Clinical trial NCT02657356
Conditions: Connective Tissue Disease-Associated Pulmonary Arterial Hypertension
Keywords: Pulmonary Hypertension Pulmonary Arterial Hypertension Connective Tissue Disease-Associated Pulmonary Arterial Hypertension Bardoxolone methyl PAH RTA 402 6-minute walk distance
Sponsor: Biogen
Start date: 2016-10-04; Completion date: 2020-05-07
Enrollment: 202 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study assesses the safety and efficacy of bardoxolone methyl relative to placebo in patients with connective tissue disease-associated pulmonary arterial hypertension to determine the recommended dose range and evaluate the change from baseline in 6-minute walk distance (6MWD) following 24 weeks of study participation.

Detailed description:
This double-blind, randomized, placebo-controlled trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with World Health Organization Group I Connective Tissue Disease Pulmonary Arterial Hypertension (WHO Group I CTD-PAH).

Qualified patients will be randomized 1:1 to either bardoxolone methyl or placebo to be administered once daily for 24 weeks. Patients randomized to placebo will remain on placebo throughout the study. Patients randomized to bardoxolone methyl will start at 5 mg and will dose-escalate to 10 mg at Week 4 unless contraindicated clinically. Dose de-escalation is permitted during the study if indicated clinically.

All patients in the study will follow the same visit and assessment schedule. Following randomization, patients will be scheduled to be assessed in person during treatment at Weeks 1, 2, 4, 6, 8, 16, and 24 and by telephone contact on Days 3, 10, 21, 31, 38, 84, and 140. Patients will also be scheduled to be assessed at an in person follow up visit at Week 28, four weeks after the end of treatment.

Arms: arm 1: Placebo capsules will be administered orally once a day for 24 weeks. arm 2: Each patient will receive bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage for each patient is 5 mg and will dose-escalate to 10 mg at Week 4, unless contraindicated clinically.
Interventions: intervention 1: Placebo capsules intervention 2: Bardoxolone methyl capsules
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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1. 
TITLE PAGE 
 
 
 
RTA 402 
 
402-C-1504 
 
 
 
A STUDY OF THE EFFICACY AND SAFETY OF 
BARDOXOLONE METHYL IN PATIENTS WITH 
CONNECTIVE TISSUE DISEASE-ASSOCIATED 
PULMONARY ARTERIAL HYPERTENSION 
 
VERSION 2.0 – 18 OCT 2016 
 
 
 
The information contained herein is confidential and the proprietary property of 
Reata Pharmaceuticals, Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of Reata Pharmaceuticals, 
Inc. is expressly prohibited. 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for bardoxolone methyl.  I have read the 
402-C-1504 clinical study protocol and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Medical and Scientific 
Leader 
 
 
 
 
 
 
 
 
Clinical Study 
Manager 
 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
SAE Reporting 
 
 
 
 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Product: 
Bardoxolone methyl 
Title of Study:  
A Study of the Efficacy and Safety of Bardoxolone Methyl in Patients with Connective Tissue 
Disease-Associated Pulmonary Arterial Hypertension 
Study center(s): Approximately 100 study centers  
Studied period: 24 months 
Estimated date first patient enrolled: October 2016 
Estimated date last patient completed: October 2018 
Phase of development:  
3 
Objectives:   
For patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) 
enrolled in this study, the objectives are as follows: 
Primary:   
 
To assess the efficacy of bardoxolone methyl relative to placebo. 
Secondary: 
 
To assess the safety of bardoxolone methyl relative to placebo. 
Endpoints: 
Primary Efficacy Endpoint: 
Change from baseline in six-minute-walk distance (6MWD) relative to placebo at Week 24 
Secondary Efficacy Endpoint: 
Time-to-first clinical improvement event consisting of a persistent change for any of the following: 
 
Improvement by at least one WHO functional class 
 
Increase from baseline in 6MWD by at least 10% 
 
Decrease from baseline in creatine kinase (as a surrogate biomarker for muscle injury and 
inflammation) by at least 10%  
Exploratory Efficacy Endpoint: 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Safety: 
Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, and 
change from baseline in the following assessments: physical examinations, vital sign measurements, 
12-lead electrocardiograms (ECGs), clinical laboratory measurements, and weight. 
Additional Exploratory Endpoints: 
 
 
Methodology:  
This double-blind, randomized, placebo-controlled trial will study the safety, tolerability, and efficacy 
of bardoxolone methyl in qualified patients with WHO Group I CTD-PAH. 
Qualified patients will be randomized 1:1 to either bardoxolone methyl or placebo to be administered 
once daily for 24 weeks.  Patients randomized to placebo will remain on placebo throughout the study.  
Patients randomized to bardoxolone methyl will start at 5 mg and will dose-escalate to 10 mg at 
Week 4 unless contraindicated clinically.  Dose de-escalation is permitted during the study if indicated 
clinically.  Please refer to Section 7.3.1 for additional details on dose escalation and dose de-escalation.  
All patients in the study will follow the same visit and assessment schedule.  Following randomization, 
patients will be scheduled to be assessed in person during treatment at Weeks 1, 2, 4, 6, 8, 16, and 24 
and by telephone contact on Days 3, 10, 21, 31, 38, 84, and 140.  Patients will also be scheduled to be 
assessed at an in person follow up visit at Week 28, four weeks after the end of treatment. 
Patients who complete the study and are treatment-compliant to their assigned dose will be eligible for 
a separate open-label extension study.   
Number of patients (planned):  
Approximately 130 patients will be enrolled; this number may be increased up to approximately 
200 patients based upon a blinded sample size re-calculation. 
Diagnosis and main criteria for inclusion: 
1. Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent; 
2. BMI > 18.5 kg/m2; 
3. Symptomatic pulmonary hypertension WHO/NYHA FC class II and III; 
4. WHO Group I PAH associated with connective tissue disease;  
5. Had a diagnostic right heart catheterization performed and documented within 36 months prior 
to Day 1 that confirmed a diagnosis of PAH according to all the following criteria: 
a. Mean pulmonary artery pressure ≥ 25 mm Hg (at rest); 
b. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; 
c. Pulmonary vascular resistance > 240 dyn•sec/cm5 or > 3 mm Hg/liter (L)/minute; 
6. Has BNP level ≤ 400 pg/mL; 
7. Had an average 6MWD ≥ 150 meters on two consecutive tests performed on different days 
prior to randomization, with a percent difference ≤ 15% between tests;   
8. Has been receiving no more than two (2) approved disease-specific PAH therapies.  PAH 


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therapy must have been at a stable dose for at least 90 days prior to Day 1.  No additions or 
changes should be made to PAH therapies and doses should remain stable for the duration of 
the study;  
9. Has maintained a stable dose for 30 days prior to Day 1 if receiving therapies that may affect 
walking distance, including but not limited to:  vasodilators (including calcium channel 
blockers), digoxin, L-arginine supplementation, oxygen supplementation, diuretics, agents to 
treat neuropathic pain associated with peripheral neuropathy (such as pregabalin), and/or 
agents to treat anemia (such as supplemental iron, erythropoietin, or intravenous iron).  If the 
patient receives intravenous iron therapy during Screening, the intravenous infusion must be 
performed at least 30 days prior to Day 1; 
10. If receiving treatment for CTD with prednisone or any other drugs, the medications must 
remain the same for at least 90 days prior to Day 1.  Doses for medications prescribed for the 
treatment of CTD must remain stable for at least 30 days prior to Day 1 and for the duration of 
the study; 
11. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 with total lung capacity 
≥ 65% (predicted); 
12. Had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed 
tomography (CT), or pulmonary angiogram prior to Day 1 that shows no evidence of 
thromboembolic disease (i.e., should note normal or low probability for pulmonary embolism).  
If V/Q scan was abnormal (i.e., results other than normal or low probability), then a 
confirmatory CT or selective pulmonary angiography must exclude chronic thromboembolic 
pulmonary hypertension; 
13. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥ 45 mL/min/1.73 m2 as measured by the central lab; 
14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
study procedures; 
15. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects of the 
study prior to initiation of any patient-mandated procedures. 
Major exclusion criteria: 
1. Participation in other investigational clinical studies involving interventional products being 
tested or used in a way different from the approved form or when used for an unapproved 
indication within 30 days prior to Day 1; 
2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 90 days prior to 
Day 1 or planned initiation during the study;   
3. Stopped receiving any PAH chronic therapy within 60 days prior to Day 1; 
4. Received a dose of prednisone > 20 mg/day (or equivalent dose if other corticosteroid) within 
30 days prior to Day 1; 
5. Received intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues within 
90 days prior to Day 1; 


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6. Received intravenous inotropes within 30 days prior to Day 1;  
7. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) 
> 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period of rest; 
8. Has systolic BP < 90 mm Hg during Screening after a period of rest; 
9. Has a history of clinically significant left-sided heart disease and/or clinically significant 
cardiac disease, including but not limited to any of the following: 
a. Congenital or acquired valvular disease if clinically significant apart from tricuspid 
valvular insufficiency due to pulmonary hypertension; 
b. Pericardial constriction; 
c. Restrictive or congestive cardiomyopathy; 
d. Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 90 days of 
Day 1; 
e. Symptomatic coronary artery disease within the last 3 years; 
10. Acutely decompensated heart failure within 30 days prior to Day 1, per investigator 
assessment; 
11. Has more than two of the following clinical risk factors for left ventricular diastolic 
dysfunction: 
a. Age > 65 years; 
b. BMI ≥ 30 kg/m2; 
c. History of systemic hypertension; 
d. History of type 2 diabetes; 
e. History of atrial fibrillation; 
12. History of atrial septostomy within 180 days prior to Day 1; 
13. Uncontrolled obstructive sleep apnea;   
14. Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or 
hepatitis C (with evidence of recent infection and/or active virus replication) defined as mild to 
severe hepatic impairment (Child-Pugh Class A-C); 
15. Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at 
Screening;  
16. Hemoglobin (Hgb) concentration < 10.5 g/dL at Screening; 
17. Diagnosis of Down syndrome; 
18. History of malignancy within 5 years prior to Screening, with the exception of localized skin or 
cervical carcinomas; 
19. Untreated or uncontrolled active bacterial, fungal, or viral infection; 
20. Known or suspected active drug or alcohol abuse, per investigator judgment; 


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21. Use of inhaled nitric oxide within 7 days prior to Screening and Day 1 visits, excluding acute 
vasodilator testing during diagnostic cardiac catheterization;  
22. Major surgery within 30 days prior to Day 1 or planned to occur during the course of the study; 
23. Unwilling to practice acceptable methods of birth control (both males who have partners of 
childbearing potential and females of childbearing potential) during Screening, while taking 
study drug, and for at least 30 days after the last dose of study drug is ingested;  
24. Women who are pregnant or breastfeeding; 
25. Any disability or impairment that would prohibit performance of the 6MWT; 
26. Any abnormal laboratory level that, in the opinion of the investigator, would put the patient at 
risk by trial enrollment; 
27. 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; 
28. Known hypersensitivity to any component of the study drug;  
29. Unable to communicate or cooperate with the investigator because of language problems, poor 
mental development, or impaired cerebral function. 
30. Patient has active myositis;  
31. Use of total parenteral nutrition within one year of the Day 1 study visit; 
32. History of acute renal crisis within one year of the Day 1 study visit; 
33. Patient has participated in investigational trials where bardoxolone methyl was administered. 
Investigational product, dosage and mode of administration:  
Bardoxolone methyl will be administered orally once a day at 2.5, 5, or 10 mg.   
Duration of treatment:  
Bardoxolone methyl or placebo will be administered once a day for 24 weeks. 
Reference therapy, dosage and mode of administration:  
Placebo will be administered orally once a day for 24 weeks. 
Criteria for evaluation: 
Efficacy: 6MWD, clinical improvement composite events,
 
Safety: Results of physical examinations, laboratory results (clinical chemistry, hematology, 
urinalysis), vital sign measurements, ECG results, weight, adverse events, and serious adverse events. 
 
 
Pharmacokinetics: Bardoxolone methyl plasma concentration-time data, and estimated 
pharmacokinetic parameters for each analyte. 
Statistical methods: 
 
 
   


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Primary analysis of efficacy:  A mixed-model repeated measures (MMRM) analysis will compare the 
treatment groups with respect to the primary endpoint.  The dependent variable will be change from 
baseline in 6MWD.  The model will include treatment, visit, and the treatment-by-visit interactions as 
fixed effects; stratification by number of background PAH therapies (0, 1, or 2); and visit as a repeated 
measure having an unstructured covariance structure.  Covariates may be defined in the statistical 
analysis plan as appropriate.  Missing data will not be imputed for the primary analysis.   
 
 
Schema for Study of Bardoxolone Methyl in Patients with CTD-PAH 
6-Minute Walk Test
T Telephone Contact
Screening
Dose-Titration Period
W2
W1
W8
Scr
D1
D3
T
D10
T
W3
T
W4
Maintenance
R
Placebo
1:1 Randomization
D31
T
W5
T
W6
W12
T
W16
Bardoxolone Methyl (5 mg)
Bardoxolone Methyl (10 mg)
W24
W28
W20
T
Follow
-Up
 
Patients who complete the study and are treatment-compliant to their assigned dose will be eligible for a 
separate open-label extension study.   


