT03918447 
Document Date: 27 Jul 2023 


Reata Pharmaceuticals, Inc. 
 
402-C-1808 
Statistical Analysis Plan v3.0 
 
27 Jul 2023 
 
1 
STATISTICAL ANALYSIS PLAN 
 
VERSION 3.0 
DATE OF PLAN: 
27 JUL 2023 
 
 
BASED ON: 
Protocol Version 7.0 (25 May 2022) 
 
STUDY DRUG: 
RTA 402, BARDOXOLONE METHYL 
PROTOCOL NUMBER: 
402-C-1808 
STUDY TITLE: 
A PHASE 3 TRIAL OF THE EFFICACY AND SAFETY OF BARDOXOLONE METHYL IN 
PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE  
 
SPONSOR: 
Reata Pharmaceuticals, Inc. 
5320 Legacy Drive 
Plano, Texas 75024  
 (972) 865-2219 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
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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SIGNATURE PAGE 
 
This document has been prepared by: 
 
, M.S. 
 
{See Appended Electronic Signature 
Page} 
 
 
Reata Pharmaceuticals, Inc. 
 
Signature 
 
Date 
 
This document has been reviewed and accepted by: 
 M.S. 
 
{See Appended Electronic Signature 
Page} 
 
 
Reata Pharmaceuticals, Inc. 
 
Signature 
 
Date 
 M.D. 
 
{See Appended Electronic Signature 
Page} 
 
 
Reata Pharmaceuticals, Inc. 
 
Signature 
 
Date 
 
 PharmD 
 
{See Appended Electronic Signature 
Page} 
 
 
Reata Pharmaceuticals, Inc. 
 
 
Signature 
 
Date 


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TECHNICAL SUMMARY REPORT (TSR) 
 
Name of Sponsor/Company 
Reata Pharmaceuticals 
Individual Study Table Referring 
to Part of the Dossier: 
Volume: 
(For National Authority Use 
Only): 
Name of Finished Product: 
Bardoxolone methyl  
Page: 
 
Name of Active Ingredient: 
Bardoxolone methyl 
 
 
Title of Study: A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal 
Dominant Polycystic Kidney Disease 
Studied period: ~6 years  
(Estimated based on enrollment of 
the first patient [May 2019] and the 
estimated date of last patient last 
visit [November 2025]) 
 
Phase of development: 3 


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Study Endpoints: 
 
Primary Efficacy Endpoint 
• 
Off-treatment change from baseline in estimated glomerular filtration rate (eGFR) at Week 108.  
Secondary Efficacy Endpoint 
• 
Change from baseline in eGFR at Week 100. 
 
• 
  
• 
The off-treatment change from baseline in eGFR at Week 112. 
• 
 
  
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
 
− 
 
− 
− 
 
− 
 
• 
 
 
− 
 
− 
− 
 
− 
 


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• 
 
 
− 
 
− 
− 
 
− 
 
• 
 
 
− 
 
− 
− 
 
− 
 
Safety Endpoints 
• 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse 
events (SAEs) and change from baseline in the following assessments: vital sign measurements, 
12-lead electrocardiograms (ECGs), clinical laboratory measurements, pediatric growth (height and 
weight), and sexual maturity using Tanner staging. 
 


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Methodology: 
This international, multi-center randomized, double-blind, placebo-controlled Phase 3 trial will study the safety, 
tolerability, and efficacy of bardoxolone methyl in qualified patients with ADPKD.  Approximately 850 patients 
will be enrolled. 
Patients will be randomized 1:1 to either bardoxolone methyl or placebo. Randomization will be stratified by 
eligibility eGFR category (30 to <60; ≥60 to 90), concomitant tolvaptan use (yes, no), and screening albumin to 
creatinine ratio (ACR; ≤300 mg/g, >300 mg/g).  Patients randomized to placebo will remain on placebo 
throughout the study, undergoing sham titration.  Patients with eGFR 60 to 90 mL/min/1.73 m2 at screening 
should not comprise more than approximately 40% of enrolled patients. 
The maximum bardoxolone methyl dose will be determined by baseline proteinuria status.  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 assessed during treatment in person at Week 1, 2, 4, 6, 8, 12, 24, 36, 48, 52, 64, 76, 88, and 100 
and by telephone contact on Day 3, 10, 21, 31, 38, and 45.  Patients will continue study drug treatment through 
Week 100.  Patients will also be scheduled to be assessed at an in-person follow-up visit at Weeks 103, 104, 108, 
and 112 after the end of treatment, respectively.  
Efficacy endpoints will be analyzed after final database lock.   
The conduct of the study, according to protocol specifications, was impacted by the COVID-19 (Coronavirus 
Disease 2019) pandemic.  As a result, and as of Version 4 of the protocol, modifications intended to address 
access to and administration of study drug, and adherence to protocol-specified visits and laboratory assessments 
were implemented. These modifications are described in Appendix 1 of the protocol (COVID-19 Mitigations), 
Appendix 2 of the protocol (Use of Home Healthcare), and throughout the protocol. 
Number of Subjects (planned and analyzed): 
Planned: Approximately 850 


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Diagnosis and main criteria for inclusion: 
1. Male and female patients 12≤age≤70 upon study consent; 
2. Diagnosis of ADPKD: 
a. 
For adult (18≤age≤70) diagnosis of ADPKD by modified Pei-Ravine criteria:  
i. at least 3 cysts per kidney by sonography or at least 5 cysts by CT or MRI with family 
history of ADPKD; or  
ii. at least 10 cysts per kidney by any radiologic method and exclusion of other cystic 
kidney diseases if without family history;  
b. For adolescent (12≤age<18) diagnosis of ADPKD by:  
i. the presence of family history and/or genetic diagnosis and the presence of at least 
1 cyst of 0.5 cm on ultrasound or MRI; or 
ii. patients without a family history or genetic diagnosis must have at least 10 bilateral 
renal cysts in total, and exclusion of other cystic kidney diseases. 
3. eGFR must: 
a. 
Have a percent difference ≤25% at screening (the values at Screen A and Screen B) and; 
b. Have an average (the values at Screen A and Screen B) ≥30 to ≤90 mL/min/1.73 m2 for patients 
12 to 55 years or ≥30 to ≤44 mL/min/1.73 m2 for patients 56 to 70 years and; 
c. 
Support ADPKD disease progression (i.e., average yearly eGFR decline of 
≥2.0 mL/min/1.73 m2 for the past 2 years) for patients with either screening eGFR ≥60 to 
≤90 mL/min/1.73 m2 or age 56 to 70 years;  
4. ACR ≤2500 mg/g at Screen B visit; 
5. Systolic blood pressure ≤140 mmHg and diastolic blood pressure ≤90 mmHg at Screen A or Screen B 
visit after a period of rest. Patients receiving an angiotensin-converting enzyme (ACE) inhibitor and/or 
an angiotensin II receptor blocker (ARB) must be on a stable dose for at least 6 weeks prior to the 
Screen A visit;  
6. Adequate bone marrow reserve and organ function at the Screen A visit as follows: 
a. 
Hematologic: Absolute neutrophil count >1.5× 10
9/L, platelets >100× 10
9/L, hemoglobin 
(Hgb) ≥9 g/dL; 
b. Hepatic: Total bilirubin (TBL), alanine aminotransferase (ALT), and aspartate aminotransferase 
(AST) ≤ the upper limit of normal (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/assent document indicating that the patient 
has been informed of all pertinent aspects of the study prior to initiation of any protocol-mandated 
procedures.  
10. Patients receiving an sodium glucose co-transporter 2 inhibitor must be on a stable dose for at least 
4 weeks prior to the Screen A visit 
Major exclusion criteria: 
1. Prior exposure to bardoxolone methyl; 
2. Use of tolvaptan within 2 months prior to Screen A.  Initiation of concomitant tolvaptan use during the 
study is not permitted; 
3. History of administration of polycystic kidney disease-modifying agents (somatostatin analogues) within 
2 months prior to the Screen A visit;   
4. B-type natriuretic peptide (BNP) level >200 pg/mL at Screen A visit; 


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5. Uncontrolled diabetes (HbA1c >11.0%) at Screen A visit; 
6. Serum albumin <3 g/dL at Screen A visit; 
7. History of intracranial aneurysms;  
8. Kidney or any other solid organ transplant recipient or a planned transplant during the study; 
9. Acute dialysis or acute kidney injury within 12 weeks prior to Screen A visit or during Screening; 
10. 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 III or IV; 
h. 
History of untreated atrial fibrillation; 
i. 
History of unstable arrhythmias; 
11. Systolic BP <90 mm Hg at Screen A visit after a period of rest; 
12. BMI <18.5 kg/m2 at the Screen A visit; 
13. History of malignancy within 5 years prior to Screen A visit, with the exception of localized skin or 
cervical carcinomas; 
14. Systemic immunosuppression for more than 2 weeks, cumulatively, within the 12 weeks prior to 
randomization or anticipated need for immunosuppression during the study; 
15. Untreated or uncontrolled active bacterial, fungal, or viral infection; 
16. Participation in other interventional clinical studies within 30 days prior to Day 1; 
17. 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;  
18. Women who are pregnant or breastfeeding; 
19. Known hypersensitivity to any component of the study drug;  
20. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at risk by 
trial enrollment; 
21. 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; 
22. Coronavirus disease 2019 (COVID-19) pneumonia, related acute kidney injury, or 
related hospitalization within 6 months prior to Day 1. 
Test product, dose and mode of administration: 
Bardoxolone methyl will be administered orally at 5, 10, 20, or 30 mg once daily (QD). 
Duration of treatment:  
Bardoxolone methyl or placebo will be administered through Week 100. 
Reference therapy, dose and mode of administration: 
Placebo will be administered orally through Week 100, QD.   