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3. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................11 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Clinical Experience with Bardoxolone Methyl ..........................................................21 
5.1.1. 
Safety and Tolerability ...............................................................................................21 
5.1.2. 
Fluid Overload ............................................................................................................22 
5.1.3. 
Transaminase and GGT Elevations ............................................................................22 
5.1.4. 
Muscle Spasms ...........................................................................................................23 
5.1.5. 
Weight Loss ................................................................................................................23 
5.1.6. 
Hypomagnesaemia ......................................................................................................23 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25 
6.1. 
Objectives ...................................................................................................................25 
6.1.1. 
Primary Objective .......................................................................................................25 
6.1.2. 
Secondary Objective ...................................................................................................25 
6.2. 
Endpoints ....................................................................................................................25 
6.2.1. 
Primary Efficacy Endpoint .........................................................................................25 
6.2.2. 
Secondary Efficacy Endpoints ....................................................................................25 
6.2.3. 
Exploratory Efficacy Endpoints .................................................................................25 
6.2.4. 
Safety Endpoints .........................................................................................................26 
6.2.5. 
Additional Exploratory Endpoints ..............................................................................26 
6.2.6. 
Pharmacokinetic Endpoints ........................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.1.1. 
Blinded Sample Size Re-Calculation ..........................................................................27 
7.2. 
Number of Patients .....................................................................................................27 
7.3. 
Treatment Assignment ................................................................................................27 
7.3.1. 
Dose Escalation and Dose De-Escalation ...................................................................28 


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7.4. 
Criteria for Study Termination ...................................................................................28 
7.5. 
Schedule of Assessments ............................................................................................28 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................32 
8.1. 
Patient Inclusion Criteria ............................................................................................32 
8.2. 
Patient Exclusion Criteria ...........................................................................................33 
8.3. 
Patient Re-Screening ..................................................................................................35 
8.4. 
Patient Discontinuation and Termination ...................................................................35 
8.4.1. 
Patient Discontinuation Criteria .................................................................................35 
8.4.2. 
Patient Termination Criteria .......................................................................................36 
9. 
TREATMENT OF PATIENTS ..................................................................................37 
9.1. 
Select Management Guidelines ..................................................................................37 
9.1.1. 
Management of Fluid Status .......................................................................................37 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................38 
9.1.3. 
Management of Muscle Spasms .................................................................................38 
9.1.4. 
Weight Loss ................................................................................................................38 
9.1.5. 
Hypomagnesaemia ......................................................................................................38 
9.1.6. 
Nausea .........................................................................................................................38 
9.1.7. 
Anemia ........................................................................................................................38 
9.2. 
Description of Study Drug ..........................................................................................39 
9.3. 
Concomitant Medications ...........................................................................................39 
9.3.1. 
Excluded Medications ................................................................................................39 
9.3.2. 
Permitted Medications ................................................................................................40 
9.4. 
Treatment Compliance ................................................................................................41 
9.5. 
Randomization ............................................................................................................41 
9.6. 
Blinding ......................................................................................................................41 
9.6.1. 
Patient Unblinding ......................................................................................................41 
9.6.2. 
Unblinding for Regulatory Submission ......................................................................42 
9.6.3. 
Data Safety Monitoring Board ....................................................................................42 
9.7. 
Unscheduled Visits .....................................................................................................43 
9.8. 
Pregnancy ...................................................................................................................43 
9.8.1. 
Women of Childbearing Potential ..............................................................................43 
9.8.2. 
Methods of Birth Control............................................................................................43 
9.8.3. 
Suspected Pregnancy ..................................................................................................44 


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9.9. 
Serious Toxicities .......................................................................................................45 
9.10. 
Study Procedures ........................................................................................................45 
9.10.1. 
Informed Consent .......................................................................................................45 
9.10.2. 
Inclusion/Exclusion ....................................................................................................45 
9.10.3. 
Demographics and Baseline Disease Characteristics .................................................45 
9.10.4. 
Prior and Current Concomitant Medications ..............................................................45 
9.10.5. 
Current PAH Background Medications ......................................................................45 
9.10.6. 
Medical History ..........................................................................................................46 
9.10.7. 
Height .........................................................................................................................46 
9.10.8. 
Echocardiogram ..........................................................................................................46 
9.10.9. 
Weight and Body Mass Index (BMI) .........................................................................46 
9.10.10. 
Electrocardiograms (ECG) .........................................................................................46 
9.10.11. 
Vital Sign Measurements ............................................................................................46 
9.10.12. 
Physical Examination .................................................................................................46 
9.10.13. 
Pulmonary Function Testing 
 
9.10.14. 
Ventilation-Perfusion (V/Q) Lung Scan, Spiral/Helical/Electron Beam 
Computed Tomography (CT) or Pulmonary Angiogram ...........................................47 
9.10.15. 
Right Heart Catheterization ........................................................................................47 
9.10.16. 
Pregnancy Test ............................................................................................................47 
9.10.17. 
Study Drug Administration.........................................................................................47 
9.10.18. 
Study Drug Dispensation and Collection ...................................................................48 
9.10.19. 
Telephone Contact ......................................................................................................48 
9.10.20. 
Adverse Event Collection ...........................................................................................48 
9.10.21. 
Clinical Chemistry ......................................................................................................48 
9.10.22. 
N-Terminal Pro-Brain Natriuretic Peptide (NT-Pro BNP) and Brain 
Natriuretic Peptide (BNP) ...........................................................................................48 
9.10.23. 
Hematology .................................................................................................................49 
9.10.24. 
Urinalysis and Microscopy .........................................................................................49 
9.10.25. 
Virus Serology ............................................................................................................49 
9.10.26. 
6-Minute Walk Test ....................................................................................................49 
 
50 
 
50 
9.10.29. 
WHO/NYHA Functional Class Assessment ..............................................................50 


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 ......................................................................................51 
9.10.32. 
Pharmacokinetic (PK) Blood Samples .......................................................................51 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................52 
10.1. 
Study Drug ..................................................................................................................52 
10.2. 
Study Drug Packaging and Labeling ..........................................................................52 
10.3. 
Study Drug Storage .....................................................................................................52 
10.4. 
Study Drug Administration.........................................................................................52 
10.5. 
Study Drug Accountability .........................................................................................53 
10.6. 
Study Drug Handling and Disposal ............................................................................53 
11. 
SAFETY ASSESSMENTS ........................................................................................54 
11.1. 
Safety Parameters .......................................................................................................54 
11.2. 
Adverse and Serious Adverse Events .........................................................................54 
11.2.1. 
Definition of Adverse Events .....................................................................................54 
11.2.1.1. 
Adverse Event .............................................................................................................54 
11.2.1.2. 
Serious Adverse Event ................................................................................................54 
11.3. 
Eliciting Adverse Event Information ..........................................................................55 
11.4. 
Assessment of Causality .............................................................................................56 
11.5. 
Assessment of Severity ...............................................................................................56 
11.6. 
Recording Adverse Events .........................................................................................56 
11.7. 
Reporting Serious Adverse Events .............................................................................57 
12. 
STATISTICS ..............................................................................................................60 
12.1. 
Sample Size ................................................................................................................60 
12.2. 
Study Variables ...........................................................................................................60 
12.2.1. 
Pharmacokinetic Variables .........................................................................................60 
12.2.2. 
Efficacy Variables ......................................................................................................60 
12.2.3. 
Safety Variables ..........................................................................................................60 
12.3. 
Statistical Analyses .....................................................................................................60 
12.3.1. 
Primary Analysis of Efficacy ......................................................................................61 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................62 
13.1. 
Study Monitoring ........................................................................................................62 
13.2. 
Audits and Inspections ................................................................................................62 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63 


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14.1. 
Quality Assurance .......................................................................................................63 
14.2. 
Financial Disclosure ...................................................................................................63 
14.3. 
Sponsor Obligations....................................................................................................63 
14.4. 
Investigator Documentation ........................................................................................63 
14.5. 
Clinical Study Insurance .............................................................................................64 
14.6. 
Use of Information ......................................................................................................64 
15. 
ETHICS ......................................................................................................................65 
15.1. 
Institutional Review Board (IRB) or Ethics Committee Review ...............................65 
15.2. 
Ethical Conduct of the Study ......................................................................................65 
15.3. 
Written Informed Consent ..........................................................................................65 
15.4. 
Confidentiality ............................................................................................................66 
15.5. 
Modification of the Protocol .......................................................................................66 
15.6. 
Protocol Deviations ....................................................................................................67 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................68 
16.1. 
Retention of Records ..................................................................................................68 
16.2. 
Case Report Forms .....................................................................................................68 
17. 
PUBLICATION POLICY ..........................................................................................69 
18. 
REFERENCES ...........................................................................................................70 
19. 
APPENDIX 1: ATS GUIDELINES FOR THE SIX-MINUTE WALK TEST ..........72 
20. 
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF PULMONARY 
HYPERTENSION MODIFIED AFTER THE NEW YORK HEART 
ASSOCIATION FUNCTIONAL CLASSIFICATION ACCORDING TO 
THE WHO 1998 (GALIE, 2009) ...............................................................................80 
 
 ........................................................................81 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................17 
Table 3: 
Schedule of Assessments ............................................................................................29 
Table 4: 
Bardoxolone Methyl Drug Product Information ........................................................39 
Table 5: 
Placebo Information ....................................................................................................39 
Table 6: 
SAE Reporting Contact Information ..........................................................................58 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
AE 
Adverse event 
ACA 
Anti-centromere 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear 
Anti-RNAP 
Anti-RNA polymerase enzyme 
Anti-U1RNP 
Anti-U1 nuclear ribosome 
Anti-U3RNP 
Anti-U3 nuclear ribosome 
Anti-Th/To 
Anti-ribonucleoprotein 
Anti-Ds-DNA 
Anti-double stranded DNA 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
ATS 
American Thoracic Society 
AUC 
Area under the concentration-time curve 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations (US) 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
Cmax 
Maximum drug concentration in plasma 
CT 
Computed tomography 
CTD 
Connective tissue disease 
CTD-PAH 
Connective tissue disease-associated pulmonary arterial 
hypertension 


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Abbreviation or Specialist Term 
Explanation 
CTEPH 
Chronic thromboembolic pulmonary hypertension 
 
 
DSMB 
Data safety monitoring board 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ERA 
Endothelin receptor antagonist 
FADH2 
Flavin adenine dinucleotide 
FDA 
Food and Drug Administration (US) 
FEV1 
Forced expiratory volume  
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
HCV 
Hepatitis C virus 
HDPE 
High-density polyethylene 
Hgb 
Hemoglobin 
ICH 
International Conference on Harmonization 
IKKβ 
Inhibitor of nuclear factor kappa β kinase beta subunit 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
ITT 
Intent-to-treat 
Keap1 
Kelch-like ECH associated protein-1 
LDH 
Lactate dehydrogenase 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MMRM 
Mixed model repeated measures 


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Abbreviation or Specialist Term 
Explanation 
MRI 
Magnetic resonance imaging 
NADH 
Nicotinamide adenine dinucleotide 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B-cells 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
NYHA FC 
New York Heart Association Functional Classification 
PAH 
Pulmonary arterial hypertension 
PCWP 
Pulmonary capillary wedge pressure 
PEF 
Peak expiratory flow 
PFT 
Pulmonary function test 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic 
RBC 
Red blood cell 
RHC 
Right heart catheterization 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
 
 
SLE 
Systemic lupus erythematosus 
SRC 
Sample size re-calculation committee  
TBL 
Total bilirubin 
TLC 
Total lung capacity 
Tmax 
Time when maximum drug concentration in plasma is achieved 
TV 
Tidal volume 
ULN 
Upper limit of normal 
US 
United States 
V/Q 
Ventilation-perfusion 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 


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5. 
INTRODUCTION 
Bardoxolone methyl and its analogs are oleanolic acid-derived synthetic triterpenoid compounds 
that potently induce the Nrf2-Keap1 pathway (Wu, 2011; Rojas-Rivera, 2012).  Through 
interaction with the Nrf2 repressor molecule, Keap1, bardoxolone methyl and its analogs 
promote translocation of Nrf2 to the nucleus, where Nrf2 binds to antioxidant response elements 
in the promoter region of its target genes, leading to induction of many antioxidant and 
cytoprotective enzymes and related proteins (Lee, 2009; Dinkova-Kostova, 2005).  Bardoxolone 
methyl and its analogs are also potent inhibitors of the NF-κB inflammatory pathway through 
both direct (i.e., inhibition of IKKβ kinase activity) and indirect mechanisms (i.e., detoxification 
of reactive oxygen species) (Osburn, 2008).  Because of this dual mechanism of action, 
bardoxolone methyl and its analogs are hypothesized to have potential therapeutic relevance in a 
variety of disease settings involving oxidative stress and inflammation.  Activation of the Nrf2 
pathway also transcriptionally regulates multiple genes that promote the production of cellular 
energy within the mitochondria and facilitates mitochondrial homeostasis and efficiency.   
Through induction of Nrf2 and suppression of NF-κB, bardoxolone methyl has broad molecular 
and pharmacological effects that address multiple facets of the pathophysiology of PAH.  
Induction of NF-κB is markedly elevated in macrophages, endothelial cells and smooth muscle 
cells of PAH patients (Price, 2010).  Recent evidence demonstrates that genetic or 
pharmacologic induction of Nrf2 suppresses formation of the PAH phenotype in a mouse model 
of hypoxic pulmonary hypertension (Eba, 2013).   
Additionally, an emerging concept in the pathogenesis of pulmonary hypertension is the role of 
systemic metabolic and skeletal muscle dysfunction as a major cause of reduced functional 
capacity and fatigue, as well as disease progression.  A high frequency of insulin resistance and 
metabolic syndrome-like features have been described in patients with PAH, and glucose 
intolerance is associated with a decrease in 6MWD (Pugh, 2011).  Pulmonary hypertension 
patients have decreased ATP production (Sutendra, 2014), which results in skeletal muscle 
dysfunction and impaired functional capacity (Mainguy, 2010; Batt, 2014).  Indeed, the skeletal 
muscle within pulmonary hypertension patients displays a decreased expression of mitochondrial 
respiration enzymes, defects in mitochondrial oxidative phosphorylation, and impairments in 
mitochondrial biogenesis (Batt, 2014; Malenfant, 2015).   
Several lines of evidence suggest that Nrf2 activation can increase mitochondrial respiration and 
biogenesis, in addition to inducing expression of numerous antioxidative genes to counter 
reactive oxygen species (ROS).  Specifically, by increasing the availability and production of 
reducing equivalents such as NADH and FADH2, Nrf2 activation improves mitochondrial ATP 
production and improves the efficiency of mitochondrial respiration and oxygen consumption.  
In addition, Nrf2 activation results in improved beta-oxidation of fatty acids and improved 
uptake of glucose, which leads to improvement in mitochondrial respiration, oxygen 
consumption, and energy production.  Since Nrf2 activation can increase mitochondrial 
respiration (Holmström, 2013; Ludtmann, 2014), bardoxolone methyl may restore metabolic 
deficits in PAH, thereby acutely improving energy production and 6MWD. 
Common connective tissue diseases (CTD) associated with PAH (CTD-PAH) include 
autoimmune diseases such as scleroderma, systemic lupus erythematosus (SLE), and mixed 


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CTD.  Nrf2 is a gene that determines susceptibility to autoimmune disease, and genetic deletion 
of Nrf2 results in the spontaneous development of lupus-like autoimmune nephritis (Yoh, 2001) 
and systemic autoimmune disease (Li, 2004) in mice.  An autoimmune mechanism associated 
with vascular endothelial damage appears to play a key pathogenic role in the development of 
PAH in these patients.  Preclinical data demonstrate that bardoxolone methyl and analogs are 
therapeutically effective in autoimmune disease models by significantly reducing auto-antibody 
levels, disease burden, and improving survival (Wu, 2014; Wei, 2014).  Thus, in addition to the 
aforementioned anti-inflammatory and bioenergetics effects, bardoxolone methyl targets 
autoimmune-associated inflammation, which likely causes bioenergetics and other deficits in 
CTD-PAH patients.   
Despite available therapies, the prognosis for PAH remains poor, especially for patients with 
connective tissue disease (Chung, 2014).  Approved vasodilation therapies generally do not yield 
significant functional improvements in CTD-PAH patients (Ghofrani, 2013; Tapson, 2013).  
Notably, none of the approved therapies target the metabolic and mitochondrial dysfunction.  
 
 
  Thus, bardoxolone methyl may 
provide a novel approach to PAH therapy through improvements in bioenergetics and 
mitochondrial function that translate to increased muscular function and exercise capacity, 
especially in CTD-PAH patients who do not respond well to vasodilator treatment.   
Preliminary efficacy data from a Phase 2 study in World Health Organization (WHO) Group I 
PAH patients with bardoxolone methyl (402-C-1302, LARIAT, NCT02036970) showed that 
bardoxolone methyl improves 6MWD on top of optimal vasodilation background therapies in 
CTD-PAH patients.  These observed benefits may reflect bardoxolone methyl’s novel anti-
inflammatory and mitochondrial effects, as well as the attenuation of autoimmune processes that 
likely contribute to PAH in patients with connective tissue diseases.   
Thus, the established pharmacologic effects of bardoxolone methyl, including the suppression of 
pathologic NF-κB signaling and inflammation, mitochondrial dysfunction, and autoimmune 
processes, are directly applicable to the treatment of WHO Group I CTD-PAH.  Given the 
nonclinical and clinical evidence supporting potential efficacy of bardoxolone methyl in 
CTD-PAH, the Sponsor proposes a clinical study to test bardoxolone methyl in patients with 
CTD-PAH. 
5.1. 
Clinical Experience with Bardoxolone Methyl 
Approximately 1900 individuals have been exposed to bardoxolone methyl.  Sixteen studies 
have been completed (seven in patients with CKD who also had type 2 diabetes, four in non-
CKD indications, and five in healthy subjects) and one study is ongoing in patients with PH.   
5.1.1. 
Safety and Tolerability 
Please refer to the Investigator’s Brochure for a detailed discussion of safety findings for studies 
in healthy subjects, oncology, CKD, and PH patients with bardoxolone methyl. 