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Criteria for evaluation (see protocol section 6.2, 11.0): 
Efficacy: Change from baseline in eGFR; 
 
Safety: Results of laboratory results (clinical chemistry, hematology, urinalysis, and microscopy), vital sign 
measurements, ECG results, pediatric growth (height and weight), 
, AEs, and SAEs.   
Statistical methods: 
With 850 patients enrolled, the study will have approximately 80% power to detect a difference between the 
2 treatment groups in change from baseline eGFR of 2.3 mL/min/1.73 m2.  The power calculation was based on a 
2-sample t-test as an estimate for the planned analysis of covariance (ANCOVA) analysis and assumes the 
following: 
• 
Overall two-sided Type I error rate total of 0.05;  
• 
Standard deviation of change from baseline in eGFR of 12 mL/min/1.73 m2;  
• 
Analyses are based on the intent-to-treat (ITT) population; 
• 
Missing data will be imputed using multiple imputation. 
 
 


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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
TECHNICAL SUMMARY REPORT (TSR) ..................................................................................3 
1. 
LIST OF ABBREVIATIONS.....................................................................................16 
2. 
INTRODUCTION ......................................................................................................18 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................20 
3.1. 
Study Objectives .........................................................................................................20 
3.1.1. 
Primary Objectives .....................................................................................................20 
3.1.2. 
Secondary Objective ...................................................................................................20 
 
20 
3.2. 
Study Endpoints ..........................................................................................................21 
3.2.1. 
Primary Efficacy Endpoint .........................................................................................21 
3.2.2. 
Secondary Efficacy Endpoint .....................................................................................21 
 
21 
3.2.4. 
Safety Endpoints .........................................................................................................23 
4. 
STUDY DESIGN .......................................................................................................24 
4.1. 
Summary of Study Design ..........................................................................................24 
4.2. 
Definition of Study Drugs ..........................................................................................25 
4.3. 
Sample Size Considerations .......................................................................................25 
4.3.1. 
Primary Endpoints ......................................................................................................25 
4.4. 
Randomization ............................................................................................................25 
4.5. 
Clinical Assessments ..................................................................................................26 
5. 
PLANNED ANALYSES ............................................................................................31 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................32 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........32 
6.2. 
Data Presentation Conventions ...................................................................................32 
6.3. 
Analysis Populations ..................................................................................................33 
6.4. 
Baseline Definitions ....................................................................................................33 
6.4.1. 
Age ..............................................................................................................................33 
6.4.2. 
Estimated Glomerular Filtration Rate .........................................................................33 
6.4.3. 
Serum Creatinine ........................................................................................................34 


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6.4.4. 
Safety Assessments .....................................................................................................34 
6.4.5. 
Urine Albumin to Creatinine Ratio .............................................................................34 
6.4.6. 
Natural log (ACR)/eGFR ............................................................................................34 
6.5. 
Derived and Transformed Data ..................................................................................34 
6.5.1. 
Study Day ...................................................................................................................34 
6.5.2. 
Visit Windows ............................................................................................................35 
6.5.2.1. 
Off-Treatment Visit Windows Relative to Last Dose for Safety ...............................37 
6.5.3. 
Laboratory Evaluations Imputations ...........................................................................37 
6.5.4. 
eGFR ...........................................................................................................................38 
6.5.4.1. 
Prognosis of CKD by eGFR and Albuminuria Category ...........................................38 
6.5.5. 
Urine Albumin to Creatinine Ratio (ACR) .................................................................40 
6.5.5.1. 
Baseline Urine Albumin to Creatinine Ratio (ACR) Categorical Status ....................40 
6.5.5.2. 
eGFR Category used in Stratification (eGFR_STRAT) .............................................40 
6.5.5.3. 
ACR Category used in Stratification (ACR_STRAT) ................................................41 
6.5.6. 
Electrocardiogram Fridericia Corrected QT Interval .................................................41 
6.5.7. 
ACR adjusted for eGFR ..............................................................................................41 
6.6. 
Handling of Missing Data ...........................................................................................41 
6.6.1. 
Missing Efficacy Endpoint Data .................................................................................41 
6.6.2. 
Missing Start and Stop Dates for Concomitant Medications ......................................41 
6.6.3. 
Missing Start and Stop Dates for Adverse Events ......................................................41 
6.6.4. 
Missing End of Treatment Date ..................................................................................42 
7. 
STUDY POPULATION .............................................................................................43 
7.1. 
Subject Disposition .....................................................................................................43 
7.2. 
Protocol Deviations ....................................................................................................44 
7.3. 
Demographic and Baseline Characteristics ................................................................44 
7.4. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................45 
7.5. 
Medical History ..........................................................................................................45 
7.5.1. 
Historical eGFR ..........................................................................................................45 
8. 
EFFICACY .................................................................................................................47 
8.1. 
General Considerations ...............................................................................................47 
8.2. 
Statement of the Null and Alternate Hypotheses ........................................................48 
8.3. 
Multiple Comparisons and Multiplicity......................................................................48 


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8.4. 
Primary Endpoint ........................................................................................................48 
8.4.1. 
Primary Endpoint Analysis .........................................................................................48 
8.5. 
Secondary Efficacy Endpoint .....................................................................................49 
8.5.1. 
Secondary Efficacy Endpoint Analyses ......................................................................49 
 
50 
 
50 
 
50 
8.6.1.2. 
Off Treatment eGFR ANCOVA Analyses – No Imputation for Missing Data .........50 
 
50 
 
51 
 
51 
 
52 
 
52 
 
52 
9. 
SAFETY AND TOLERABILITY ..............................................................................54 
9.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............54 
9.1.1. 
Missing and Partial Adverse Event Onset Dates ........................................................55 
9.1.2. 
Summaries of Adverse Events ....................................................................................55 
9.2. 
Exposure and Compliance ..........................................................................................56 
9.3. 
Concomitant Medications ...........................................................................................57 
9.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........57 
9.4. 
Prior and Concomitant Procedures and Surgeries ......................................................58 
9.5. 
Clinical Laboratory Evaluations .................................................................................58 
9.5.1. 
Continuous Summaries of Laboratory Results ...........................................................58 
9.5.1.1. 
Natural log (ACR)/eGFR ............................................................................................58 
9.5.2. 
Categorical Summaries of Laboratory Results ...........................................................58 
9.5.2.1. 
Transaminases .............................................................................................................59 
 
60 
9.7. 
Vital Signs ..................................................................................................................60 
9.8. 
24-hr ABPM Sub-study ..............................................................................................61 
9.9. 
Electrocardiogram .......................................................................................................62 
9.10. 
Pregnancy ...................................................................................................................62 


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10. 
PHARMACOKINETICS ...........................................................................................63 
11. 
COVID-19 IMPACT ..................................................................................................64 
11.1. 
Operational Impact .....................................................................................................64 
11.2. 
Impact on Efficacy ......................................................................................................65 
11.3. 
Impact on Safety .........................................................................................................65 
12. 
REFERENCES ...........................................................................................................66 
 


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LIST OF TABLES 
Table 1.  
LIST OF ABBREVIATIONS.....................................................................................16 
Table 2. 
SCHEDULE OF ASSESSMENTS.............................................................................27 
Table 3: 
ANALYSIS POPULATION DEFINITION ...............................................................33 
Table 4. 
ANALYSIS VISIT WINDOWS .................................................................................36 
Table 5: 
ANALYSIS VISITS FOR OFF-TREATMENT SAFETY FOLLOWING 
EARLY TREATMENT DISCONTINUATION ........................................................37 
Table 6.   
CKD STAGE ..............................................................................................................39 
Table 7.   
ALBUMINURIA CATEGORY .................................................................................40 
Table 8:   LABELS FOR SUMMARY OF HISTORICAL CHANGE IN eGFR ......................46 
Table 9.   
MODEL PARAMETER ABBREVIATIONS ............................................................47 
Table 10: PRE-SPECIFIED THRESHOLD LEVELS FOR TRANSAMINASES ....................59 
Table 11: 24-HOUR ABPM PARAMETERS ............................................................................62 
Table 12: PRE-SPECIFIED THRESHOLD LEVELS FOR ECG PARAMETERS ..................62 


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LIST OF FIGURES 
Figure 1.  STUDY SCHEMA ........................................................................................................25 
Figure 2:  PROGNOSIS OF CKD BY eGFR AND ALBUMINURIA CATEGORIES ...............39 
 
 