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5.1.2. 
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 
15-29 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 
30-44 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 adverse events with bardoxolone 
methyl in late-stage CKD patients has not been observed in PAH patients.   
5.1.3. 
Transaminase and GGT Elevations  
In clinical studies of bardoxolone methyl, almost all patients had increases of transaminase 
enzymes above baseline upon initiation of treatment, which followed a consistent pattern.  These 
increases were not associated with elevations in bilirubin or other signs of liver toxicity.  In 
BEACON, fewer hepatobiliary SAEs were observed in the bardoxolone methyl arm than in the 
placebo arm.  The elevations begin immediately after initiation of treatment or an increase in 
dose; they peak approximately two to four weeks later.  In most patients, transaminase elevations 
were mild, but approximately 4% to 11% of patients experienced an elevation greater than 3X 
the ULN.  The elevations resolved to levels less than the ULN in most all patients with 
elevations, within two weeks after peak values while patients continued taking study drug.  
Patients who experienced elevations to greater than 3X the ULN sometimes required additional 
time to resolve.  While some patients have had elevations to above 3X the ULN, persistent 
elevations to above 3X the ULN have not been observed, and the elevations did not recur once 
resolved, unless caused by other factors. 
Bardoxolone methyl regulates GGT, a known Nrf2 target gene.  In clinical studies, low level 
GGT elevations during treatment were common, mild, and typically lasted longer than ALT/AST 
elevations.  Bilirubin levels in patients experiencing transaminase or GGT elevations due to 


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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.  
5.1.4. 
Muscle Spasms 
Muscle spasm was the most frequently reported adverse event 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 
PAH 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 PAH patients.  Muscle 
spasms may result from improved insulin sensitivity and glucose uptake in skeletal muscle cells.  
Increases in glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp procedure, 
were observed in response to bardoxolone methyl in a defined subset of patients enrolled in a 
Phase 2a study.  To date, in those cases where serum creatinine kinase (CK) levels have been 
measured, no association has been observed between muscle spasms and elevated CK levels in 
patients treated with bardoxolone methyl.  Clinical signs and laboratory findings associated with 
the reports of muscle spasms have not been consistent with muscle toxicity.  Bardoxolone methyl 
subjects showed no increase in prominent laboratory findings associated with muscle toxicity, 
such as increased levels of serum markers, including creatinine, lactate dehydrogenase (LDH), 
blood urea nitrogen (BUN), uric acid, phosphorus, and potassium, which were monitored weekly 
during the first two months of a prior study (BEAM) 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).   
5.1.5. 
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 adverse events of weight 
decrease or decreased appetite (irrespective of relationship to treatment).  Weight reduction was 
more pronounced in patients treated with bardoxolone methyl than in those given placebo. 
Weight loss of approximately one kilogram per month was observed, with patients of higher 
body-mass index at baseline losing more weight (in absolute terms) than those of normal or 
moderately-elevated body-mass index. 
Bardoxolone methyl-treated PAH patients have also had decreases in weight, with mean weight 
decreases of approximately 3 kg versus placebo at Week 16.  Weight loss in PAH patients has 
not coincided with reports of decreased appetite or anorexia adverse events. 
5.1.6. 
Hypomagnesaemia 
Hypomagnesaemia has not been reported in PAH patients to date, but was reported as an adverse 
event for 15.5% of patients with CKD who also had type 2 diabetes who received bardoxolone 


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methyl.  The adverse event 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 adverse events or 
cardiac adverse events, 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.  


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
For patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-
PAH) enrolled in this study, the objectives are as follows: 
6.1.1. 
Primary Objective   
To assess the efficacy of bardoxolone methyl relative to placebo. 
6.1.2. 
Secondary Objective 
To assess the safety of bardoxolone methyl relative to placebo. 
6.2. 
Endpoints 
6.2.1. 
Primary Efficacy Endpoint 
Change from baseline in six-minute-walk distance (6MWD) relative to placebo at Week 24 
6.2.2. 
Secondary Efficacy Endpoints 
Time-to-first clinical improvement event consisting of a persistent change for any of the 
following: 
 Improvement by at least one WHO functional class 
 Increase from baseline in 6MWD by at least 10% 
 Decrease from baseline in creatine kinase (as a surrogate biomarker for muscle injury 
and inflammation) by at least 10% 
The persistence of the change in WHO functional class, 6MWD, or creatinine kinase must be 
confirmed by a successive assessment also meeting the defined criteria.  The confirmatory 
assessment must be at least 14 days after the initial assessment, or at the next scheduled 
assessment.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2.4. 
Safety Endpoints 
Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, 
and change from baseline in the following assessments: physical examinations, vital sign 
measurements, 12-lead electrocardiograms (ECGs), clinical laboratory measurements, and 
weight. 
 
 
 
 
 
 
6.2.6. 
Pharmacokinetic Endpoints 
Systemic exposure to bardoxolone methyl will be assessed in all patients.  Additional blood 
sampling will be performed in a subset of patients for the purpose of obtaining more robust 
pharmacokinetic (PK) parameter estimates (e.g., AUC, Cmax, Tmax) for bardoxolone methyl in the 
CTD-PAH population.  


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This double-blind, randomized, placebo-controlled trial will study the safety, tolerability, and 
efficacy of bardoxolone methyl in qualified patients with WHO Group I CTD-PAH.  
Qualified patients will be randomized 1:1 to either bardoxolone methyl or placebo to be 
administered once daily for 24 weeks.  Patients randomized to placebo will remain on placebo 
throughout the study and undergo sham titration.  Patients randomized to bardoxolone methyl 
will start at 5 mg and will dose-escalate to 10 mg at Week 4, unless contraindicated clinically.  
Dose de-escalation is permitted during the study if indicated clinically.  Please refer to 
Section 7.3.1 for additional details on dose escalation and dose de-escalation.  
All patients in the study will follow the same visit and assessment schedule.  Following 
randomization, patients will be scheduled to be assessed in person during treatment at Weeks 1, 
2, 4, 6, 8, 16, and 24 and by telephone contact on Days 3, 10, 21, 31, 38, 84, and 140.  Patients 
will also be scheduled to be assessed at an in-person follow up visit at Week 28, four weeks after 
the end of treatment. 
Patients who complete the study and are treatment-compliant to their assigned dose will be 
eligible for a separate open-label extension study.   
7.1.1. 
Blinded Sample Size Re-Calculation 
A sample size re-calculation will be performed to evaluate on a blinded basis the study 
assumptions used to calculate sample size.  A sample size re-calculation committee (SRC), 
comprised of Sponsor personnel and the study’s blinded statistician, will be established to re-
calculate sample size based on blinded assessment of study assumptions.  The SRC will review 
available data (e.g., baseline characteristics, study drug discontinuations, variability in 6MWD 
change from baseline, intra-patient autocorrelations of 6MWD) when approximately 100 patients 
have been enrolled in the study.  The Sponsor may increase the sample size of the study up to 
approximately 200 patients.  An increase of sample size within this range will be documented in 
a note-to-file to the investigators/IRBs/ECs (as appropriate) and will not require a protocol 
amendment.  Because these analyses will be based on pooled, blinded data they will not impact 
the Type I error rate.  An appendix to the Statistical Analysis Plan (SAP) will present details 
regarding the planned re-calculation of sample size. 
7.2. 
Number of Patients 
Approximately 130 patients will be enrolled; this number may be increased up to approximately 
200 patients based upon a blinded sample size re-calculation.  
7.3. 
Treatment Assignment 
Qualified patients will be randomized 1:1 to either bardoxolone methyl or placebo to be 
administered once daily for 24 weeks.  Randomization will be performed using an interactive 


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web response system (IWRS).  Patients randomized to placebo will remain on placebo 
throughout the study, but will follow sham titration to maintain the blind.   
7.3.1. 
Dose Escalation and Dose De-Escalation  
Patients randomized to bardoxolone methyl will start at 5 mg and will dose-escalate to 10 mg at 
Week 4, unless contraindicated clinically.  The investigator should discuss any reason for not 
dose-escalating at Week 4 with the medical monitor.  The investigator may choose to decrease 
the patient’s dose to one-half of the prior dose (e.g., 10 mg to 5 mg) if clinically indicated.  Dose 
de-escalation can occur more than once, but the minimum dose permitted is 2.5 mg.  Reasons for 
dose de-escalation should be discussed with the medical monitor prior to changing dose.   
The Week 4 visit is the only study visit when dose escalation is permitted.  Patients may have 1 
dose de-escalation prior to Week 4.  At Week 4, all patients should dose escalate, unless contra-
indicated and discussed with the medical monitor. 
If patients did not dose de-escalate prior to Week 4, then: 
 If patients dose escalate at Week 4, at most 2 dose de-escalations are permitted after 
Week 4 
 If patients did not dose escalate at Week 4, then only 1 dose de-escalation is permitted 
after Week 4 
If patients did dose de-escalate prior to Week 4, then: 
 If patients did dose escalate at Week 4, only 1 dose de-escalation is permitted after Week 
4 
 If patients did not dose escalate at Week 4, then no further dose de-escalations are 
permitted after Week 4 
After Week 4, once a patient’s dose has been reduced, dose escalation back to a higher dose is 
not permitted.  If a patient’s dose was reduced to 2.5 mg prior to the Week 4 visit, they are 
permitted to escalate to 5 mg at Week 4. 
Unscheduled visits due to dose de-escalation should include assessments detailed in Section 9.7.  
7.4. 
Criteria for Study Termination 
Although the Sponsor intends to complete the study, the Sponsor reserves the right to 
discontinue the study at any time for clinical or administrative reasons, or if required by 
regulatory agencies.  If the Sponsor discontinues the study, all study drug will be discontinued 
and the investigator will be responsible for securing any alternative therapy to be administered, 
as appropriate. 
7.5. 
Schedule of Assessments 
Table 3 lists the overall schedule of assessments for the study. 


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Table 3: 
Schedule of Assessments  
Study Week  
(Day) 
Assessment 
Screen Aa 
Screen Bb Day 1c 
Week 1 
(Phone) 
Day 3±2 
Week 1  
Day 7±3 
Week 2  
(Phone) 
Day 10±2 
Week 2 
Day 14±3 
Week 3 
(Phone) 
Day 21±2 
Week 4 
Day 28±3 
Week 4 
(Phone) 
Day 31±2 
Week 5  
(Phone) 
 Day 38±2 
Week 6 
Day 42±3 
Informed consent 
X 
 
 
 
Inclusion/ exclusion 
X 
 
Xd 
 
 
Demographics and baseline disease characteristics 
X 
 
 
 
Prior and Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current PAH background medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
 
 
Height 
X 
 
 
 
Echocardiograme 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight at home 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense weight diary 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Collect/review weight diary 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight in clinic  
X 
 
X 
X 
X 
X 
 
 
X 
ECG 
X 
 
 
 
Vital sign measurements 
X 
X 
X 
X 
X 
X 
 
 
X 
Physical examf 
X 
 
X 
X 
X 
X 
 
 
X 
Pulmonary function testing 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Right heart catheterization 
Xi 
 
 
 
 
 
 
 
 
 
 
 
V/Q scanj 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test for WOCBPk 
X 
X 
X 
X 
 
 
Study drug administration 
 
 
X 
------------------------------------------------------------------ X ------------------------------------------------------- 
Dispense study drug 
 
X 
X 
 
 
Collect study drug 
 
X 
 
 
Telephone contact 
 
X 
X 
X 
X 
X 
Adverse event collection 
 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
 
 
X 
BNP and NT-Pro BNP 
X 
X 
X 
X 
X 
X 
 
 
X 
Hematology 
X 
X 
X 
X 
X 
X 
 
 
X 
Urinalysis and microscopy 
X 
 
X 
X 
X 
X 
 
 
X 
Virus serology 
X 
 
 
 
6-min walk test 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Xn 
 
Xo 
 
 
 
 
 
 
 
 
 
X 
 
 
WHO functional classp 
X 
 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
PK samplesr 
 
 
 


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Study Week  
(Day) 
Assessment 
Week 8 
Day 56±3 
Week 12 
(Phone) 
Day 84±2 
Week 16  
Day 112±3 
Week 20 
(Phone)  
Day 140±2 
Week 24 (1) or  
Week 24 Day Prior Visitu 
Day 167±3 
Week 24 (2) or  
End of Treatment Visitv 
Day 168±3 
Week 28 
Follow-upv 
Day 196±3 
Informed consent 
 
 
 
 
Inclusion/ exclusion 
 
 
 
 
Demographics and baseline disease characteristics 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
 
X 
X 
PAH medications 
X 
X 
X 
X 
 
X 
X 
Medical history 
 
 
 
 
Height 
 
 
 
 
Echocardiograme 
 
 
 
 
 
 
 
Weight at home 
X 
X 
X 
X 
 
X 
 
Dispense weight diary 
X 
 
X 
 
 
X 
 
Collect/review weight diary 
X 
 
X 
 
 
X 
 
Weight in clinic  
X 
 
X 
 
 
X 
X 
ECG 
 
 
 
 
X 
X 
Vital sign measurements 
X 
 
X 
 
 
X 
X 
Physical examf 
X 
 
X 
 
 
X 
X 
Pulmonary function testing 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
Right heart catheterization 
 
 
 
 
 
 
 
V/Q scanj 
 
 
 
 
 
 
 
Pregnancy test for WOCBPk 
X 
 
X 
 
 
X 
X 
Study drug administration 
---------------------------------------------------------------- X ------------------------------------------------------- 
 
Dispense study drug 
X 
 
X 
 
 
Collect study drug 
X 
 
X 
 
 
X 
Telephone contact 
X 
 
X 
 
Adverse event collection 
X 
X 
X 
X 
 
X 
X 
Clinical chemistry 
X 
 
X 
 
 
X 
X 
BNP and NT-Pro BNP 
X 
 
X 
 
 
X 
X 
Hematology 
X 
 
X 
 
 
X 
X 
Urinalysis and microscopy 
X 
 
X 
 
 
X 
X 
Virus serology 
 
 
 
 
6-min walk test 
X 
 
X 
 
Xu 
Xu 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
Xn 
 
 
Xo 
 
 
 
 
 
 
X 
WHO functional classp 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
PK samplesr 
Xs 
 
 
 
Xs,t 
Xt 


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a Total Screening period should not exceed 90 days.   
b Screen B is only required for patients if the Day 1 visit is more than 28 days after the Screen A visit.   
c Day 1 is the day of administration of the first dose.  On Day 1, all procedures should be performed before study drug administration. 
d Screening eligibility procedures do not need to be repeated on Day 1; however, a review of any changes in eligibility criteria should be evaluated prior to Day 1 procedures, and a urine pregnancy 
test should be performed for WOCBP.   
e If an echocardiogram has not been performed within 90 days of Day 1, echocardiogram must be performed during Screening to confirm left ventricular ejection fraction ≥ 40%. 
f 
. 
g Pulmonary function tests within 90 days prior to Day 1 may be used to determine eligibility.  
h
  
i Right heart catheterization within 36 months prior to Day 1 may be used to determine eligibility. 
 
j Patients who have not had a V/Q scan, spiral/helical/electron beam computed tomography (CT), or pulmonary angiogram prior to Screening should have this assessment performed to determine 
eligibility.  If V/Q scan is abnormal at Screening (i.e., results other than normal or low probability), then a confirmatory CT or selective pulmonary angiography must also be performed at 
Screening to exclude chronic thromboembolic pulmonary hypertension (CTEPH). 
k A serum pregnancy test will be performed at the Screening 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 if requested by a local health authority or IRB/EC.  For WOCBP enrolled in the UK and 
Argentina, pregnancy testing will be performed every 4 weeks while taking study drug. 
l AE assessments on Day 1 should be performed following study drug administration.  
m 
 
n 
  
o 
   
p 
 
q 
 
r Patients must be instructed to not take their study drug prior to coming to the clinic for visits when PK samples will be collected.  Patients must administer the study drug dose in the clinic on PK 
sample collection visits after the 0 hour PK blood sample is collected.  Patients will have blood samples for PK analysis drawn just prior to (0 hour) and after (2 and 4 hours) dose administration.   
s Patients participating in the PK sub-study will have 5 additional blood samples for PK analysis drawn for this visit.  PK sub-study patients will have blood samples for PK analysis drawn just 
prior to (0 hour) and after (1, 2, 3, 4, 6, 8, and 24 hours) dose administration for this visit. 
t Patients not participating in the PK sub-study may have blood collected on either day of the Week 24 visit. 
u The 6-minute walk test must be performed on two separate days within the 3-day window at Week 24. 
v Patients who terminate from the study prior to the Week 24 study visit should be brought back to the clinic as soon as possible for early termination assessments (i.e., Week 24 Day Prior and end-
of-treatment visits) as well as a follow-up visit 4 weeks later.  Patients should complete the end-of-treatment procedures, including the 6MWT, prior to any adjustments being made to their PAH 
treatment regimen. 
 