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1. 
LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this statistical analysis plan (SAP). 
Table 1.  
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ABPM 
ambulatory blood pressure monitoring 
ACEi 
angiotensin converting enzyme inhibitor 
ACR 
albumin/creatinine ratio 
ACR_STRAT 
ACR strata used in randomization 
ADPKD 
autosomal dominant polycystic kidney disease  
 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
ARB 
angiotensin II receptor blocker 
AST 
aspartate aminotransferase 
BARD 
bardoxolone methyl 
BMI 
body mass index 
BNP 
B-type natriuretic peptide 
 
 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CSR 
clinical study report 
CT 
computed tomography 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
eGFR_STRAT 
eGFR strata used in randomization 
ESKD 
end stage kidney disease 
FDA 
Food and Drug Administration (US) 
FMV 
first morning void 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 


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Abbreviation 
Term 
INR 
international normalized ratio 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
KDIGO 
Kidney Disease: Improving Global Outcomes 
LLD 
lower limit of detection 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
MRI 
magnetic resonance imaging 
NCS 
Not clinically significant 
NT-ProBNP 
N-Terminal Pro-Brain Natriuretic Peptide   
OTAE 
off-treatment adverse event 
 
 
pH 
potential of hydrogen 
PK 
pharmacokinetic(s) 
PT 
preferred term 
QTcF 
corrected QT interval using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCr 
serum creatinine 
SD 
standard deviation 
SOC 
system organ class 
STD 
Study Termination Date 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
ULD 
upper limit of detection 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
women of childbearing potential 


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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 Study 402-C-1808. This SAP was developed in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) E9 guidelines. All decisions regarding the final analysis, 
as defined in this SAP document, were made prior to Database Lock (unblinding) of the study 
data.   
The SAP is based on:  
• Protocol 402-C-1808, Version 7.0, dated 25 May 2022 
• ICH guidelines E4 (Dose-Response Information to Support Drug Registration) and 
E9 (Statistical Principles for Clinical Trials)  
• Feedback received from FDA throughout clinical development, including the 
following communications: 
− FDA End of Phase 2 Meeting Minutes 
 for the 31 October 2018 
meeting 
− FDA Advice/Information Request 
 dated 16 July 2019 
− FDA Advice/Information Request 
 dated 08 October 2020  
− FDA Type B Meeting Minutes 
 for the 23 July 2021 meeting 
− FDA Type A Meeting Minutes 
 for the 08 April 2022 meeting 
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 Study 402-C-1808.  Should the SAP and the protocol be inconsistent with 
respect to the planned analyses, the language of the SAP is governing.   
This version of the SAP describes the analyses as planned prior to the final database lock.  This 
SAP will be finalized, approved by the Reata Pharmaceuticals, and placed on file before the 
database lock.  Unless otherwise specified, the final CSR will summarize these analyses.  Any 
deviations from the final approved SAP will be documented in the CSR.  Any analyses in 
addition to those specified in the SAP prior to the database lock are considered ad hoc and will 
be documented in the CSR.   
In May 2023, Kyowa Kirin Co., Ltd. (Kyowa Kirin) announced results from AYAME (402-006), 
a Phase 3, multi-center, randomized, double-blind, placebo-controlled trial to evaluate the 
efficacy and safety of bardoxolone methyl (bardoxolone) for patients with diabetic kidney 
disease. The study enrolled 1013 patients who were treated with 5 to 15 mg of bardoxolone or 
placebo for 3 to 4 years. 
The AYAME (402-006) study met the primary endpoint and key secondary endpoint; however, 
there was no separation in the occurrence of end-stage renal disease events between the 2 groups. 
Based on the AYAME (402-006) efficacy results, Kyowa Kirin and Reata have decided to 
discontinue clinical development of bardoxolone. 


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This decision was communicated to all sites on 10 May 2023, which is referred to as the study 
drug termination (SDT) date.  
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objectives 
• To assess the off-treatment change from baseline in estimated glomerular filtration 
rate (eGFR) at Week 108. 
• To assess safety and tolerability. 
3.1.2. 
Secondary Objective 
• To assess the change from baseline in eGFR at Week 100. 
 
   
• 
 
• To assess the off-treatment change from baseline in eGFR at Week 112. 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
 
• 
 
 
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• 
 
 
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• 
 
 
− 
  
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− 
 
3.2. 
Study Endpoints 
In patients with autosomal dominant polycystic kidney disease (ADPKD), 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.  Primary efficacy 
analyses are described in Section 8 
 
 
3.2.1. 
Primary Efficacy Endpoint  
• Off-treatment change from baseline in eGFR at Week 108. 
3.2.2. 
Secondary Efficacy Endpoint 
• Change from baseline in eGFR at Week 100.   
 
 
• 
 
• The off-treatment change from baseline in eGFR at Week 112. 
• 
 
  
• 
 
 
• 
 
   


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− 
  
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• 
 
 
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• 
 
 
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• 
 
 
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− 
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3.2.4. 
Safety Endpoints 
• Frequency, intensity, and relationship to study drug of adverse events (AEs) and 
serious adverse events (SAEs) and change from baseline in the following 
assessments: vital sign measurements, 12-lead electrocardiograms (ECGs), clinical 
laboratory measurements, pediatric growth (height and weight), and sexual maturity 
using Tanner staging. 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This international, multi-center, randomized, double-blind, placebo-controlled Phase 3 trial will 
study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with 
ADPKD.  Approximately 850 patients will be enrolled. 
Patients will be randomized 1:1 to either bardoxolone methyl or placebo.  Randomization will be 
stratified by eligibility eGFR category (30 to <60; ≥60 to 90), concomitant tolvaptan use (yes, 
no), and screening albumin to creatinine ratio (ACR; ≤300 mg/g, >300 mg/g).  Patients 
randomized to placebo will remain on placebo throughout the study, undergoing sham titration. 
Patients with eGFR 60 to 90 mL/min/1.73 m2 at screening should not comprise more than 
approximately 40% of enrolled patients. 
The maximum bardoxolone methyl dose will be determined by baseline proteinuria status.  
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 Week 1, 2, 
4, 6, 8, 12, 24, 36, 48, 52, 64, 76, 88, and 100 and by telephone contact on Day 3, 10, 21, 31, 38, 
and 45.  Patients will continue study drug treatment through Week 100.  Patients will also be 
scheduled to be assessed at an in-person follow-up visit at Weeks 103, 104, 108, and 112, after 
the end of treatment, respectively.  The Data Monitoring Committee performs quarterly reviews 
of unblinded data for safety throughout the study. 
Efficacy endpoints will be analyzed after all enrolled patients have completed the study and the 
final database lock.  
The conduct of the study, according to protocol specifications, was impacted by the COVID-19 
(Coronavirus Disease 2019) pandemic.  As a result, modifications intended to address access to 
and administration of investigational product (IP), and adherence to protocol-specified visits and 
laboratory assessments were implemented and are described in Appendix 1 of the protocol 
(COVID-19 Mitigations), Appendix 2 of the protocol (Use of Home Healthcare), and throughout 
the protocol.  The COVID-19-related impact on study conduct will be summarized as described 
in Section 10 of this SAP. 
 


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Figure 1.  STUDY SCHEMA 
Schema for Study of Bardoxolone Methyl in Patients with ADPKD
 
4.2. 
Definition of Study Drugs 
Bardoxolone methyl capsules, 5 mg (size #4), 10 mg (size #2), 15 mg (size #1), and 20 mg 
(size #0) may be used in this study.  The 30 mg dose will be given as two 15 mg capsules.  
Placebo capsules will have matching capsule sizes to have the same appearance as the active 
doses.   
4.3. 
Sample Size Considerations 
4.3.1. 
Primary Endpoints 
With 850 patients enrolled, the study will have approximately 80% power to detect a difference 
between the 2 treatment groups in change from baseline eGFR of 2.3 mL/min/1.73 m2.  The 
power calculation was based on a 2-sample t-test as an estimate for the planned analysis of 
covariance (ANCOVA) analysis and assumes the following: 
• Overall two-sided Type I error rate total of 0.05;  
• Standard deviation of change from baseline in eGFR of 12 mL/min/1.73 m2;  
• Analyses are based on the intent-to-treat (ITT) population; 
• Missing data will be imputed using multiple imputation. 
PASS 13 software was used to calculate sample size. 
4.4. 
Randomization 
Patients will be randomized 1:1 to either bardoxolone methyl or placebo.  Randomization will be 
performed using an interactive web response system (IWRS) and will be stratified by eligibility 
eGFR category (30 to <60; ≥60 to 90 mL/min/1.73 m2), concomitant tolvaptan use (yes, no), and 
screening ACR (≤300 mg/g, >300 mg/g).  Eligibility eGFR is the average of the screening eGFR 
visits.  Patients randomized to placebo will remain on placebo throughout the study, undergoing 
sham titration. 


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4.5. 
Clinical Assessments 
All patients in the study follow the same visit and assessment schedule for the duration of the 
trial. Table 2 lists the overall schedule of assessments for the study.   
 