Abbreviations: ECG = electrocardiogram, PK = pharmacokinetic, V/Q = ventilation-perfusion, WOCBP = women of child-bearing potential, 6MWT = 6-minute walk test, 


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Diagnosis and main criteria for inclusion:  
1. Adult male and female patients ≥ 18 to ≤ 75 years of age upon study consent; 
2. BMI > 18.5 kg/m2; 
3. Symptomatic pulmonary hypertension WHO/NYHA FC class II and III; 
4. WHO Group I PAH associated with connective tissue disease;  
5. Had a diagnostic right heart catheterization performed and documented within 36 months 
prior to Day 1 that confirmed a diagnosis of PAH according to all the following criteria:  
a. Mean pulmonary artery pressure ≥ 25 mm Hg (at rest); 
b. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; 
c. Pulmonary vascular resistance > 240 dyn•sec/cm5 or > 3 mm Hg/liter (L)/minute; 
6. Has BNP level ≤ 400 pg/mL; 
7. Had an average 6MWD ≥ 150 meters on two consecutive tests performed on different 
days prior to randomization, with a percent difference ≤ 15% between tests; 
8. Has been receiving no more than two (2) approved disease-specific PAH therapies.  PAH 
therapy must have been at a stable dose for at least 90 days prior to Day 1.  No additions 
or changes should be made to PAH therapies and doses should remain stable for the 
duration of the study;  
9. Has maintained a stable dose for 30 days prior to Day 1 if receiving therapies that may 
affect walking distance, including but not limited to:  vasodilators (including calcium 
channel blockers), digoxin, L-arginine supplementation, oxygen supplementation, 
diuretics, agents to treat neuropathic pain associated with peripheral neuropathy (such as 
pregabalin), and/or agents to treat anemia (such as supplemental iron, erythropoietin, or 
intravenous iron).  If the patient receives intravenous iron therapy during Screening, the 
intravenous infusion must be performed at least 30 days prior to Day 1; 
10. If receiving treatment for CTD with prednisone or any other drugs, the medications must 
remain the same for at least 90 days prior to Day 1.  Doses for medications prescribed for 
the treatment of CTD must remain stable for at least 30 days prior to Day 1 and for the 
duration of the study;   
11. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 with total lung 
capacity ≥ 65% (predicted); 
12. Had a ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed 
tomography (CT), or pulmonary angiogram prior to Day 1 that shows no evidence of 
thromboembolic disease (i.e., should note normal or low probability for pulmonary 
embolism).  If V/Q scan was abnormal (i.e., results other than normal or low probability), 


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then a confirmatory CT or selective pulmonary angiography must exclude chronic 
thromboembolic pulmonary hypertension; 
13. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥ 45 mL/min/1.73 m2 as measured by the central lab; 
14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures; 
15. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects 
of the study prior to initiation of any patient-mandated procedures. 
8.2. 
Patient Exclusion Criteria 
All patients with any of the following conditions or characteristics must be excluded from the 
study: 
1. Participation in other investigational clinical studies involving interventional products 
being tested or used in a way different from the approved form or when used for an 
unapproved indication within 30 days prior to Day 1; 
2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 90 days prior 
to Day 1 or planned initiation during the study;   
3. Stopped receiving any PAH chronic therapy within 60 days prior to Day 1; 
4. Received a dose of prednisone >20 mg/day (or equivalent dose if other corticosteroid) 
within 30 days prior to Day 1; 
5. Received intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues 
within 90 days prior to Day 1; 
6. Received intravenous inotropes within 30 days prior to Day 1;  
7. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure 
(BP) > 160 mm Hg or sitting diastolic BP > 100 mm Hg during Screening after a period 
of rest; 
8. Has systolic BP < 90 mm Hg during Screening after a period of rest; 
9. Has a history of clinically significant left-sided heart disease and/or clinically significant 
cardiac disease, including but not limited to any of the following: 
a. Congenital or acquired valvular disease if clinically significant apart from 
tricuspid valvular insufficiency due to pulmonary hypertension; 
b. Pericardial constriction; 
c. Restrictive or congestive cardiomyopathy; 
d. Left ventricular ejection fraction < 40% per echocardiogram (ECHO) within 
90 days of Day 1; 
e. Symptomatic coronary artery disease within the last 3 years; 


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10. Acutely decompensated heart failure within 30 days prior to Day 1, per investigator 
assessment; 
11. Has more than two of the following clinical risk factors for left ventricular diastolic 
dysfunction: 
a. Age > 65 years; 
b. BMI ≥ 30 kg/m2; 
c. History of systemic hypertension; 
d. History of type 2 diabetes; 
e. History of atrial fibrillation; 
12. History of atrial septostomy within 180 days prior to Day 1; 
13. Uncontrolled obstructive sleep apnea;   
14. Has a history of portal hypertension or chronic liver disease, including hepatitis B and/or 
hepatitis C (with evidence of recent infection and/or active virus replication) defined as 
mild to severe hepatic impairment (Child-Pugh Class A-C); 
15. Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at 
Screening;  
16. Hemoglobin (Hgb) concentration < 10.5 g/dL at Screening; 
17. Diagnosis of Down syndrome; 
18. History of malignancy within 5 years prior to Screening, with the exception of localized 
skin or cervical carcinomas; 
19. Untreated or uncontrolled active bacterial, fungal, or viral infection; 
20. Known or suspected active drug or alcohol abuse, per investigator judgment; 
21. Use of inhaled nitric oxide within 7 days prior to Screening and Day 1 visits, excluding 
acute vasodilator testing during diagnostic cardiac catheterization;  
22. Major surgery within 30 days prior to Day 1 or planned to occur during the course of the 
study; 
23. Unwilling to practice acceptable methods of birth control (both males who have partners 
of childbearing potential and females of childbearing potential) during Screening, while 
taking study drug, and for at least 30 days after the last dose of study drug is ingested;  
24. Women who are pregnant or breastfeeding; 
25. Any disability or impairment that would prohibit performance of the 6MWT; 
26. Any abnormal laboratory level that, in the opinion of the investigator, would put the 
patient at risk by trial enrollment; 
27. 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; 
28. Known hypersensitivity to any component of the study drug;  


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29. Unable to communicate or cooperate with the investigator because of language problems, 
poor mental development, or impaired cerebral function. 
30. Patient has active myositis;  
31. Use of total parenteral nutrition within one year of the Day 1 study visit; 
32. History of acute renal crisis within one year of the Day 1 study visit; 
33. Patient has participated in investigational trials where bardoxolone methyl was 
administered.  
8.3. 
Patient Re-Screening 
Patients may repeat the Screening procedures to qualify for the study with approval from the 
medical monitor. 
8.4. 
Patient Discontinuation and Termination 
Patients have the right to discontinue study drug or withdraw from the study at any time for any 
reason, without prejudice to their medical care.  Furthermore, the investigator may discontinue a 
patient from study drug.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study.  The reason for a patient’s 
discontinuation from study drug or study termination will be recorded in the electronic case 
report form (eCRF).  
8.4.1. 
Patient Discontinuation Criteria 
Discontinuation refers to a patient’s stopping administration of study drug.  Reasons for study 
drug discontinuation may include the following: 
 Confirmed clinical worsening event 
 Occurrence of an AE or change in medical status that leads the investigator to be 
concerned about the patient’s welfare 
 Administrative reasons (e.g., inability to continue) 
 Sponsor termination of the study 
 Voluntary withdrawal 
 Females who become pregnant during the study 
 Investigator unblinding 
Patients must discontinue study drug if any of the following occur. 
 ALT or AST > 8X ULN; 
 ALT or AST > 5X ULN for 14 days; 
 ALT or AST > 3X ULN and (total bilirubin > 2X ULN or INR > 1.5); 
 ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%); 


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Patients who are discontinued from study drug should still continue in the study, completing all 
study visits and undergo all scheduled study assessments, if possible.   
8.4.2. 
Patient Termination Criteria 
Termination refers to a patient’s stopping study drug and all study assessments and visits.  
Reasons for study termination include the following: 
 Loss to follow-up 
 Death 
 Withdrawal of consent 
Every reasonable effort should be made to contact patients who do not return for a scheduled 
visit.  The investigator should inquire about the reason for withdrawal, request the patient return 
all unused investigational product, request the patient return for end-of-treatment and follow-up 
visits (if applicable), and follow up with the patient regarding any unresolved AEs.   


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9. 
TREATMENT OF PATIENTS 
9.1. 
Select Management Guidelines 
The following guidelines apply to the management of study participants:   
9.1.1. 
Management of Fluid Status 
Specific risk mitigation procedures will be employed to reduce the potential for bardoxolone 
methyl-induced fluid overload.  These procedures include exclusion of patients with any 
clinically significant renal disease, defined as an eGFR value of < 45 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 > 400 pg/mL, will also be excluded.  Laboratory data will also be used 
to monitor fluid status after randomization.   
Additionally, after randomization patients will be closely monitored for rapid weight gain 
suggestive of fluid overload.  Patients will be given a Sponsor-provided scale to use at home to 
collect and record their weights daily during the first 8 weeks of the treatment period and weekly 
thereafter.  Patients who experience a five-pound (2.3 kilogram) or greater increase in weight 
since their Day 1 weight during the first 8 weeks of the study will be instructed to stop taking 
their study medication immediately and return to the clinic for an unscheduled physical 
examination and laboratory assessment by the investigator.  Patients who experience a five 
pound (2.3 kilogram) or greater increase in weight between Day 1 and Week 8 may not restart 
their study medication until the investigator has completed and documented an assessment of 
fluid overload.  
Patients who experience a five pound (2.3 kilogram) or greater increase in weight after the Week 
8 study visit will be instructed return to the clinic for an unscheduled physical examination and 
laboratory assessment by the investigator.  Study medication should not be discontinued unless 
the investigator has completed and documented an assessment of fluid overload and determines 
that the patient should be discontinued. 
Investigators should advise patients to watch for signs and symptoms of fluid overload.  Patients 
should be informed to notify their physicians immediately if they experience swollen feet, chest 
pain, shortness of breath with mild exertion or while lying down, or other relevant symptoms.  
The investigator should immediately assess symptoms of fluid overload and determine 
appropriate medical management, as necessary, including whether stopping drug administration 
is required.  At the earliest sign of worsening or new onset peripheral edema or other signs and 
symptoms of acute volume overload, investigators will also be expected to determine if changes 
to a patient’s diuretic regimen is needed. 


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9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) 
Nearly all instances of elevated transaminases are expected to be asymptomatic.  Check 
transaminase levels (as well as total bilirubin (TBL), GGT, alkaline phosphatase (ALP), and 
International Normalized Ratio (INR)) within 48 to 72 hours during an unscheduled visit if the 
following occurs: 
 ALT or AST levels > 3X ULN 
Repeat testing every 72 to 96 hours until transaminase levels are below 3X the ULN for at least 
one week or until the patient withdraws consent. 
Discontinue study drug administration permanently if any of the following occurs: 
 ALT or AST > 8X ULN 
 ALT or AST > 5X ULN for more than 2 weeks 
 ALT or AST > 3X ULN and (TBL > 2X ULN or INR > 1.5) 
 ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%);  
The hepatobiliary tree must be visualized (e.g., ultrasound, MRI) and assessed if a patient 
discontinues taking study drug secondary to elevated transaminase levels.  Additional 
tests/studies may be warranted depending on the clinical presentation. 
9.1.3. 
Management of Muscle Spasms 
Basic symptomatic relief is the first step in managing muscle spasm, including walking, adequate 
hydration, wearing socks, and stretching before bedtime.  Assessment of levels of electrolytes 
such as magnesium, calcium and potassium may indicate the need for replacement.  If vitamin D 
levels are low, supplementation may be warranted.  Muscle relaxants may also help relieve 
symptoms. 
9.1.4. 
Weight Loss 
Ongoing assessments to ensure that the patient is receiving adequate nutrition and consideration 
of other etiologies of weight loss may be warranted for patients receiving bardoxolone methyl.   
9.1.5. 
Hypomagnesaemia 
In instances where a patient experiences hypomagnesaemia, defined as serum magnesium less 
than 1.3 mEq/L (0.65 mmol/L), consideration should be given to repletion of serum magnesium. 
9.1.6. 
Nausea 
Nausea may occur with higher doses of bardoxolone methyl.  Nausea adverse events are 
typically mild and reversible within a few weeks after treatment initiation.  If symptoms do not 
resolve, dose de-escalation, with consultation of the medical monitor, may be necessary.   
9.1.7. 
Anemia 
Anemia is a common occurrence in PAH patients.  If a patient has serum levels of hemoglobin 
< 10.5 g/dL at Screening, the patient will be allowed to re-screen following anemia treatment.  
Re-screening can occur no sooner than 30 days following initiation of anemia treatment.  