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, PK = pharmacokinetic, SARS-CoV-2 = Severe Acute Respiratory Syndrome Coronavirus 2, Wk = week, WOCBP = women of child-bearing 
potential
 
a Total Screening period should not exceed 90 days. 
b Screen B visit should be at least 1 day after Screen A and no more than 30 days prior to Day 1. 
c Day 1 should be the day of randomization and administration of the first dose.  Where randomization in the IWRS must occur earlier than Day 1, the Day 1 visit must align 
with the administration of the first dose.  On Day 1, all procedures must 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 
e Height will be recorded in centimeters.  Adult patients (18≤age≤70 years at Screen A visit) will be measured at Screen A only.  Adolescent patients (12≤age<18 years at 
Screen A visit) will be measured at all specified timepoints. 
f An echocardiogram performed during screening or within 6 months prior to Day 1 may be used to determine eligibility. 
g Screen B vital sign measurements are needed only if re-assessing blood pressure for eligibility. 
h 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. 
i AE assessments on Day 1 should be performed following study drug administration. 
j Kidney ultrasound (historical or one obtained during screening) may be used to diagnose ADPKD for patients without a prior ADPKD diagnosis. 
k  eGFR will be calculated and appear on lab reports for Screen A and Screen B visits, eGFR will no longer be calculated for any visits after the Screening period. 
l 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. 
 
 
n Patients must refrain from taking study drug prior to coming to the clinic for PK draws at Week 12 and Week 100. 
o Ambulatory Blood Pressure Monitoring (ABPM) is an optional sub-study for adult patients (18≤age≤70 years at Screen A) who enroll under protocol version 6.0 (or 
greater) and consent to the procedure prior to randomization. See Protocol Section 9.10.33 for details and timing on ABPM. ABPM will not be performed on adolescent 
patients (12≤age<18 years at randomization). 
p For patients who consent to the optional ABPM sub-study, the initial (baseline) 24-hour monitoring assessment must be done during the Screening period prior to Day 1.  
See Protocol Section 9.10.33 for detailed information.  
q Adolescent patients (12≤age<18 years at Screen A visit) will be assessed by Tanner staging at all specified timepoints. 
r For adult patients who consent to the optional ABPM sub-study, the final 24-hour monitoring assessment occurs after Week 88 and prior to Week 100 (last dose).  For 
patients who discontinue study drug prior to Week 100, patients who consented to ABPM should have the assessment at End of Treatment if no ABPM was conducted in the 
four weeks prior to the date of last dose. 
s See Protocol Section 8.3.3 and Protocol Section 8.5.1 for details on the Off-Treatment Period.    
t Unless permitted in the protocol, all study activities, including assessments and sample collection, are expected to be completed on the same day (i.e., day of the visit). 


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5. 
PLANNED ANALYSES 
The final analyses are based on final locked data and performed after all enrolled patients have 
completed the end of study visit. A separate database lock plan will describe details of the 
database lock. 
 


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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 treatment group, patient number and assessment date (time and 
parameter, as applicable).   
Any laboratory value (including eGFR), vital sign assessment, or ECG value collected after 
ESKD is considered invalid and will be treated as missing.   
Efficacy and safety data collected while a patient has temporarily discontinued study drug will be 
included in analyses.  All data will be presented in by-patient listings. 
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 family-wise overall 
Type I error rate of 0.05 is described in Section 8.3.  For endpoints not described in Section 8.4, 
the reported significance levels are nominal, and the following statistical conventions are used: 
• Unless otherwise noted, all statistical testing is two-sided and is performed at the 0.05 
significance level.  
• 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), standard error (SE), first quartile (Q1), 
median, third quartile (Q3), 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 are presented when reporting SD or SE.  
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, the percentages are based on the 
total number of patients in each treatment group. 


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6.3. 
Analysis Populations  
Table 3 lists the analysis populations in the study. 
Table 3: 
ANALYSIS POPULATION DEFINITION  
Analysis 
Population 
Definition 
ITT (Intent-to-
Treat) 
All enrolled patients categorized by their randomized treatment group (whether 
or not they received study drug).   
Safety  
All enrolled patients who received at least 1 dose of study drug. The safety 
population is used for evaluation of safety variables. Patients who received 
1 dose of bardoxolone methyl will be classified in the bardoxolone methyl group. 
Patients who received at least 1 dose of placebo and no dose of bardoxolone 
methyl will be classified in the placebo group. 
6.4. 
Baseline Definitions 
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. If the first study drug 
administration date is not present, the baseline values are the last non-missing assessment on or 
prior to the Day 1 visit date. 
When assessment time is not available, assessments that are 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. 
Age 
Baseline age is defined as the age at consent (Screen A). 
6.4.2. 
Estimated Glomerular Filtration Rate 
Baseline eGFR is defined as the average of Screening and Day 1 eGFR measurements, 
calculated as shown below:  
• Screening eGFR=average of the last 2 eGFR measurements collected prior to the 
Day 1 eGFR collection 
• Day 1 eGFR=the measurement after screening but on or before the date of first study 
drug administration  
• Baseline eGFR=(0.5×Day 1 eGFR)+(0.5×Screening eGFR)  
If there are only 2 observations available, then the average of the 2 values is used as baseline. 
Since patients must have Screen A and Screen B eGFR values within a percent difference ≤25% 
to be eligible for enrollment, the variability of Screening eGFR is mediated by the study 
inclusion/exclusion criteria.  Furthermore, the Screening eGFR value may be collected up to 


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3 months prior to study entry.  The Day 1 eGFR value carries greater weight in the baseline 
eGFR calculation to account for the reduced variability in the screening eGFR values. 
6.4.3. 
Serum Creatinine 
Baseline serum creatinine (SCr) is defined in the same way as baseline eGFR (Section 6.4.2).  
6.4.4. 
Safety Assessments 
Baseline for continuous safety assessments (i.e., vital sign assessments, weight, body mass index 
[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.    
6.4.5. 
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.  
6.4.6. 
Natural log (ACR)/eGFR 
Baseline of natural log (ACR)/eGFR is defined as the ratio of the natural log of baseline ACR 
(Section 6.4.5) divided by baseline eGFR (Section 6.4.2). 
6.5. 
Derived and Transformed Data 
6.5.1. 
Study Day 
Study day is the day relative to the date of first dose.  Day 1 is defined as the date of first dose.   
If date of first dose is not present, then date of randomization is used to calculate the study day. 
Assessments without timestamp 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 first dose, day is calculated as: 
• Study day=visit (or event) date-date of first dose+1 
For visits (or events) before first dose, day is calculated as: 
• Study day=visit (or event) date-date of first dose 
The quantity ‘days since first dose’ is defined as: 
• Days since first dose=visit (or event) date–date of first dose+1  
The quantity ‘days since last dose’ is defined as: 
• Days since last dose=visit (or event) date-date of last dose 
For summaries that present distribution of time expressed in weeks and months, weeks are 
defined as days divided by seven and months as days divided by 30.4. 


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6.5.2. 
Visit Windows 
Analysis visits and their windows are defined using derived study day (Section 6.5.1) 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 4 and Table 5.  They are included in analyses of safety and efficacy as 
follows: 
• Efficacy analyses for endpoints assessed through Week 100 use the analysis windows 
in Table 4, irrespective of whether or not a patient is receiving treatment of study 
drug.  
• Efficacy analyses for endpoints assessed during the follow-up period after Week 100 
use the analysis window in Table 4 irrespective of how long a patient has been off-
treatment. 
• Protocol version 6 eliminated the off-treatment period from Week 48 to Week 52.  
Patients completing the Week 52 visit prior to consenting to protocol version 6 will 
be considered “off-treatment” at Week 52.  All other patients are expected to be on-
treatment at Week 52.  Week 52 analysis values in Table 4 will not be used in the 
efficacy analyses unless otherwise specified.  Week 52 values are only summarized 
descriptively because of the mix of on-treatment and off-treatment values. 
• Safety analyses use the analysis windows defined in Table 4  so long as the patient is 
receiving treatment of study drug.  Once a patient permanently discontinues study 
treatment, safety data are summarized according to time since last dose as defined in 
Table 5. 
Unless otherwise specified 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 2 assessments are equidistant from a target, the earlier assessment is used. If 2 assessments are 
on the same day, the average of 2 assessments will be used for non-laboratory parameters. For 
laboratory parameters, if both an original and retest result are available in the laboratory dataset, 
the original result will be used and the second (i.e., “retested”) result will be ignored.  
One exception is that 2 scheduled chemistry values (including eGFR) are collected within the 
Week 52 (prior to protocol version 6), Week 104, Week 108, and Week 112 analysis windows.   
Protocol specified 2 off-treatment chemistry values collected within the Week 52 (prior to 
protocol version 6), Week 104, Week 108 and Week 112 analysis window at A and B visits.  At 
Week 52, Week 104, Week 108, and Week 112 visits, the 2 off-treatment measurements that are 
in the analysis window and closest to the target day specified in Table 4 are averaged for the 
purpose of data summary and analysis.  All values included in the Week 103, 104, 108, and 112 
analysis windows must also be assessed after last dose.  
Records from visits not closest to the target study day, and therefore not used in analyses, are 
presented in by-patient data listings. 