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Patients with anemia who re-screen must repeat all Screening assessments at the re-screening.  If 
the patient takes agents to treat anemia (including but not limited to supplemental iron, 
erythropoietin, or intravenous iron) the patient must remain on a stable dosage for at least 
30 days prior to Day 1.  If the patient receives intravenous iron therapy during Screening, the 
intravenous infusion must be performed at least 30 days prior to Day 1.  
9.2. 
Description of Study Drug 
Bardoxolone methyl (RTA 402) drug product information is shown in Table 4.  Information 
about the placebo is shown in Table 5. 
Table 4: 
Bardoxolone Methyl Drug Product Information 
Description 
Bardoxolone methyl capsule (2.5 mg, 
5 mg) 
 
 
 
  
  
  
 
 
 
  
 
 
Route of Administration 
Oral 
Table 5: 
Placebo Information 
Description 
Placebo for bardoxolone methyl capsule 
(2.5 mg, 5 mg) 
Ingredients 
Silicified Microcrystalline Cellulose  
Lactose monohydrate 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide (capsule pigment) 
Route of Administration 
Oral 
9.3. 
Concomitant Medications 
9.3.1. 
Excluded Medications 
Patients taking these medications or treatments will be ineligible for enrollment: 
 Any other investigational drug or device as part of an interventional study; 


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 Intravenous or subcutaneous prostacyclin/prostacyclin analogue; 
 Intravenous inotropes;  
 Inhaled nitric oxide (excluding acute vasodilator testing during diagnostic cardiac 
catheterization);  
 Prednisone at a dosage > 20 mg/day within 30 days prior to Day 1 or at any time 
during the study; 
Patients who take excluded medications during the study should not discontinue study drug 
solely on this basis.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study. 
9.3.2. 
Permitted Medications 
Allowed concomitant medications include the following: 
 Antibiotics; 
 Daily multivitamins or recommended daily supplements; 
 Other medications intended to manage concurrent diseases, as authorized by the 
treating physician; 
 Oral, implantable, or injectable contraceptives. 
Patients taking medication chronically 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, as medically feasible.   
The use of the following therapies, which may affect walking distance, are permitted during the 
study, provided the patients have been receiving a stable dosage for at least 30 days prior to 
Day 1.  Unless medically indicated and discussed with the medical monitor, the doses of these 
agents should remain unchanged during the study. 
 Vasodilators (including calcium channel blockers);  
 Digoxin; 
 L-Arginine supplementation;  
 Diuretics; 
 Agents to treat anemia (including but not limited to supplemental iron, erythropoietin, 
or intravenous iron);  
 If the patient receives intravenous iron therapy during Screening, the intravenous 
infusion must be performed at least 30 days prior to Day 1; 
 Agents to treat neuropathic pain associated with peripheral neuropathy (such as 
pregabalin); 
 Oxygen supplementation. 
If receiving treatment for CTD with prednisone or any other drugs, the medications must remain 
the same for at least 90 days prior to Day 1.  Doses for medications prescribed for the treatment 


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of CTD must remain stable for at least 30 days prior to Day 1 and for the duration of the study.  
PAH-specific background therapy should be taken as clinically indicated and prescribed by the 
physician for the duration of the study. 
Refer to Section 9.10.26 for guidelines on oxygen use during 6MWTs.  Initiation of 
supplemental long-term oxygen therapy (oxygen application for more than 30 consecutive days) 
or persistent modification of a pre-existing supplemental long-term oxygen therapy (i.e., need for 
a persistent increase of the amount of delivered oxygen for more than 30 days) due to worsening 
PAH is permitted.  
Diuretics may be prescribed as clinically indicated throughout the study.  Any changes to the 
doses of oxygen or diuretics throughout the course of the study must be recorded in the eCRF.   
9.4. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to patients enrolled in the study in accordance with the protocol.  The study drug must not be 
used for reasons other than that described in the protocol.  Patients who miss more than 42 doses 
(i.e., 25% of the 168 expected doses) will not be considered treatment-compliant.  Patients must 
be considered treatment-compliant to be eligible for the open-label extension study.   
9.5. 
Randomization 
An IWRS will be utilized to randomize patients 1:1 to bardoxolone methyl or placebo.  
Randomization will be stratified by number of background PAH therapies: 0, 1, or 2.  
9.6. 
Blinding 
In this double-blind study all patients, investigators, site personnel, laboratories and central 
readers with direct involvement in the conduct of the study or their designees will be blinded to 
treatment assignments.  To prevent potential bias, appropriate measures will be taken to ensure 
the blind is maintained for the patients and personnel mentioned previously.  To maintain the 
blind, investigators will distribute blinded study drug treatment kits to patients as directed by the 
IWRS system.  Investigators and patients will not be blinded to dose level, but will be blinded to 
treatment assignment (i.e., active study drug vs. placebo).  
An IWRS system will manage treatment assignments.  The only people with direct access to 
treatment assignments will be those individuals who develop and maintain the randomization 
code, the DSMB and the statistical group reporting to the DSMB.   
9.6.1. 
Patient Unblinding 
Although there is no known antidote to bardoxolone methyl, under rare circumstances 
unblinding may be considered medically necessary.  The investigator is strongly encouraged to 
contact the medical monitor to discuss situations in which he or she believes that the blind should 
be broken, but ultimately the investigator has the right to break the blind (e.g., in the event of a 
serious or life-threatening medical situation). 


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If unblinding is required, the investigator will utilize the IWRS to perform the unblinding.  If a 
study drug assignment is unblinded, the investigator must describe the event that required 
unblinding in the patient’s source documents.  
Patients must discontinue taking study drug if their treatment assignment has been unblinded to 
the investigator (or designee).  Such patients must undergo the same study drug discontinuation 
procedures as those patients who discontinue taking study drug for other reasons. 
Patient treatment assignments must not be unblinded in the case of an AE or SAE, except as 
described above. 
9.6.2. 
Unblinding for Regulatory Submission 
In situations where regulation requires unblinding and reporting of a particular serious adverse 
event, the appropriate bodies (e.g., ethics committees, IRBs, regulatory agencies) must be 
provided with unblinded information according to the applicable regulatory requirement.  This 
information must not be conveyed to any investigator, site personnel or patient; therefore, this 
type of unblinding does not necessitate that the patient discontinue taking study drug.  In cases 
when unblinded information must be conveyed to local health authorities, personnel without 
direct involvement in the conduct of the study must be responsible for unblinding the patient’s 
treatment using the IWRS and conveying the necessary information. 
9.6.3. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will review unblinded safety data 
throughout the study and make recommendations as appropriate.  The DSMB will begin 
quarterly data reviews approximately 3 months after the first patient is enrolled and continue 
through the last dose of the last patient enrolled.   
The DSMB will consist of external experts supported by an independent statistical group.  The 
independent statistical group will prepare unblinded analyses for the DSMB and will not have a 
role in the statistical analysis plan (SAP) after the study has started enrolling patients.  A 
separate, blinded statistical group (i.e., not associated with the DSMB) will be responsible for 
producing and finalizing the SAP and executing final data analysis of the study.   
The DSMB will be governed by a charter that will describe the following: 
 Roles and responsibilities of the DSMB members and the independent statistical 
group 
 Meeting format and frequency 
 Communication channels between the DSMB, 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  
 Process for interim analysis of efficacy, including the alpha spending function 


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Briefly, the DSMB will review the progress of the study and the accumulating unblinded data 
while the study is ongoing.  The DSMB will make recommendations to Sponsor representatives 
following each meeting.  The DSMB may recommend that the study continue as is, be modified 
to protect patient safety, or be terminated.  However, investigators, and not the DSMB, will make 
intra-patient dose-escalation decisions at the Week 4 visit for each patient and may choose to 
decrease the patient’s dose (to one-half of the prior dose).   
9.7. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
 Assessment of weight gain per Section 9.1.1;  
 Management of an adverse event or serious adverse event; 
 Performance of additional laboratory tests for clinically abnormal laboratory test 
values or to confirm a possible pregnancy; 
 Dose de-escalation; 
 Any time the investigator feels that it is clinically appropriate for patient safety. 
At a minimum, unscheduled visits should include collection of adverse events, clinical 
chemistry, hematology, concomitant medications and vital signs, as well as collection/review of 
weight diary.  Additional conversations may be necessary with the medical monitor following an 
unscheduled visit to assess patient safety. 
9.8. 
Pregnancy 
9.8.1. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) are those who are not surgically sterile (no history 
of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy) do not have 
fallopian inserts with confirmed blockage, have not had reproductive potential terminated by 
radiation, and are not postmenopausal for at least 1 year. 
9.8.2. 
Methods of Birth Control 
During Screening, while taking study drug and until 30 days following administration of the final 
dose of study medication, WOCBP must practice one of the following acceptable methods of 
birth control: 
 Use double barrier contraception method defined as male use of a condom and female 
use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, 
diaphragm [always use with spermicidal jelly/cream]); 
 Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
90 days prior to start of study drug administration; 
 Use of an intrauterine device; 


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 Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
During Screening, while taking study drug and until 30 days after the final dose of study 
medication is taken, males who have female partners of childbearing potential must practice one 
of the following methods of birth control: 
 Have had a vasectomy (at least 6 months earlier); 
 Use double barrier contraception method, defined as male use of a condom and 
female use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, 
diaphragm [always use with spermicidal jelly/cream]); 
 Partner use of an intrauterine device; 
 Partner use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) for 
at least 90 days prior to start of study drug administration; 
 Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
9.8.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).  Male patients must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a patient or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If the serum pregnancy test 
confirms the pregnancy, the patient must permanently discontinue taking study drug.  The 
investigator must immediately report to the medical monitor a pregnancy associated with study 
drug exposure.  The early discontinuation protocol-required procedures outlined for End-of-
treatment and Follow-up visits must be performed on the patient.  
Pregnancy is not considered an AE; however, the investigator must follow a pregnant patient, or 
the pregnant female partner of a male patient (if consenting), and report follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome.  Infants 
resulting from such pregnancies should be followed for a minimum of 8 weeks.  Reata or 
designee may contact the investigator to request additional information throughout the course of 
the pregnancy. 
The following pregnancy outcomes must be considered SAEs and will require additional 
reporting in the eCRF and reported as a serious adverse event: 
 Congenital anomaly/birth defect; 
 Stillbirth; 
 Spontaneous miscarriage. 


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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.  Dose 
escalations are not permitted beyond the scheduled Week 4 visit.  Once a patient’s dose has been 
reduced, that dose should be maintained until the Week 24 visit.  Patients who resume therapy 
after an interruption will follow the originally planned study schedule.  
9.10. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 3.  All Day 1 procedures, except AE assessments, should be completed prior to 
administration of first dose of study drug. 
9.10.1. 
Informed Consent 
Written informed consent (see Section 15.3) must be obtained from the patient before any 
study-related procedures are performed, and again if there is a change in the study procedures 
that would affect the patient’s willingness to participate. 
9.10.2. 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Table 3.  Patients must meet all 
of the inclusion and none of the exclusion criteria for entry in the study.  Investigators should 
contact the medical monitor with any questions regarding eligibility prior to randomizing the 
patient on Day 1. 
9.10.3. 
Demographics and Baseline Disease Characteristics 
Demographic data including sex, age, race, and ethnicity, will be collected as indicated in  
Table 3.  Baseline disease characteristics will be collected as indicated in Table 3.   
9.10.4. 
Prior and Current Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking.  
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug names 
should be used where possible.  Concomitant medications will be reviewed as indicated in  
Table 3 and all changes will be recorded. 
9.10.5. 
Current PAH Background Medications 
The name, dose, and frequency must be recorded for all PAH background medications that the 
patient is taking.  PAH background medications are those that have been approved by the FDA 
or the local health authority for the treatment of PAH.  Trade or generic drug names should be 
used where possible.  PAH background medications will be reviewed as indicated in Table 3 and 
all changes will be recorded.  Additional background PAH medications may only be prescribed 
after a clinical worsening event is confirmed.  


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9.10.6. 
Medical History 
A complete medical history (e.g., per patient report) that includes all medical history within the 
past 5 years must be collected.  Medical history will be recorded as indicated in Table 3.   
9.10.7. 
Height 
Height should be measured without footwear or prosthetics as indicated in Table 3. 
9.10.8. 
Echocardiogram 
If an echocardiogram has not been performed within 90 days of Day 1, an echocardiogram must 
be performed during Screening to confirm eligibility as indicated in Table 3. 
9.10.9. 
Weight and Body Mass Index (BMI) 
Weight must be measured as indicated in Table 3.  Body mass index (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 and the self-administration of study drug.  Weights recorded in patient diaries will 
not be entered in the eCRF.  Weights should be taken at the same time each day and recorded in 
a patient diary.  During the first eight weeks, weights will be recorded daily; weekly weights will 
be recorded thereafter.  Patients will be instructed to stop administering study drug and contact 
the investigator if their daily weight increases per the criteria outlined in Section 9.1.1.  Patients 
will be provided instructions within the Informed Consent Form to help ensure consistent weight 
collection throughout the study.  
9.10.10. 
Electrocardiograms (ECG) 
A 12-lead ECG will be recorded as indicated in Table 3 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. 
9.10.11. 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), respiration rate, and body temperature.  Blood pressure should be taken after the 
patient has rested in a sitting position for at least 5 minutes.  The same arm (usually the non-
dominant arm) and the appropriate size cuff should be used for each measurement.  Vital sign 
measurements should be taken as indicated in Table 3.  
9.10.12. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner as indicated in Table 3 and as documented within the table 
footnotes.  The examination must include the following organ or body system assessments: head, 
eyes, ears, nose, throat, musculoskeletal, cardiovascular, lymphatic, respiratory, abdomen, skin, 
extremities, and neurological.  Assessments of any specific signs or symptoms reported by the 
patient must also be performed and documented along with any other findings of note.  Findings 
at Screening must be characterized as either normal or abnormal; if abnormal, a description of 
the abnormality must be provided.  Following the examination at Screening, changes must be 


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classified as new, worsened, or improved from the last time the body system was assessed.  If 
possible, the same individual should perform each physical examination on a patient during the 
study. 
9.10.13. 
Pulmonary Function Testing 
 
Pulmonary function testing that includes forced vital capacity (FVC), FVC percent predicted 
(FVC%), forced expiratory volume in 1 second (FEV1), FEV1 percent predicted (FEV1%), 
FEV1/FVC ratio, peak expiratory flow (PEF), and total lung capacity (TLC), must be performed 
as indicated in Table 3.   
 