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Table 4. 
ANALYSIS VISIT WINDOWS  
 
Analysis 
Visit  
 
Label 
Target  
 
 
Analysis Window 
Study Daya 
Days After Last 
Dose 
1 
Week 1 
7 
- 
2≤study day≤10 
2 
Week 2 
14 
- 
11≤study day≤21 
4 
Week 4 
28 
- 
22≤study day≤35 
6 
Week 6 
42 
- 
36≤study day≤49 
8 
Week 8 
56 
- 
50≤study day≤70 
12 
Week 12 
84 
- 
71≤study day≤126 
24 
Week 24 
168 
- 
127≤study day≤210 
36 
Week 36 
252 
- 
211≤study day≤294 
48 
Week 48 
336 
- 
295≤study day≤350 
52 
Week 52 
364 
- 
351≤study day≤406 
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 100b 
700 
- 
659≤study day≤720 
103 
Week 103c 
721 
21 
721≤study day≤727d or  
21≤after last dose≤27e 
104 
Week 104c 
728 
28 
728≤study day≤755d or  
28≤after last dose<55e 
108 
Week 108c 
756 
56 
756≤study day≤783d or  
56≤after last dose≤83e 
112 
Week 112 c 
784 
84 
784≤study day≤806d or  
84≤after last dose<106e 
a Study Day is relative to the date of first dose (Section 6.5.1).   
b Week 100 is the end of the dosing interval and should coincide with the last dose. 
c Including off-treatment values only. 
d Analysis windows are based on study day for patients who discontinued treatment early. Analysis windows are 
based on days after last dose for patients who complete treatment. Last dose for analysis is the Week 100 dose.  
e Analysis windows are based on days after last dose for patients who complete treatment. Last dose for analysis is 
the Week 100 dose. 


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6.5.2.1. 
Off-Treatment Visit Windows Relative to Last Dose for Safety 
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 9.5), vital signs (Section 9.7), and electrocardiograms 
(Section 9.9) are those that occur after the last dose date for patients permanently discontinuing 
study drug prior to Week 100, and are summarized relative to their last dose of study drug.  Off-
treatment safety assessments (clinical labs, vital signs, and ECGs) are grouped for analyses 
according to the strategy in Table 5.  Assessments that occur on or before the date of last dose 
through 20 days after last dose are considered on-treatment period. 
Table 5: 
ANALYSIS VISITS FOR OFF-TREATMENT SAFETY FOLLOWING 
EARLY TREATMENT DISCONTINUATION  
Off-Treatment 
Safety Analysis 
Visit 
Label 
Target Study 
Day 
(days after last 
dose) 
Analysis Window 
0 
Last dose 
(on-treatment)a 
0 
0 
(days after last dose ≤20) 
4 
Off Treatment 
4-weeksb 
28 
21≤days after last dose≤35 
8 
Off Treatment 
8-weeksb 
56 
36≤days after last dose≤71 
12 
Off Treatment 
12-weeksb 
84 
72≤days after last dose≤99 
24 
Off Treatment 
24-weeksb 
168 
100≤days after last dose≤252 
48 
Off Treatment 
48-weeksb 
336 
253≤days after last dose≤350 
72 
Off Treatment 
72-weeksb 
504 
351≤days after last dose≤518 
96 
Off Treatment 
96-weeksb 
672 
519≤days after last dose≤686 
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 21 days after last dose are considered on treatment and summarized using Table 4 
 windows. 
b The off-treatment values indicate the value closest to the date of last dose and at least 21 days after last dose.  
6.5.3. 
Laboratory Evaluations Imputations 
Any laboratory assessments less than the lower limit of detection (i.e., < LLD) are imputed as 
LLD/2 (e.g., <25 is 25/2=12.5).  Laboratory assessments above the upper limit of detection 
(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.  


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6.5.4. 
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):  
• 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 Adolescents (≥12 and <18 years age old at consent) - the eGFR value will be calculated by 
using Bedside Schwartz equation: 
• eGFR (mL/min/1.73 m2)=(0.41 × Height in cm)/Scr  
where Scr is serum creatinine (mg/dL), κ is 0.7 for females or 0.9 for males, and α is -0.329 for 
females or -0.411 for males.  Min indicates the minimum of Scr/κ and 1, and max indicates the 
maximum of Scr/κ and 1.  Age and height indicates at time of serum creatinine collection as 
collected in the associated case report form (CRF).  
6.5.4.1. 
Prognosis of CKD by eGFR and Albuminuria Category 
Prognosis of chronic kidney disease (CKD) is determined by the intersection of the following 
eGFR and albuminuria categories (KDIGO, 2013):  


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Figure 2:  PROGNOSIS OF CKD BY eGFR AND ALBUMINURIA CATEGORIES  
 
The Prognosis of Kidney Disease: Improving Global Outcomes (KDIGO) CKD progression risk 
scores is summarized by cell and color (Green, Yellow, Orange and Red). 
 
Table 6.   
CKD STAGE 
CKDa Stage 
eGFRb (mL/min/1.73 m2) 
1 
≥90 
2 
60 to <90 
3a 
45 to <60 
3b 
30 to <45 
4 
15 to <30 
5 
<15 
a Chronic kidney disease 
b Estimated glomerular filtration rate 
 


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Table 7.   
ALBUMINURIA CATEGORY 
ACRa Category 
ACR (mg/g) 
1 (normo-albuminuria) 
<30 
2 (micro-albuminuria) 
30 to ≤300 
3 (macro-albuminuria) 
>300 
a Urine albumin to creatinine ratio 
6.5.5. 
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 not calculated 
in the central laboratory database when the FMV urine albumin result is < LLD.  Urine albumin 
results < LLD and the corresponding ACR missing values are imputed as follows: 
• If urine albumin result ≤LLD, then  
− Imputed urine albumin result (mg/dL)=LLD/2  
− Imputed ACR (mg/g)=(imputed urine albumin result in mg/dL)/[(urine creatinine 
in mg/dL)/1000] 
The ACR results are log-transformed for analysis to produce data that are more normally 
distributed.  Any imputed ACR result where ACR=0 is considered to be 0.1 mg/g for purposes of 
calculating the geometric mean. 
6.5.5.1. 
Baseline Urine Albumin to Creatinine Ratio (ACR) Categorical Status 
Baseline ACR status will be grouped by the following categories using baseline ACR (see 
Section 6.4.5): 
• ACR ≤300 mg/g 
• ACR >300 mg/g  
Baseline ACR accounts for screening and Day 1 values and may not match ACR used for 
stratification based on screening values only. 
6.5.5.2. 
eGFR Category used in Stratification (eGFR_STRAT) 
The eGFR category used for stratification (eGFR_STRAT) is determined by the randomization 
list with the following categories: 
• 30 mL/min/1.73 m2 <eGFR<60 mL/min/1.73 m2 
• 60 mL/min/1.73 m2 ≤eGFR≤90 mL/min/1.73 m2 


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6.5.5.3. 
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: 
• ACR ≤300 mg/g 
• ACR >300 mg/g  
6.5.6. 
Electrocardiogram Fridericia Corrected QT Interval 
Electrocardiogram intervals are assessed locally at each site.   
The following formula is used to calculate the Fridericia corrected QT interval (QTcF) for 
analysis from QT and RR intervals:  
• 𝑄𝑇𝑐𝐹=  𝑄𝑇/√𝑅𝑅
3
       where RR=60/(Heart Rate) 
6.5.7. 
ACR adjusted for eGFR 
To evaluate ACR after adjusting for filtration rate, ln (ACR)/eGFR (Sections 6.5.5 and 
Section 6.5.4) is assessed. 
6.6. 
Handling of Missing Data  
6.6.1. 
Missing Efficacy Endpoint Data 
Missing data will not be imputed for analyses of efficacy endpoints. 
6.6.2. 
Missing Start and Stop Dates for Concomitant Medications 
Missing start dates for concomitant medications are not imputed.   
Concomitant medications with incomplete end dates are considered concomitant medications if: 
• Day and month are missing, and the year is equal to or after the year of the first date 
of study drug administration;  
• Day is missing and the year is after the year of the first date of study drug 
administration;  
• Day is missing and the year is equal to the year of the first date of study drug 
administration and the month is equal to or after the month of the first date of study 
drug administration; or 
• Year is missing. 
6.6.3. 
Missing Start and Stop Dates for Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined in Section 9.1.   
Adverse events with incomplete start dates are considered after the date of first dose, if: 
• Day and month are missing and the year is equal to or after the year of the first date 
of study drug dosing;  


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


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7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
A disposition summary includes the number and percentage of patients in all analysis 
populations in the following categories:  
• ITT population  
• Safety population  
• Received at least 1 dose at or after Week 52 
• Completed treatment or follow-up through Week 52 
− Week 48 to Week 52 On-treatment 
− Week 48 to Week 52 Off-treatment 
• Discontinued treatment prior to Week 100 
− Reason for discontinuing treatment  
− Treatment discontinuation related to COVID-19  
• Completed study follow-up through Week 104 
− Completed treatment through Week 100 
− Discontinued treatment early but completed study visits 
− Discontinued treatment early but completed eGFR assessments through Week 104 
• Completed study follow-up through Week 108 
− Completed treatment through Week 100 
− Discontinued treatment early but completed study visits 
− Discontinued treatment early but completed eGFR assessments through Week 108 
• Completed study follow-up through Week 112 
− Completed treatment through Week 100 
− Discontinued treatment early but completed study visits 
− Discontinued treatment early but completed eGFR assessments through Week 112  
• Completed study follow-up through Study Termination Date (STD) 
− Completed treatment through Week 100 
− Discontinued treatment early but completed study visits 
− Discontinued treatment early but completed eGFR assessments through STD 
• Terminated from the trial before Week 112 
− Reason for study termination 