 
  
9.10.14. 
Ventilation-Perfusion (V/Q) Lung Scan, Spiral/Helical/Electron Beam 
Computed Tomography (CT) or Pulmonary Angiogram 
Ventilation-perfusion (V/Q) lung scan, spiral/helical/electron beam computed tomography (CT) 
or pulmonary angiogram are required to determine eligibility.  If this assessment has not been 
previously performed for a patient, it must be performed at Screening.  If V/Q scan is abnormal 
at Screening (i.e., results other than normal or low probability), then a confirmatory CT or 
selective pulmonary angiography must be performed at Screening to exclude chronic 
thromboembolic pulmonary hypertension (CTEPH). 
9.10.15. 
Right Heart Catheterization 
A right heart catheterization (RHC) completed within 36 months of Day 1 is required.  However, 
if a patient has not had a RHC completed within 36 months of planned Day 1, it should be 
performed after the patient has signed Informed Consent and has passed the Screening eligibility 
procedures.   
In addition, data resulting from a RHC performed within 36 months before Day 1 or during the 
course of the study as part of the patient's standard of care should be collected on the patient's 
case report form.  Other data resulting from procedures conducted as part of the standard of care 
for the patient that may contribute to the Sponsor's understanding of the safety or efficacy of the 
compound may also be requested.   
9.10.16. 
Pregnancy Test 
WOCBP (see Section 9.8) will complete a pregnancy test as indicated in Table 3, or at any time 
if pregnancy is suspected.  Negative test results are required on Day 1 before study drug 
administration.  Any patient who becomes pregnant during the study must discontinue taking 
study drug immediately.  See Section 9.8.3 for a description of procedures to be followed in case 
of pregnancy. 
9.10.17. 
Study Drug Administration 
Patients should self-administer one capsule from each bottle included in the study drug kit orally 
once a day, preferably in the morning, as indicated in Table 3.  On days when PK samples are 


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collected, patients must not self-administer study drug.  Study staff will administer study drug at 
the clinic following collection of the first PK sample.   
At the Week 24 visit, patients who opt to participate in a sub-study of 24-hr PK must not 
administer study drug before either day of the Week 24 visit.  On the second day of the Week 24 
visit, patients must administer study drug after the 24-hr PK blood collection has been 
performed. 
A vomited dose must not be replaced.  A double dose (e.g., missed dose from previous day and 
dose for current day) must not be taken. 
9.10.18. 
Study Drug Dispensation and Collection 
Study drug will be dispensed to the patient and collected from the patient as indicated in Table 3.  
The patient will be dispensed one treatment kit at Day 1 and Week 4; two treatment kits will be 
dispensed at Week 8 and Week 16.  Dispensed treatment kits from each visit should be returned 
to the site for collection at the subsequent visit. 
9.10.19. 
Telephone Contact 
Patients will be contacted by telephone as indicated in Table 3.  Patients will be asked about their 
body weight and other signs of fluid retention, as well as adverse events and any changes to 
concomitant medications.  If fluid retention is suspected, the patient must be brought into the 
clinic and evaluated by the investigator as soon as possible, as detailed in Section 9.1.1. 
9.10.20. 
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 3.  Patients must be instructed to volunteer any 
information regarding AEs on or after the first dose of study drug or query the patients with an 
open question regarding any AEs they may be experiencing (e.g., “How have you been feeling 
since your last visit?”).  Any findings are to be documented.  Patients must be asked if they have 
been hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (including prescription drugs, over-the-counter medications, vitamins, 
herbal products, and minerals).  Responses must be documented in the source documents. 
9.10.21. 
Clinical Chemistry 
Samples will be collected for the following clinical chemistry analyses as indicated in Table 3: 
ferritin, creatine kinase (CK), blood urea nitrogen (BUN), creatinine, total bilirubin, direct 
bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), sodium, potassium, calcium, phosphorus, uric acid, total protein, glucose, 
albumin, lactate dehydrogenase (LDH), magnesium, chloride, bicarbonate, gamma-glutamyl 
transpeptidase (GGT).  Women of child-bearing potential will require a serum pregnancy test 
(hCG-Qual) at Screening or at any point in time if a pregnancy is suspected. 
9.10.22. 
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 3.  As recent exercise 
may affect BNP and NT-Pro BNP levels, patients must be allowed to rest for a minimum period 


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of one hour following arrival at the clinic and prior to obtaining this blood sample.  Similarly, 
this sample must be taken prior to the 6MWT or at least one hour after 6MWT.  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.   
9.10.23. 
Hematology 
Samples will be collected for the following hematology assessments as indicated in Table 3: 
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). 
9.10.24. 
Urinalysis and Microscopy 
Samples will be collected for the following urinalysis and microscopy assessments as indicated 
in Table 3: specific gravity, ketones, pH, protein, blood, glucose, clarity, color, leukocytes, 
nitrite, bilirubin, and a microscopic examination (if indicated based on laboratory results). 
9.10.25. 
Virus Serology 
Blood samples will be collected for testing for hepatitis B and hepatitis C as indicated in Table 3.  
If the initial hepatitis C result is positive, then the patient will need to return for an unscheduled 
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. 
9.10.26. 
6-Minute Walk Test 
A 6-minute walk test (6MWT) will be administered to patients as indicated in Table 3.  Unless 
otherwise indicated as described below, each test must be performed in strict accordance with the 
American Thoracic Society (ATS) guidelines [ATS Statement 2002] provided in Section 19 
Appendix 1.  The appropriate language version will be applied for patients with a non-English 
informed consent.  The walking course must be 30 m in length, except at sites granted prior 
sponsor agreement. 
Determination of eligibility for 6MWD is based on the 6MWTs performed on separate days at 
Screening and Day 1.  If a Screen B 6MWT is performed, 6MWD eligibility is based on the 
Screen B and Day 1 6MWDs.  Otherwise, 6MWD eligibility is based on the Screen A and Day 1 
6MWDs.  
The two 6MWD values used to determine eligibility must have a percent difference ≤ 15%, as 
determined by the following calculation:   
Percent Difference = |X-Y| / ((X+Y)/2) 
X=1st 6MWD value (Screen A or Screen B) 
Y=2nd 6MWD value (Day 1) 
|X-Y|=absolute value of the difference between the two 6MWD values 


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The assessor of the 6MWT must not provide the patient with the results of the assessment once 
complete.  A patient should wear the same shoes for all 6MWTs.  Additionally, if a patient uses a 
walking aide for the first test, this same aide should be used during all subsequent tests.  The 
shoes worn and walking aid used for each 6MWT should be noted in source documents.   
Patients who require supplemental oxygen with exercise may use their prescribed oxygen level 
during 6MWTs.  The oxygen level administered during Screening should be used during all 
subsequent tests.  Titration of supplemental oxygen levels used during the 6MWT should only 
occur during the Screening Visit 6MWT via the site’s standard oxygen titration/administration 
processes.  If a patient’s health status deteriorates during study participation and it is determined 
by a physician that the patient requires additional supplemental oxygen, the patient may continue 
study participation.  However, the original supplemental oxygen level used during the Screening 
Visit 6MWT should continue to be used during all subsequent 6MWTs.  In the opinion of the 
investigator, if a patient’s health status deteriorates to the point that the patient can no longer 
safely conduct subsequent 6MWTs using the original supplemental oxygen set at the Screening 
Visit, then 6MWT should not be conducted.   
9.10.27. 
 
 
 
 
 
 
 
 
 
 
   
9.10.28. 
Quality of Life 
 
 
9.10.29. 
WHO/NYHA Functional Class Assessment 
WHO/NYHA functional class will be assessed (Section 20, Appendix 2) as indicated in Table 3 
  To the extent feasible, the 
same evaluator should assess WHO/NYHA FC for a particular patient over the entire course of 
the study. 
 
 


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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 3.  Patients must be instructed to not take their 
study drug prior to coming to the clinic for visits when PK samples will be collected.  Patients 
will be asked by site personnel to provide the time of their last two administrations of study drug 
prior to the blood samples being collected.  Blood sample collection instructions should be 
referenced in the laboratory manual. 
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 may participate in an optional PK sub-study, which will involve additional PK blood 
draws prior to dosing and 1, 2, 3, 4, 6, 8, and 24 hours after dose administration during the 2-day 
Week 24 visit.  Patients who participate in the PK sub-study will also have PK blood draws 
collected during the Week 8 visit as indicated in Table 3.  Patients not participating in the PK 
sub-study may have blood collected on either day of the Week 24 visit. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 2.5 mg and 5 mg, will be used in this study. 
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied in tamper-evident kits containing two 30-cc high-density 
polyethylene (HDPE) bottles.  Each bottle will utilize foil induction-seal liners and a child-
resistant closure.  Each bottle of study drug will contain 30 capsules of 2.5 mg or 5 mg strength 
bardoxolone methyl or the matching placebo capsules.  Each bottle will also contain a desiccant 
insert that must not be ingested.  Labeling on each kit bottle will contain at minimum the 
following information: 
 Medication ID number; 
 Protocol 402-C-1504; 
 Caution Statement: New Drug – Limited by Federal Law to Investigational Use.  
Keep out of sight and reach of children; 
 Control or lot number 
 Store at 20° – 25°C (68° – 77°F), short term excursions allowed to 15° – 30°C (59° – 
86°F); 
 Reata Pharmaceuticals, Inc., Irving, TX. 
A double panel label will be presented on the treatment kit carton containing this and other 
information as well.  Additionally, labeling, in the relevant local languages for investigational 
medicinal product (IMP) for use and distribution in the EU shall adhere to current Eudralex, 
Volume 4 Annex 13 guidance and requirements.   
10.3. 
Study Drug Storage 
The stability of the drug product has been and is currently being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location with room 
temperature conditions of 20° - 25°C (68° - 77°F), with brief excursions allowed to 15° – 30°C 
(59° – 86°F).   
10.4. 
Study Drug Administration 
Please refer to Section 9.10.17 for details on study drug administration.  Clear instructions will 
be provided to the patient regarding the number and type of capsules to be ingested at each study 
drug administration time point listed in Table 3.  Patients must be instructed to continue taking 
study drug once daily up through their Week 24 visits unless: (1) patient has been otherwise 
instructed by the investigator or (2) the patient has been formally discontinued from the study.    


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


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11. 
SAFETY ASSESSMENTS 
11.1. 
Safety Parameters 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all safety assessments.  Safety 
parameters include vital sign measurements, ECG results, physical examination results, adverse 
events, serious adverse events, weight, and laboratory test results (clinical chemistry, 
hematology, urinalysis and microscopy).  
11.2. 
Adverse and Serious Adverse Events 
11.2.1. 
Definition of Adverse Events 
11.2.1.1. Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient regardless of 
its causal relationship to study drug.  An AE can be any unfavorable and unintended sign 
(including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study drug, whether or not it is considered to be 
study-drug related.  Included in this definition are any newly-occurring events or previous 
condition that has increased in severity or frequency since the administration of study drug. 
All AEs that are observed or reported by the patient during the study (from time of 
administration of the first dose at the Day 1 visit until the final visit indicated in Table 3 must be 
reported, regardless of their relationship to study drug or their clinical significance. 
11.2.1.2. Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring at any dose and regardless of causality that: 
 Results in death; 
 Is life-threatening; 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 Is a congenital anomaly or birth defect in an offspring of a patient taking study drug; 
 Is an important medical event.  
The term "life-threatening" refers to an event in which the patient was at immediate risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 


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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 final visit 
indicated in Table 3, as appropriate).  Certain pregnancy outcomes will require submission as an 
SAE (See Section 9.8). 
The investigator is responsible for reporting to Reata or designee all AEs and SAEs that are 
observed or reported by the patient during the study (from the time of administration of the first 
dose of study drug until the final visit indicated in Table 3, as appropriate), regardless of their 
relationship to study drug or their clinical significance.   
The Sponsor, or the Contract Research Organization (CRO) on the behalf of the Sponsor, must 
be notified immediately regarding the occurrence of any SAE that occurs after the patient is 
randomized and throughout the study, regardless of study drug administration, including SAEs 
resulting from protocol-associated procedures, as defined in relevant legislation.  The procedures 
for reporting all SAEs, regardless of causal relationship, are as follows: 
 Record the SAE on the AE eCRF and complete the “Serious Adverse Event Report” 
form within the electronic database. 
 In the event the electronic database is not functional, a paper SAE form will be 
available for the reporting of SAEs. 
The Sponsor may request additional information from the investigator to ensure the timely 
completion of accurate safety reports. 
All SAEs reported or observed during the study must be followed to resolution or until the 
investigator deems the event to be chronic or the patient to be stable.  Reata or designee may 
contact the investigator to obtain additional information on any SAE which has not resolved at 
the time the patient completes the study. 
11.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, non-directed question, such as, “How 
have you been feeling since your last visit?” to elicit any medically related changes in their 
well-being.  They may also be asked if they have been hospitalized, had any accidents, used any 
new medications, or changed concomitant medication regimens (including prescription drugs, 
over-the-counter medications, vitamins, herbal products, and minerals).  Responses must be 
documented in the source documents. 
In addition to patient observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, or ECG 
abnormalities, or from other documents that are relevant to patient safety. 


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11.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Not Related: This relationship suggests that there is no association between the study drug and 
the reported event. 
Unlikely Related: This relationship suggests that the temporal sequence of the event with study 
drug administration makes a causal relationship improbable and/or other factors also provide 
plausible explanations. 
Possibly Related: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence from the time 
of study drug administration, and/or, follows a known response pattern to the study drug, but 
could have been produced by other factors. 
Probably Related: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
Definitely Related: This relationship suggests that a definite causal relationship exists between 
the drug administration and the AE, and other conditions (e.g., concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
11.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities 
Severe: Symptoms causing inability to perform usual social and functional activities  
11.6. 
Recording Adverse Events 
All conditions present prior to the administration of the first dose of study drug (Day 1) should 
be documented as medical history.  After the first dose, documentation of adverse events (AEs) 
shall continue until 28 days following administration of the final dose of study medication, 
regardless of the relationship of the AE to study drug.  Information to be collected includes type 
of event, date of onset, date of resolution, investigator-specified assessment of severity and 
relationship to study drug, seriousness, as well as any action taken.  
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents, but when documenting the AE, only the total duration and 


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greatest severity should be recorded in the eCRF.  AEs characterized as intermittent require 
documentation of onset and duration. 
All drug-related (possibly, probably, or definitely related, see Section 11.4) AEs and abnormal 
laboratory test results reported or observed during the study must be followed to resolution 
(either return to baseline or within normal limits).  All other AEs will be followed through the 
final visit indicated in Table 3, as appropriate. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Preexisting conditions 
(present before the start of the AE collection period) are considered concurrent medical 
conditions and should NOT be recorded as AEs.  However, if the patient experiences a 
worsening or complication of such a concurrent condition, the worsening or complication should 
be recorded as an AE.  Investigators should ensure that the AE term recorded captures the 
change in the condition (e.g., “worsening of…”).  Any improvement in condition should be 
documented per Section 9.10.12. 
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.  The eCRF 
system within the clinical database is the preferred method of reporting an SAE.  
To report the SAE, the investigator will complete the SAE form in the clinical database and 
submit 
 (Refer to Table 6) within 24 hours of awareness.  If the clinical database is 
down for any reason, the manual SAE forms should be used; however, sites are responsible for 
ensuring the information on the manual SAE forms is entered into the clinical database once 
available. 


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Table 6: 
SAE Reporting Contact Information 
 
 
 
 
 
 
 
 
For questions regarding SAE reporting, contact your study manager, monitor,
 
 
Follow-Up Reports 
The investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment, or the 
subject dies. 
Within 24 hours of receipt of new information, the SAE form should be updated within the 
clinical database and submitted along with any supporting documentation (e.g., subject discharge 
summary or autopsy reports) 
 (refer to Table 6).  If the clinical database is 
down for any reason, the manual SAE forms should be used; however, sites are responsible for 
ensuring the updated information on the manual SAE forms is entered into the clinical database 
once available.  
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 adverse events which are commonly observed in this patient population 
will not be reported to regulatory authorities as individual expedited reports, except in unusual 
circumstances. 

Shortness of breath

Lightheaded/dizzy


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 Syncope 
 Chest pain 
 Palpitations 
 Fatigue 
 Edema/fluid retention 
 Exertional dyspnea 
 Hypoxemia 
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 
 
 
 
 
 
 
 
 
 
 
12.2. 
Study Variables 
12.2.1. 
Pharmacokinetic Variables 
The pharmacokinetic variables include bardoxolone methyl plasma concentration-time data, and 
estimated pharmacokinetic parameters for each analyte. 
12.2.2. 
Efficacy Variables 
The primary efficacy variable is the change from baseline in 6MWD.  The secondary efficacy 
variable is the time-to-first clinical improvement event.  
 