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− Study termination related to COVID-19 
− Study week at study termination  
− Terminated prior to STD  
− Terminated after STD 
• Number of patients by study visit 
− On treatment 
− Off treatment 
− In study follow-up 
− Stopped study 
Patients who completed follow-up are defined as those who were in the study through Week 112 
visit.  A listing of disposition is provided for all enrolled patients.   
7.2. 
Protocol Deviations 
All protocol deviations are listed, and the frequency of patients with protocol deviations and 
major protocol deviations are summarized by deviation type and treatment group.  
7.3. 
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 randomized dose level 
(20 mg, 30 mg, or placebo).   
The demographic and other baseline characteristics include:  
• Baseline Age, Baseline Age category (<18, ≥18) 
• Sex, Race, Ethnicity 
• Weight (kg), Height (cm), BMI (kg/m2) 
• Diastolic and systolic blood pressure (mmHg), Heart rate (bpm) 
• Serum creatinine, eGFR, eGFR categorical status (<60, ≥60), eGFR Stratum 
• ACR, ACR categorical status (≤300; >300), ACR Stratum 
• KDIGO CKD progression risk score: color (Green, Yellow, Orange, Red) and cell in 
Figure 2  
• CKD Stage (Table 6) 
• Angiotensin converting enzyme inhibitor (ACEi) treatment and/or Angiotensin II 
receptor blocker (ARB) (yes/no) 
• Other baseline variables of interest 


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ADPKD related information includes: 
• Age at ADPKD diagnosis 
• Family history of ADPKD 
• For patients with family history of ADPKD: 
− Sonography (indicating 3 or more cysts) for adult patients  
− Sonography (indicating 1 or more cyst) for adolescent patients 
− Computed tomography (CT) or magnetic resonance imaging (MRI) (indicating 
5 or more cysts)  
• For patients without family history of ADPKD: 
− Other cystic kidney diseases present 
− 10 or more cysts 
• Use of Tolvaptan 
− Currently using Tolvaptan 
− Previously used Tolvaptan  
− Never received Tolvaptan 
• 
 
7.4. 
Listing of Subject Inclusion and Exclusion Criteria 
A listing of screened patients who did not meet inclusion or exclusion criteria is generated. 
7.5. 
Medical History  
Medical history is summarized by treatment.  Medical history is coded using MedDRA (Medical 
Dictionary for Regulatory Activities).  Medical history items are summarized by MedDRA 
system organ class (SOC) and preferred term (PT).  A by-patient listing of medical history will 
be provided. 
7.5.1. 
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 is calculated for analysis 
according to the to the appropriate equation (Section 6.5.4) using the patient age at laboratory 
collection for adult patients, or patient height at Screening for adolescent 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.   


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The eGFR values used in the analysis dataset for the baseline label (Table 8) are the baseline 
eGFR values for each patient (defined in Section 6.4.2), 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: 
• Study Day=(Date of Historical Lab Collection)–(Date of Screen A)  
Summary statistics of eGFR results by historical year (listed in Table 8) will be presented for the 
ITT population.  Summary statistics of available historical eGFR results are based on the 
following analysis windows:  
Table 8:   
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.   
 


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8. 
EFFICACY  
Analyses of efficacy described in this section are the primary analyses of the efficacy endpoints, 
and pertain to the ITT population (i.e., all patients randomized in the study), unless otherwise 
specified.  The trial includes endpoints following 2 years of treatment. 
Stratification factors including tolvaptan use (yes/no) and screening ACR (≤300 mg/g, 
>300 mg/g) will only be used in the efficacy models as covariates if the category with the 
smallest number of patients comprise >20% of patients enrolled in the study.  Continuous 
baseline eGFR will be included as a covariate instead of the categorical eGFR stratification 
factor.  The following abbreviations are used in descriptions of the ANCOVA and MMRM 
analysis models: 
Table 9.   
MODEL PARAMETER ABBREVIATIONS 
Abbreviation 
Model Term 
BASE_eGFR 
Baseline eGFR 
*Tolv_STRAT 
Concomitant tolvaptan use (yes, no) 
*ACR_STRAT 
Screening ACR (≤300 mg/g, >300 mg/g) 
TRT 
treatment group 
TRT x VISIT 
the interaction between treatment and time 
VISIT 
analysis visit used as time 
* Tolvaptan use (yes/no) and screening ACR (≤300 mg/g, >300 mg/g) will only be used in the efficacy models as 
 covariates if the category with the smallest number of patients comprises >20% of patients enrolled in the study. 
 
8.1. 
General Considerations 
Data collected from individual study centers will be pooled; results will not be presented by 
individual study center.  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 handled as described in Section 6.6.   


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8.2. 
Statement of the Null and Alternate Hypotheses 
All primary efficacy analyses compare the change from baseline in eGFR for patients 
randomized to bardoxolone methyl (ΔeGFR_BARD) to the change from baseline in eGFR for 
patients randomized to placebo (ΔeGFR_PBO) at the endpoint-specified visit according to the 
following hypotheses: 
• Null hypothesis, H0: (ΔeGFR_BARD)–(ΔeGFR_PBO)=0 mL/min/1.73 m2  
• Alternative hypothesis, H1: (ΔeGFR_BARD)–(ΔeGFR_PBO)≠0 mL/min/1.73 m2 
Because eGFR decreases with disease progression, a higher change from baseline in eGFR for 
bardoxolone methyl relative to placebo is considered evidence of benefit. 
8.3. 
Multiple Comparisons and Multiplicity 
All objectives are presented with nominal significance levels for descriptive purposes only. 
8.4. 
Primary Endpoint  
8.4.1. 
Primary Endpoint Analysis   
The primary endpoint of this study is the off-treatment change from baseline in eGFR at Week 
108.  The ITT population will be used for all analyses. For all patients enrolled in the trial, Week 
108 is the off-treatment eGFR assessed closest to 108 weeks after Study Day 1.  For a patient 
who completed 2 years of treatment, the 8-week drug treatment withdrawal period occurs at 
Week 108 (i.e., 56 days after last dose).  For a patient who stopped drug treatment early, the 
eGFR assessment at Week 108 is analyzed, irrespective of how long a patient has been off-
treatment.  Analysis of Week 108 (after a planned 8-week drug treatment withdrawal period) 
assesses the preserved drug benefit (relative to placebo) following withdrawal of treatment.     
The off-treatment change from baseline eGFR at Week 108 for patients treated with bardoxolone 
methyl is compared to placebo using an ANCOVA model, with BASE_eGFR as a covariate, and 
TRT as fixed effects.  The ANCOVA analysis uses eGFR values collected in the Week 108 
analysis window (Section 6.5.2), which includes the follow-up assessment at Week 108 for 
patients who discontinued treatment early irrespective of time after last dose.  
Missing Week 108 eGFR data will not be imputed. 
The difference between bardoxolone methyl and placebo in change from baseline of eGFR is 
estimated along with the 95% confidence interval at Week 108.   
Example SAS code as follows: 
proc glm data=efficacy; 
   class TRT ACR_STRAT; 
   model DELT_eGFR=trt ACR_strat base_egfr /solution; 
   lsmeans trt / diff stderr pdiff cl alpha=0.05; 
run; 
 
 


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8.5. 
Secondary Efficacy Endpoint 
The ITT population will be used for all analyses unless otherwise specified. 
8.5.1. 
Secondary Efficacy Endpoint Analyses 
The secondary efficacy endpoint of this study is the change from baseline in eGFR at Week 100 
(i.e., the end of the first year of drug exposure).  The change from baseline in eGFR for patients 
treated with bardoxolone methyl is compared with placebo at Week 100 using MMRM analysis, 
with BASE_eGFR as a covariate, and the following fixed factors: treatment group (TRT), time 
(i.e., VISIT; analysis visit number), and the interaction between treatment and time (TRT x 
VISIT).   
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 analysis of eGFR at Week 100 uses available eGFR values 
irrespective of whether or not a patient is receiving treatment.  Analyses for Week 100 will not 
include the Week 52 data due to mix of on-treatment and off-treatment values.  The MMRM 
analysis uses all eGFR values collected through Week 100 according to analysis visits 1, 2, 4, 6, 
8, 12, 24, 36, 48, 64, 76, 88, and 100 (Section 6.5.2).  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 no previous model did not converge. 
1. Heterogeneous Toeplitz covariance structure (assuming different variances at each time 
point and 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). 
If the MMRM model does not converge using any of the aforementioned covariance structures, 
variables from the model statement may be removed in the sequence of 1) Tolv_STRAT, 2) 
ACR_STRAT.  
The difference between bardoxolone methyl and placebo in change from baseline in eGFR is 
estimated along with the 95% confidence interval at Week 100 for the primary analysis of the 
secondary endpoint.   
Missing eGFR data will not be imputed.  
SAS example as follows: 
proc mixed data=OUT2 method=reml alpha=0.05 covtest; 
 
class  VISITNUM(ref=LAST) 
 
 
 TRT(ref=FIRST) SUBJID ACR_STRAT; 


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model DELT_eGFR = BASE_eGFR ACR_STRAT TRT VISITNUM  
            TRT*VISITNUM BASE_eGFR*VISITNUM / solution ddfm=kr; 
 
repeated VISITNUM / subject=SUBJID type=un r; 
 
lsmeans TRT*VISITNUM / pdiff om cl e; 
      estimate 'Estimate at Week 100' TRT 1 -1 TRT*VISITNUM 1 -1 / cl; 
 
ods output LSMeans=LSM diffs=Diff; 
run; 
A plot of least squared means from the MMRM model at each visit by treatment arm will be 
created. 
 