 
 
 
 
 
12.2.3. 
Safety Variables 
The safety variables include results of physical examinations, laboratory test results (clinical 
chemistry, hematology, urinalysis and microscopy), vital sign measurements, ECG results, 
weight, adverse events, and serious adverse events. 
12.3. 
Statistical Analyses 
A statistical analysis plan (SAP) detailing the analyses will be developed prior to the database 
lock.  All statistical analyses and data summaries will be performed using SAS® (Version 9.1 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized overall using descriptive statistics.  Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, relevant quartiles, 
standard deviation, coefficient of variation, and geometric mean (where applicable).  Categorical 
data will be summarized using frequency counts and percentages.  


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12.3.1. 
Primary Analysis of Efficacy 
The intent-to-treat (ITT) population, which includes all randomized patients who received at 
least one dose of study medication, will be used as the primary population for assessment of 
efficacy.  Likelihood-based estimation with mixed-model repeated measures (MMRM) analysis 
will compare the treatment groups with respect to the primary endpoint.  The dependent variable 
will be change from baseline in 6MWD.  The model will include treatment, visit, and the 
treatment-by-visit interactions as fixed effects; stratification by number of background PAH 
therapies (0, 1, or 2); and visit as a repeated measure having an unstructured covariance 
structure.  Covariates may be defined in the SAP as appropriate.  Missing data will not be 
imputed for the primary analysis.   
To assess the assumption of missing at random (MAR), a tipping point approach for imputing 
missing data will be performed as a sensitivity analysis.  Shift parameters will adjust the imputed 
values for observations in the treatment group, not the placebo group, until the p-value > 0.05.  
Multiple imputation will be used for missing data.  Other sensitivity analyses may be performed 
as appropriate. 
 
 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
The study monitor, as a representative of the Sponsor, is obligated to follow the study conduct 
closely.  In doing so, the monitor will visit the principal investigator and study facilities 
periodically, and will maintain necessary telephone and letter contact.  The monitor will maintain 
current knowledge of the study activity of the investigator and his/her staff through observation, 
review of study records and source documentation, and discussion of the conduct of the study 
with the investigators and staff. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Conference on Harmonisation (ICH) 
guideline E6(R1): Good Clinical Practice: Consolidated Guideline and current standard operating 
procedures. 
Each investigator is expected to make a reasonable effort to accommodate the monitor when 
monitoring visits are necessary and to be available during the site visit.  Furthermore, the 
monitor should be provided direct access to source data and documents for trial-related 
monitoring and internet during the visit. 
13.2. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/EC review, and regulatory inspections, by providing direct access to 
all study records.  In the event of an audit, the principal investigator agrees to allow the Sponsor, 
representatives of the Sponsor, the US Food and Drug Administration (FDA), and other relevant 
regulatory authorities access to all study records. 
The principal investigator should promptly notify the Sponsor or designee of any audits 
scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the Sponsor or designee. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Reata may conduct a quality assurance audit of the investigator’s clinical site, including 
CTM/IMP storage facilities.   
14.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for one year following the completion 
of the study. 
No potential investigator who has a vested financial interest in the success of this study may 
participate in this study. 
14.3. 
Sponsor Obligations  
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the Screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or designee is not financially responsible for treatment of 
the patient’s underlying disease. 
14.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R1) 
8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents 
to the Sponsor or designee, which include but are not limited to the following: 
 An original investigator-signed investigator agreement page of the protocol;  
 The IRB/EC approval of the protocol; 
 The IRB- or EC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the patient or legal guardians; 
 A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
 Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
are accurate and current; 


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 Completed financial disclosure forms (Section 14.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 
designee a commitment to update this information promptly if any relevant changes 
occur during the course of the investigation and for 1 year following the completion 
of the study; 
 Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study. 
14.5. 
Clinical Study Insurance 
In accordance with the respective national drug laws, the Sponsor has taken out patient liability 
insurance for all patients who give their consent and enroll in this study.  This insurance covers 
potential fatalities, physical injuries, or damage to health that may occur during the clinical 
study. 
14.6. 
Use of Information  
All information regarding bardoxolone methyl supplied by the Sponsor to the investigator is 
privileged and confidential.  The investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor.  Furthermore, the 
investigator is obligated to provide the Sponsor with complete data obtained during the study.  
The information obtained from the clinical study will be used towards the development of 
bardoxolone methyl and may be disclosed to regulatory authorities, other investigators, corporate 
partners, or consultants as required. 


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15. 
ETHICS
15.1. 
Institutional Review Board (IRB) or Ethics Committee Review 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB/EC before study start.  Each investigator must provide the Sponsor or 
its designee a signed and dated statement that the protocol and informed consent have been 
approved by the IRB/EC for that site before consenting patients.  Prior to study initiation, the 
investigator is required to sign a protocol signature page confirming agreement to conduct the 
study in accordance with this protocol and to give access to all relevant data and records to the 
Sponsor, its designee, and regulatory authorities as required. 
The IRB/EC chairperson or designee must sign all IRB/EC approvals and must identify the 
IRB/EC by name and address, the clinical protocol, and the date approval and/or favorable 
opinion was granted. 
The principal investigator is responsible for obtaining reviews of the clinical research at intervals 
specified by the IRB/EC, but not exceeding 1 year.  The principal investigator must supply the 
Sponsor or designee with written documentation of reviews of the clinical research. 
15.2. 
Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (e.g., US Code of Federal Regulations Title 21, European Directive 2001/20/EC, 
and with the ethical principles laid down in the Declaration of Helsinki.  
The principal investigator agrees to conduct the study in accordance with the International 
Conference on Harmonization (ICH for Guidance for Industry on Good Clinical Practice (GCP 
ICH E6(R1) 
[http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_ 
Guideline.pdf] and the principles of the Declaration of Helsinki 
[http://www.wma.net/en/30publications/10policies/b3/].  The principal investigator must conduct 
all aspects of this study in accordance with all national, state, and local laws or regulations. 
15.3. 
Written Informed Consent 
Because the study will be conducted under a United States Investigational New Drug 
Application, a signed informed consent form, in compliance with Title 21 of the United States 
Code of Federal Regulations (CFR Part 50, will be obtained from each patient before the patient 
enters the study.  For sites outside of the United States, the signed consent will be obtained in 
accord with local regulations, ICH E6 (R1, and principles of the Declaration of Helsinki.  An 
informed consent template may be provided by the Sponsor or designee to the investigators.  The 
consent must be reviewed by the Sponsor or designee before IRB/EC submission.  Once 
reviewed, the consent will be submitted by the principal investigator to his or her IRB/EC for 
review and approval before the start of the study.  If the informed consent form is revised during 
the course of the study, all participants affected by the revision must sign the revised IRB/EC-
approved consent form. 


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Before enrollment, each prospective patient will be given a full explanation of the study and be 
allowed to read the approved informed consent form.  Once the principal investigator or designee 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing the informed consent form.  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.  Informed consent must be 
obtained before conducting any study-specific procedures (i.e., all of the procedures described in 
the protocol).  The process of obtaining informed consent must be documented in the patient 
source documents. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/EC, and a copy of the approved version and the notice 
of approval must be provided to the Sponsor’s designated monitor after IRB/EC approval. 
The principal investigator or designee will provide a copy of the informed consent form (signed 
copy to be provided per applicable law) to the patient and/or legal guardian.  The original form 
will be maintained in the patient’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/EC. 
The principal investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to them for the purpose of the study.  Prior 
written agreement from the Sponsor or designee must be obtained for the disclosure of any said 
confidential information to other parties. 
15.5. 
Modification of the Protocol 
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. 
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. 


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15.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviation.  The IRB/EC must 
be notified of all protocol deviations in a timely manner by the principal investigator or designee 
as appropriate.  Protocol deviations will be documented by the responsible monitor during 
monitoring visits, and those observations will be communicated to the investigator. 
If there is an immediate hazard to a patient the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/EC approval.  The Sponsor and IRB/EC must be 
notified of the deviation. 


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


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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 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.  ATS 
Statement: Guidelines for the six-minute walk test.  Am J Respir Crit Care Med 2002;166:111-7. 
Batt J, Ahmed SS, Correa J, et al. Skeletal muscle dysfunction in idiopathic pulmonary arterial 
hypertension.  Am J Respir Cell Mol Biol 2014;50:74-86. 
Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic 
sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension 
assessment and recognition of outcomes in scleroderma registry.  Arthritis Care Res 
2014;66:489-95. 
Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: Correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci USA 2005;102:4584-9. 
Eba S, Hoshikawa Y, Moriguchi T, et al. The Nrf2 activator oltipraz attenuates chronic 
hypoxia-induced cardiopulmonary alterations in mice.  Am J Respir Cell Mol Biol 2013;49:324-
33. 
Galiè N, Hoeper MM, Humbert M, et al. ESC Committee for Practice Guidelines (CPG). 
Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the 
Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology 
(ESC) and the European Respiratory Society (ERS), endorsed by the International Society of 
Heart and Lung Transplantation (ISHLT).  Eur Heart J 2009;30:2493-537. 
Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial 
hypertension.  N Engl J Med 2013;369:330-40. 
Holmström KM, Baird L, Zhang Y, et al. Nrf2 impacts cellular bioenergetics by controlling 
substrate availability for mitochondrial respiration.  Biol Open 2013;0:1-10. 
Lee D-F, Kuo H-P, Liu M, et al. KEAP1 E3 ligase-mediated downregulation of NF-kB signaling 
by targeting IKKß.  Molecular Cell 2009;36:131-40. 
Li J, Stein TD, Johnson JA. Genetic dissection of systemic autoimmune disease in Nrf2-deficient 
mice.  Physiol Genomics 2004;18:261-72. 
Ludtmann MH, Angelova PR, Zhang Y, et al. Nrf2 impacts the efficiency of mitochondrial fatty 
acid oxidation.  Biochem J 2014;457:415-24. 
Mainguy V, Maltais F, Saey D, et al. Peripheral muscle dysfunction in idiopathic pulmonary 
hypertension.  Thorax 2010;65:113-7. 
Malenfant S, Potus F, Fournier F, et al. Skeletal muscle proteomic signature and metabolic 
impairment in pulmonary hypertension.  J Mol Med 2015;93:573-84. 
Osburn WO & Kensler TW. Nrf2 signaling: An adaptive response pathway for protection against 
environmental toxic insults.  Mutat Res 2008;669:31-9. 
Price L, Caramori G, Dorfmuller P, et al. Endothelial cell NF-kB activation is increased in 
human idiopathic PAH.  Thorax 2010;65:A88-A89. 


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Pugh, ME; Robbins, IM; Rice, TW, et al. Unrecognized glucose intolerance is common in 
pulmonary arterial hypertension.  J Heart Lung Transplant 2011;30:904-11. 
Rojas-Rivera J, Ortiz A, Egido J. Antioxidants in kidney diseases: The impact of bardoxolone 
methyl.  Int J Nephrol 2012;2012:1-11. 
Saha P, Reddy V, Konopleva M, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-
oic-acid methyl ester has potent antidiabetic effects in diet-induced diabetic mice and 
Lepr(db/db) mice.  J Biol Chem 2010;285:40581-92. 
Sutendra G, Michelakis ED. The metabolic basis of pulmonary arterial hypertension.   
Cell Metab 2014;19:558-73. 
Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial 
hypertension in patients receiving background endothelin receptor antagonist and 
phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled 
trial.  Chest 2013;144:952-8. 
Wei J, Zhu H, Komura K, et al. A synthetic PPAR-γ agonist triterpenoid ameliorates 
experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses. Ann Rheum Dis 
2014;73:446-54. 
Wu QQ, Wang Y, Senitko M, et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and 
increases expression of protective genes Nrf2, PPARgamma, and HO-1. Am J Physiol Renal 
Physiol 2011;300:F1180-F1192. 
Wu T, Ye Y, Min SY, et al. Prevention of murine lupus nephritis by targeting multiple signaling 
axes and oxidative stress using a synthetic triterpenoid.  Arthritis Rheumatol 2014;66:3129-39. 
Yoh K, Itoh K, Enomoto A, et al. Nrf2-deficient female mice develop lupus-like autoimmune 
nephritis.  Kidney Int 2001;60:1343-53. 
 


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19. 
APPENDIX 1: ATS GUIDELINES FOR THE SIX-MINUTE WALK 
TEST 


American Thoracic Society
 
Am J Respir Crit Care Med
Vol 166. pp 111–117, 2002
DOI: 10.1164/rccm.166/1/111
Internet address: www.atsjournals.org
 
ATS Statement: Guidelines for the Six-Minute Walk Test
 
T
 
HIS
 
 O
 
FFICIAL
 
 S
 
TATEMENT
 
 
 
OF
 
 
 
THE
 
 A
 
MERICAN
 
 T
 
HORACIC
 
 S
 
OCIETY
 
 
 
WAS
 
 
 
APPROVED
 
 
 
BY
 
 
 
THE
 
 ATS B
 
OARD
 
 
 
OF
 
 D
 
IRECTORS
 
M
 
ARCH
 
 2002
 
CONTENTS
 
Purpose and Scope
Background
Indications and Limitations
Contraindications
Safety Issues
Technical Aspects of the 6
 
-
 
Minute Walk Test
Required Equipment
Patient Preparation
Measurements
Quality Assurance
Interpretation
References
 
PURPOSE AND SCOPE
 
This statement provides practical guidelines for the 6-minute
walk test (6MWT). Specifically, it reviews indications, details
factors that influence results, presents a brief step-by-step pro-
tocol, outlines safety measures, describes proper patient prep-
aration and procedures, and offers guidelines for clinical inter-
pretation of results. These recommendations are not intended
to limit the use of alternative protocols for research studies.
We do not discuss the general topic of clinical exercise testing.
As with other American Thoracic Society statements on
pulmonary function testing, these guidelines come out of a
consensus conference. Drafts were prepared by two members
(P.L.E. and R.J.Z.) and were based on a comprehensive Med-
line literature search from 1970 through 2001, augmented by
suggestions from other committee members. Each draft re-
sponded to comments from the working committee. The guide-
lines follow previously published methods as closely as possi-
ble and provide a rationale for each specific recommendation.
The final recommendations represent a consensus of the com-
mittee. The committee recommends that these guidelines be
reviewed in five years and in the meantime encourages further
research in areas of controversy.
 