  
 
 
 
  
8.6.1.2. 
Off Treatment eGFR ANCOVA Analyses – No Imputation for Missing Data 
The ANCOVA analysis (defined in Section 8.4.1) will be performed by using eGFR values 
collected at 
Week 112 off-
treatment analysis visits (Table 4).  Missing eGFR data per visit are not imputed.  
The difference between bardoxolone methyl and placebo in change from baseline of eGFR is 
estimated along with the 95% confidence interval at each off-treatment visits.  


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9. 
SAFETY AND TOLERABILITY 
Safety and tolerability are evaluated by AEs, SAEs, clinical laboratory test results, body weight, 
vital signs, 12-lead ECG findings.  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.  Statistical testing is not performed for safety analyses unless otherwise specified.  
On-treatment values are summarized according to the analysis study windows in Section 6.5.2; 
Off-treatment values are summarized according to the analysis study windows in Section 6.5.2.1.  
Safety data summaries are grouped by treatment. 
Continuous safety parameters (including selected clinical chemistries and vital signs) may be 
summarized using the methodology described in Section 8.4.1, and Section 8.5.1.  Only the visit 
windows outlined in Table 4 and Table 5 are included in these analyses.  
9.1. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
Treatment-emergent adverse events are summarized by treatment as defined by the safety 
analysis set.  In addition to being summarized by treatment year, AEs are also summarized 
overall. 
Treatment-emergent adverse events are events that either: 
• Have a complete date of onset on or after the date of first dose and not more than 
30 days after the date of the last dose of study drug, or  
• Have no recorded date of onset with a stop date after the first dose of study drug, or 
• Have no recorded date of onset and stop date. 
General considerations for TEAE summaries are: 
• Multiple events by PT and SOC are counted once only per patient for summaries of 
TEAE incidence. 
• For summaries of TEAE incidence by severity, only the most severe event is counted 
per patient. 
• For summaries of TEAE incidence by relationship, only the most strongly related 
event is counted per patient. 
• A TEAE with a missing resolution date or incomplete date that is not identified as 
continuing is assumed to be continuing. 
• For summaries of the number of TEAEs, all TEAEs are counted. 
Off-treatment AEs (OTAEs) are events with a start date more than 30 days after last dose and not 
considered treatment emergent.  Off-treatment AEs will be summarized separately.  
Adverse Events are coded using MedDRA.  In MedDRA, each verbatim term is mapped to a 
preferred term and high-level term (HLT), which is then mapped to a SOC.   


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The investigator grades the severity of the AEs as mild, moderate, or severe as defined in the 
study protocol.  The investigator grades association or relatedness to the study medication 
according to criteria specified in Section 11.4 of the protocol. 
As defined in the protocol, an SAE is an adverse event (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.  
9.1.1. 
Missing and Partial Adverse Event Onset Dates 
Rules for handling partial AE Onset Dates are included in Section 6.6.3.  
9.1.2. 
Summaries of Adverse Events 
Treatment-emergent adverse events and OTAEs are summarized by treatment.  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 each SOC are presented 
by decreasing frequency count.  Additionally, summary tables of events within PTs are presented 
by decreasing frequency count may be generated. 
Summary tables (number and percentage of patients and events) of TEAEs (by SOC and PT) are 
provided by treatment as follows: 
• All TEAEs 
• All related TEAEs (definitely, probably, or possibly related) 
• All TEAEs by severity 
• All serious TEAEs (including deaths)  
• All non-serious TEAEs  
• All related serious TEAEs (including deaths) 
• All TEAEs leading to permanent discontinuation of study drug  
• All TEAEs leading to study drug interruption  
• All TEAEs leading to dose de-escalation 
• TEAEs by time to onset (≤12 weeks and >12 weeks) 
• TEAEs exhibited in >5% of patients in either treatment group 


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Listings are provided showing: 
• All AEs 
• Deaths 
• SAEs 
• AEs leading to permanent discontinuation of study drug  
• TEAEs leading to study drug interruption  
• TEAEs leading to dose de-escalation 
9.2. 
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), excluding the off-
treatment period between the Week 48 visit and Week 52 visit prior to protocol version 6.  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 (including the number 
of patients with ≥80% compliance through Week 100, duration (days) of exposure during the 
study treatment period, and the number and percentage of patients who reached the goal at any 
point during the study.  The overall treatment duration for all placebo patients and bardoxolone 
methyl patients who completed treatment through Week 100 vs. bardoxolone methyl patients 
who did not complete treatment through Week 100 is also summarized.  In addition, a summary 
of the number and percentage of patients exposed by dose (placebo, 5 mg, 10 mg, 20 mg, 30 mg) 
and by visit is generated.  If a patient received more than 1 dose during a visit window, the 
duration of the longest constant dose is used to calculate exposure. A summary of the number 
and percentage of patients exposed to study drug by treatment will be summarized for the 
following duration categories: 
• ≤16 Weeks 
• >16 Weeks 
• >24 Weeks 
• >48 Weeks 
• >72 Weeks 
• >96 Weeks 
Total number of doses dispensed, and total dose (mg) dispensed is calculated from total number 
of kits (bottles) recorded on the Study Drug Dispensation electronic case report form (eCRF).  
Total number of doses received is calculated from information on the eCRF of Study Drug 
Return and Study Drug Dispensation, as the (total number of doses dispensed – total number of 
doses returned).  If a kit is not returned but the patient had a subsequent dispensation, then the 
non-returned kit is assumed to have been taken in full.  However, if a kit is not returned and no 
kit is subsequently dispensed, then the non-returned kit is assumed to not have been taken.  Study 
drug compliance (%) is calculated as 100 × total number of doses received / total number of 


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study days of study participation, excluding the off-treatment periods between Week 48 to 
Week 52 prior to protocol version 6 and Week 100 to Week 104.  
The off-treatment periods between Week 48 to Week 52 prior to protocol version 6 and 
Week 100 to Week 104 will be analyzed by the summary of days since last dose.  Indeed, for 
patients with a Week 52 off-treatment analysis visit, summary statistics of days since last dose 
are generated.  Similarly, for patients with a Week 104 analysis visit, summary statistics of days 
since last dose are generated.  
The number and percentage of patients are summarized by treatment group for Drug Interruption 
not related to COVID-19: 
− Interruption Type (Primary Investigator (PI) initiated, Patient Reported) 
− Primary reason for interruption (AE, Elevated Transaminase not clinically 
significant (NCS), Elevated BNP NCS, Fluid Overload NCS, Weight Gain NCS, 
Weight Loss NCS, Other) 
Drug Interruption due to COVID-19 will also be summarized as specified in Section 11.1. 
Patients not at per-protocol dose are listed, including reasons.  
9.3. 
Concomitant Medications 
Concomitant medications are coded using the World Health Organization (WHO) drug 
dictionary 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, 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.  Concomitant medications will be summarized by treatment year and overall.   
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 
• that are continued from screening and continued after the first study drug dosing, or 
• that have start dates or stop dates within the treatment period, or 
• that start before treatment end and 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. 
9.3.1. 
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. 


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9.4. 
Prior and Concomitant Procedures and Surgeries 
Prior and concomitant procedures and surgeries are listed. 
9.5. 
Clinical Laboratory Evaluations 
Laboratory data are summarized at baseline and at each time point by treatment.   
9.5.1. 
Continuous Summaries of Laboratory Results 
Laboratory evaluations and change from baseline are summarized by treatment, laboratory 
category (hematology, chemistry, urinalysis, and microscopy), test, and study visit using 
continuous statistics.  The eGFR results are calculated using formulas described in Section 6.5.4.   
Chemistry values (including eGFR) collected at the following visits will be averaged. 
• Week 104 A and Week 104 B 
• Week 108 A and Week 108 B 
• Week 112 A and Week 112 B 
Box plots and line graphs are generated for selected laboratory test results, such as eGFR, ACR, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBL, BNP, blood urea 
nitrogen, 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. 
Summaries of continuous statistics are provided for the following urinalysis parameters: 
albumin, creatinine, pH, erythrocytes, and specific gravity.  Qualitative lab results 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 6.5.5) will use the geometric mean (with 
standard error) 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 calculated as the ratio 
of each visit to baseline and reported as the post-baseline/baseline ratios and are summarized by 
geometric means with 95% confidence intervals at each time point.   
9.5.1.1. 
Natural log (ACR)/eGFR 
Mean ratios of natural log (ACR)/eGFR (Section 6.4.6) are summarized at each time point.  The 
ratio of natural log (ACR)/eGFR by analysis visit is summarized by arithmetic means. 
9.5.2. 
Categorical Summaries of Laboratory Results 
Select laboratory parameters will be summarized using shift tables.  Shift tables are summarized 
by treatment, laboratory category (hematology, chemistry, urinalysis, and microscopy), and 
laboratory test and present shifts from baseline status (Normal, Low, High) to worst on study 
treatment status (Normal, Low, High).  The worst abnormality values are defined as the 
maximum values while on study treatment (i.e., up to <21 days after last dose), 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 (i.e., up to <21 days 
after last dose).   


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Additionally, laboratory parameters of specific interest (ALT, AST, ACR, BNP) are summarized 
using shift tables that summarize shifts from (1) baseline status to end of treatment status, (2) 
worst on-treatment status to worst off-treatment status, (3) worst on-treatment status to end of 
study, and (4) baseline status to worst on-treatment status 5) baseline to worst off-treatment, and 
(6) worst on-treatment status to best (lowest) off-treatment status.  The number and percentage of 
patients are summarized.  For ACR, summaries will present shifts from/to the categories listed in 
Section 6.5.5.1.  For ALT and AST, summaries will present shifts from/to the following 
categories:  
• ≤ ULN 
• > ULN to <3× ULN 
• ≥3× ULN to <5× ULN 
• ≥5× ULN to <10× ULN 
• ≥10× ULN to <20× ULN 
• ≥20× ULN  
For BNP, summaries will present shifts from/to the following categories:  
• <100 pg/mL 
• ≥100 pg/ml to <200 pg/ml 
• ≥200 pg/ml to <400 pg/ml 
• ≥400 pg/ml 
In addition, a summary table is provided for the number and percentage of patients meeting a 
following pre-specified threshold level at any time during the study:  
• ACR >3500 mg/g 
• Magnesium <1.3 mEq/L (0.65 mmol/L) 
• BNP >200 pg/mL  
• NT-proBNP >1000 pg/mL 
9.5.2.1. 
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 (Table 10) at any time 
during the study are summarized by the maximum dosage received.  The pre-specified thresholds 
are consistent with FDA guidance. 
Table 10: 
PRE-SPECIFIED THRESHOLD LEVELS FOR TRANSAMINASES 
Lab Parameter 
Threshold 
ALT, AST 
≥3× upper limit of normal (ULN) and <5× ULN 


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Lab Parameter 
Threshold 
 
≥5× ULN and <10× ULN 
≥10× ULN and <20× ULN 
≥20× ULN 
≥5× ULN for more than 2 weeks 
TBL 
≥ULN and ≤1.5× ULN 
>1.5× ULN and ≤2× ULN 
>2× ULN 
ALT, AST, TBL 
ALT or AST >3× ULN and TBL >1.5× ULN 
ALT or AST >3× ULN and TBL >2× ULN 
ALT, AST, TBL, 
International 
normalized ratio (INR) 
>3× ULN and (TBL >2× ULN or INR >1.5) 
ALP 
>1.5× ULN 
A listing of subjects with abnormal ALT, AST, or TBL will also be provided. 
 
 
 
   
9.7. 
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 (cm), 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. 
In addition, a summary table is provided for the number and percentage of patients meeting a 
following pre-specified post baseline on-treatment blood pressure change categories:  
• SBP (mm Hg): 
− Maximum increase from baseline: ≥20; ≥40; ≥60 
− Maximum decrease from baseline: ≥20; ≥40 
• DBP (mm Hg):  
− Maximum increase from baseline: ≥20; ≥40 
− Maximum decrease from baseline: ≥20 


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9.8. 
24-hr ABPM Sub-study 
A subset of patients who consent to the 24-hour ambulatory blood pressure monitoring (ABPM) 
sub-study will have systolic blood pressure, diastolic blood pressure, pulse pressure and heart 
rate collected during 24-hour periods as specified in Table 2.  Observed values and change from 
baseline will be summarized at baseline and at analysis visits Week 12, Week 48 and Week 88 
for each 24-hour ABPM assessment using the following 24-hour parameters: overall mean, 
daytime mean, and nighttime mean.  Descriptive summaries will include confidence intervals.  
The 24-hour ABPM parameters will be calculated as specified in Table 11.  For each 24-hour 
period, calculation of the average values is the sum of all valid ambulatory blood pressure 
measurements divided by the number of all valid blood pressure measurements, within the range 
of time specified for the parameter. Categorical summaries for systolic blood pressure and 
diastolic blood pressure described in Section 9.7  will also be performed. 


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Table 11: 
24-HOUR ABPM PARAMETERS 
Parameter 
Calculation 
Overall (24-hour) 
SBP, DBP mean 
average of all valid measurements taken from the patient’s ambulatory blood 
pressure monitoring device 
Daytime SBP, DBP 
mean 
average of all valid measurements taken from 6 am to 10 pm 
Nighttime SBP, 
DBP mean 
average of all valid measurements taken from 10 pm to 6 am next day 
9.9. 
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 6.5.6).  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 QTcF thresholds (Table 12) are consistent with FDA guidance: 
Table 12: 
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 
Change from baseline: >30 and ≤60 msec 
Change from baseline: >60 msec 
Heart rate 
<40 beats/min 
>100 beats/min 
 
Line graphs of change from baseline over time for ECG parameters are plotted. 
9.10. 
Pregnancy 
A listing is provided for serum and urine pregnancy results of all on-study pregnancies. 


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10. 
PHARMACOKINETICS 
Individual concentration data will be listed by subject, visit and timepoint. 
 
  


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11. 
COVID-19 IMPACT 
11.1. 
Operational Impact 
The COVID-19 pandemic has impacted the conduct of the study per protocol.  To minimize 
study disruptions, alternative drug dispensation methods and remote visit completion methods 
are available if it is inadvisable for a patient to be seen for an in-person clinic visit or if a patient 
is unwilling to come to the clinic (further details provided in Appendix 1 and Appendix 2 of the 
protocol).  Any study procedures that cannot be conducted remotely will be noted as missing.   
For any visits after 01 March 2020 sites should record if visits, data collection, drug 
dispensation, and drug administration are impacted by or related to COVID-19.   
The number and percentage of patients are summarized by visit and treatment group for the 
following categories: 
• Visit impact by COVID-19 
− Visit not done 
− Visit conducted out of window 
− One or more procedures could not be performed 
• Alternative data collection methods  
− No change (occurred as expected per protocol) 
− Telephone visit 
− Video conference visit 
− Home health care visit 
− Local lab 
− Other 
• Drug dispensation impact  
− No change (office visit) 
− IP dispense not scheduled (telephone visit) 
− Mailed to patient 
− Home health care provided 
− Dose not escalated 
− Dose de-escalated 
− Other 


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The number and percentage of patients are summarized by treatment group for Drug Interruption 
due to COVID-19:  
− Tested positive for COVID-19 (yes, no, not tested) 
− Primary reason for interruption (medical monitor/sponsor recommendation, site 
mandate, patient choice, insufficient IP supply, other) 
A by-patient listing of all study visits that were affected due to COVID-19 including a 
description of how the patient’s participation was altered will be provided.   
Early discontinuations of study drug or study due to COVID-19 will be summarized and listed in 
disposition summary tables and the disposition listing (described in Section 7.1), respectively.   
All deviations due to the impacts of COVID-19 (after 01 March 2020) will be identified and 
documented accordingly by the site and the Sponsor.  The failure to complete a protocol visit 
will not be considered as a reason for study discontinuation and will not be considered as a major 
deviation.  All COVID-19-related deviations will be identified in the protocol deviation listing 
(Section 7.2)   
11.2. 
Impact on Efficacy  
The primary and key secondary endpoints, as well as the secondary endpoints are lab-based 
endpoints (i.e, change in eGFR).  Home health care visits and/or local laboratories are available 
to collect labs, including eGFR, for patients who are unable or unwilling to come for in-clinic 
visits.  Central laboratory kits are utilized at in-clinic visits, home health care visits, and local 
laboratory visits.  Therefore, the contingency measures put in place to collect this critical 
efficacy data are not expected to impact the efficacy results.  Missing data due to COVID-19 is 
handled as described in Section 6.6.    
Sensitivity analyses may be performed as appropriate to assess the potential impact of the 
COVID-19 pandemic on efficacy outcomes.  
11.3. 
Impact on Safety 
Patient narratives will be provided for all patients who test positive for severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19.  
For patients who are unable to complete an in-clinic visit, safety assessments can be performed 
through alternative remote visit methods.  Central laboratory kits are used to assess safety 
laboratory information regardless of visit method; therefore, the contingency measures put in 
place to collect this critical safety data are not expected to impact the laboratory results.   
Subgroup analyses may be performed as appropriate to assess the potential impact of the 
COVID-19 pandemic on safety outcomes. 


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12. 
REFERENCES 
Guy, W. ECDEU Assessment Manual For Psychopharmacology, DHEW Publication No. ADM 
76–338, US Government Printing Office, Washington, DC, USA, 1976.   
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney Int Suppl 2013;3;1-150.