BACKGROUND
 
There are several modalities available for the objective evalu-
ation of functional exercise capacity. Some provide a very
complete assessment of all systems involved in exercise per-
formance (high tech), whereas others provide basic informa-
tion but are low tech and are simpler to perform. The modality
used should be chosen based on the clinical question to be ad-
dressed and on available resources. The most popular clinical
exercise tests in order of increasing complexity are stair climb-
ing, a 6MWT, a shuttle-walk test, detection of exercise-induced
asthma, a cardiac stress test (e.g., Bruce protocol), and a cardio-
pulmonary exercise test (1, 2). Other professional organiza-
tions have published standards for cardiac stress testing (3, 4).
Assessment of functional capacity has traditionally been
done by merely asking patients the following: “How many
flights of stairs can you climb or how many blocks can you
walk?” However, patients vary in their recollection and may
report overestimations or underestimations of their true func-
tional capacity. Objective measurements are usually better
than self-reports. In the early 1960s, Balke developed a simple
test to evaluate the functional capacity by measuring the dis-
tance walked during a defined period of time (5). A 12-minute
field performance test was then developed to evaluate the
level of physical fitness of healthy individuals (6). The walking
test was also adapted to assess disability in patients with
chronic bronchitis (7). In an attempt to accommodate patients
with respiratory disease for whom walking 12 minutes was too
exhausting, a 6-minute walk was found to perform as well as
the 12-minute walk (8). A recent review of functional walking
tests concluded that “the 6MWT is easy to administer, better
tolerated, and more reflective of activities of daily living than
the other walk tests” (9).
The 6MWT is a practical simple test that requires a 100-ft
hallway but no exercise equipment or advanced training for
technicians. Walking is an activity performed daily by all but
the most severely impaired patients. This test measures the dis-
tance that a patient can quickly walk on a flat, hard surface in a
period of 6 minutes (the 6MWD). It evaluates the global and in-
tegrated responses of all the systems involved during exercise,
including the pulmonary and cardiovascular systems, systemic
circulation, peripheral circulation, blood, neuromuscular units,
and muscle metabolism. It does not provide specific informa-
tion on the function of each of the different organs and systems
involved in exercise or the mechanism of exercise limitation, as
is possible with maximal cardiopulmonary exercise testing. The
self-paced 6MWT assesses the submaximal level of functional
capacity. Most patients do not achieve maximal exercise capac-
ity during the 6MWT; instead, they choose their own intensity
of exercise and are allowed to stop and rest during the test.
However, because most activities of daily living are performed
at submaximal levels of exertion, the 6MWD may better reflect
the functional exercise level for daily physical activities.
 
INDICATIONS AND LIMITATIONS
 
The strongest indication for the 6MWT is for measuring the re-
sponse to medical interventions in patients with moderate to
severe heart or lung disease. The 6MWT has also been used as
a one-time measure of functional status of patients, as well as a
predictor of morbidity and mortality (
 
see
 
 Table 1 for a list of
these indications). The fact that investigators have used the
6MWT in these settings does not prove that the test is clinically
useful (or the best test) for determining functional capacity or
changes in functional capacity due to an intervention in pa-
tients with these diseases. Further studies are necessary to de-
termine the utility of the 6MWT in various clinical situations.
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112
 
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
VOL 166
2002
 
Formal cardiopulmonary exercise testing provides a global
assessment of the exercise response, an objective determina-
tion of functional capacity and impairment, determination of
the appropriate intensity needed to perform prolonged exer-
cise, quantification of factors limiting exercise, and a defini-
tion of the underlying pathophysiologic mechanisms such as
the contribution of different organ systems involved in exer-
cise. The 6MWT does not determine peak oxygen uptake, di-
agnose the cause of dyspnea on exertion, or evaluate the
causes or mechanisms of exercise limitation (1, 2). The infor-
mation provided by a 6MWT should be considered comple-
mentary to cardiopulmonary exercise testing, not a replace-
ment for it. Despite the difference between these two functional
tests, some good correlations between them have been re-
ported. For example, a significant correlation (r 
 

 
 0.73) be-
tween 6MWD and peak oxygen uptake has been reported for
patients with end-stage lung diseases (36, 37).
In some clinical situations, the 6MWT provides informa-
tion that may be a better index of the patient’s ability to per-
form daily activities than is peak oxygen uptake; for example,
6MWD correlates better with formal measures of quality of
life (38). Changes in 6MWD after therapeutic interventions
correlate with subjective improvement in dyspnea (39, 40).
The reproducibility of the 6MWD (with a coefficient of varia-
tion of approximately 8%) appears to be better than the re-
producibility of 1-second forced expiratory volume in patients
with chronic obstructive pulmonary disease (COPD) (8, 41–
43). Questionnaire indices of functional status have a larger
short-term variability (22–33%) than does the 6MWD (37).
The shuttle-walking test is similar to the 6MWT, but it uses
an audio signal from a tape cassette to direct the walking pace
of the patient back and forth on a 10-m course (44–47). The
walking speed is increased every minute, and the test ends when
the patient cannot reach the turnaround point within the re-
quired time. The exercise performed is similar to a symptom-
limited, maximal, incremental treadmill test. An advantage of
the shuttle walking test is that it has a better correlation with
peak oxygen uptake than the 6MWD. Disadvantages include
less validation, less widespread use, and more potential for
cardiovascular problems.
 
CONTRAINDICATIONS
 
Absolute contraindications for the 6MWT include the follow-
ing: unstable angina during the previous month and myocar-
dial infarction during the previous month. Relative contraindi-
cations include a resting heart rate of more than 120, a systolic
blood pressure of more than 180 mm Hg, and a diastolic blood
pressure of more than 100 mm Hg.
Patients with any of these findings should be referred to the
physician ordering or supervising the test for individual clini-
cal assessment and a decision about the conduct of the test.
The results from a resting electrocardiogram done during the
previous 6 months should also be reviewed before testing. Sta-
ble exertional angina is not an absolute contraindication for a
6MWT, but patients with these symptoms should perform the
test after using their antiangina medication, and rescue nitrate
medication should be readily available.
 
Rationale
 
Patients with the previously mentioned risk factors may be at
increased risk for arrhythmias or cardiovascular collapse during
testing. However, each patient determines the intensity of their
exercise, and the test (without electrocardiogram monitoring)
has been performed in thousands of older persons (31, 48–50)
and thousands of patients with heart failure or cardiomyopathy
(32, 51, 52) without serious adverse events. The contraindica-
tions listed previously here were used by study investigators
based on their impressions of the general safety of the 6MWT
and their desire to be prudent, but it is unknown whether ad-
verse events would occur if such patients performed a 6MWT;
they are, therefore, listed as relative contraindications.
 
SAFETY ISSUES
 
1. Testing should be performed in a location where a rapid,
appropriate response to an emergency is possible. The ap-
propriate location of a crash cart should be determined by
the physician supervising the facility.
2. Supplies that must be available include oxygen, sublingual
nitroglycerine, aspirin, and albuterol (metered dose inhaler
or nebulizer). A telephone or other means should be in
place to enable a call for help.
3. The technician should be certified in cardiopulmonary re-
suscitation with a minimum of Basic Life Support by an
American Health Association–approved cardiopulmonary
resuscitation course. Advanced cardiac life support certifi-
cation is desirable. Training, experience, and certification
in related health care fields (registered nurse, registered re-
spiratory therapist, certified pulmonary function techni-
cian, etc.) are also desirable. A certified individual should
be readily available to respond if needed.
4. Physicians are not required to be present during all tests.
The physician ordering the test or a supervising laboratory
physician may decide whether physician attendance at a
specific test is required.
5. If a patient is on chronic oxygen therapy, oxygen should be
given at their standard rate or as directed by a physician or
a protocol.
Reasons for immediately stopping a 6MWT include the follow-
ing: (
 
1
 
) chest pain, (
 
2
 
) intolerable dyspnea, (
 
3
 
) leg cramps, (
 
4
 
)
staggering, (
 
5
 
) diaphoresis, and (
 
6
 
) pale or ashen appearance.
Technicians must be trained to recognize these problems
and the appropriate responses. If a test is stopped for any of
these reasons, the patient should sit or lie supine as appropri-
ate depending on the severity or the event and the technician’s
assessment of the severity of the event and the risk of syncope.
The following should be obtained based on the judgment of
the technician: blood pressure, pulse rate, oxygen saturation,
and a physician evaluation. Oxygen should be administered as
appropriate.
 
TABLE 1. INDICATIONS FOR THE SIX-MINUTE WALK TEST
 
Pretreatment and posttreatment comparisons
Lung transplantation (9, 10)
Lung resection (11)
Lung volume reduction surgery (12, 13)
Pulmonary rehabilitation (14, 15)
COPD (16–18)
Pulmonary hypertension
Heart failure (19, 20)
Functional status (single measurement)
COPD (21, 22)
Cystic fibrosis (23, 24)
Heart failure (25–27)
Peripheral vascular disease (28, 29)
Fibromyalgia (30)
Older patients (31)
Predictor of morbidity and mortality
Heart failure (32, 33)
COPD (34, 35)
Primary pulmonary hypertension (10, 36)
Definition of abbreviation
 
: COPD 
 

 
 chronic obstructive pulmonary disease.
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TECHNICAL ASPECTS OF THE 6MWT
 
Location
 
The 6MWT should be performed indoors, along a long, flat,
straight, enclosed corridor with a hard surface that is seldom
traveled. If the weather is comfortable, the test may be per-
formed outdoors. The walking course must be 30 m in length.
A 100-ft hallway is, therefore, required. The length of the cor-
ridor should be marked every 3 m. The turnaround points should
be marked with a cone (such as an orange traffic cone). A start-
ing line, which marks the beginning and end of each 60-m lap,
should be marked on the floor using brightly colored tape.
 
Rationale.  
 
A shorter corridor requires patients to take more
time to reverse directions more often, reducing the 6MWD.
Most studies have used a 30-m corridor, but some have used
20- or 50-m corridors (52–55). A recent multicenter study
found no significant effect of the length of straight courses
ranging from 50 to 164 ft, but patients walked farther on con-
tinuous (oval) tracks (mean 92 ft farther) (54).
The use of a treadmill to determine the 6MWD might save
space and allow constant monitoring during the exercise, but
the use of a treadmill for 6-minute walk testing is not recom-
mended. Patients are unable to pace themselves on a tread-
mill. In one study of patients with severe lung disease, the
mean distance walked on the treadmill during 6 minutes (with
the speed adjusted by the patients) was shorter by a mean of
14% when compared with the standard 6MWD using a 100-ft
hallway (57). The range of differences was wide, with patients
walking between 400–1,300 ft on the treadmill who walked
1,200 ft in the hallway. Treadmill test results, therefore, are
not interchangeable with corridor tests.
 
REQUIRED EQUIPMENT
 
1. Countdown timer (or stopwatch)
2. Mechanical lap counter
3. Two small cones to mark the turnaround points
4. A chair that can be easily moved along the walking course
5. Worksheets on a clipboard
6. A source of oxygen
7. Sphygmomanometer
8. Telephone
9. Automated electronic defibrillator
 
PATIENT PREPARATION
 
1. Comfortable clothing should be worn.
2. Appropriate shoes for walking should be worn.
3. Patients should use their usual walking aids during the test
(cane, walker, etc.).
4. The patient’s usual medical regimen should be continued.
5. A light meal is acceptable before early morning or early af-
ternoon tests.
6. Patients should not have exercised vigorously within 2 hours
of beginning the test.
 
MEASUREMENTS
 
1. Repeat testing should be performed about the same time
of day to minimize intraday variability.
2. A “warm-up” period before the test should not be performed.
3. The patient should sit at rest in a chair, located near the
starting position, for at least 10 minutes before the test
starts. During this time, check for contraindications, mea-
sure pulse and blood pressure, and make sure that cloth-
ing and shoes are appropriate. Compete the first portion
of the worksheet (
 
see
 
 the A
 
PPENDIX
 
).
4. Pulse oximetry is optional. If it is performed, measure and
record baseline heart rate and oxygen saturation (SpO
 
2
 
)
and follow manufacturer’s instructions to maximize the sig-
nal and to minimize motion artifact (56, 57). Make sure the
readings are stable before recording. Note pulse regularity
and whether the oximeter signal quality is acceptable.
 
The rationale for measuring oxygen saturation is that al-
though the distance is the primary outcome measure, im-
provement during serial evaluations may be manifest either
by an increased distance or by reduced symptoms with the
same distance walked (39). The SpO
 
2
 
 should not be used for
constant monitoring during the exercise. The technician
must not walk with the patient to observe the SpO
 
2
 
. If worn
during the walk, the pulse oximeter must be lightweight (less
than 2 pounds), battery powered, and held in place (perhaps
by a “fanny pack”) so that the patient does not have to hold
or stabilize it and so that stride is not affected. Many pulse
oximeters have considerable motion artifact that prevents
accurate readings during the walk. (57)
 
5. Have the patient stand and rate their baseline dyspnea
and overall fatigue using the Borg scale (
 
see
 
 Table 2 for
the Borg scale and instructions [58]).
6. Set the lap counter to zero and the timer to 6 minutes. As-
semble all necessary equipment (lap counter, timer, clip-
board, Borg Scale, worksheet) and move to the starting
point.
7. Instruct the patient as follows:
 
“The object of this test is to walk as far as possible for 6
minutes. You will walk back and forth in this hallway. Six
minutes is a long time to walk, so you will be exerting your-
self. You will probably get out of breath or become ex-
hausted. You are permitted to slow down, to stop, and to
rest as necessary. You may lean against the wall while rest-
ing, but resume walking as soon as you are able.
You will be walking back and forth around the cones.
You should pivot briskly around the cones and continue
back the other way without hesitation. Now I’m going to
show you. Please watch the way I turn without hesitation.”
Demonstrate by walking one lap yourself. Walk and
pivot around a cone briskly.
“Are you ready to do that? I am going to use this
counter to keep track of the number of laps you complete. I
will click it each time you turn around at this starting line.
Remember that the object is to walk AS FAR AS POSSI-
BLE for 6 minutes, but don’t run or jog.
Start now, or whenever you are ready.”
 
TABLE 2. THE BORG SCALE
 
0
Nothing at all
0.5
Very, very slight (just noticeable)
1
Very slight
2
Slight (light)
3
Moderate
4
Somewhat severe
5
Severe (heavy)
6
7
Very severe
8
9
10
Very, very severe (maximal)
This Borg scale should be printed on heavy paper (11 inches high and perhaps lami-
nated) in 20-point type size. At the beginning of the 6-minute exercise, show the scale
to the patient and ask the patient this: “Please grade your level of shortness of breath
using this scale.” Then ask this: “Please grade your level of fatigue using this scale.”
At the end of the exercise, remind the patient of the breathing number that they
chose before the exercise and ask the patient to grade their breathing level again. Then
ask the patient to grade their level of fatigue, after reminding them of their grade be-
fore the exercise.
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8. Position the patient at the starting line. You should also
stand near the starting line during the test. Do not walk
with the patient. As soon as the patient starts to walk,
start the timer.
9. Do not talk to anyone during the walk. Use an even tone
of voice when using the standard phrases of encourage-
ment. Watch the patient. Do not get distracted and lose
count of the laps. Each time the participant returns to the
starting line, click the lap counter once (or mark the lap
on the worksheet). Let the participant see you do it. Ex-
aggerate the click using body language, like using a stop-
watch at a race.
 
After the first minute, tell the patient the following (in
even tones): “You are doing well. You have 5 minutes to
go.”
When the timer shows 4 minutes remaining, tell the pa-
tient the following: “Keep up the good work. You have 4
minutes to go.”
When the timer shows 3 minutes remaining, tell the pa-
tient the following: “You are doing well. You are halfway
done.”
When the timer shows 2 minutes remaining, tell the pa-
tient the following: “Keep up the good work. You have only
2 minutes left.”
When the timer shows only 1 minute remaining, tell the
patient: “You are doing well. You have only 1 minute to
go.”
Do not use other words of encouragement (or body lan-
guage to speed up).
If the patient stops walking during the test and needs a
rest, say this: “You can lean against the wall if you would
like; then continue walking whenever you feel able.” Do
not stop the timer. If the patient stops before the 6 minutes
are up and refuses to continue (or you decide that they
should not continue), wheel the chair over for the patient to
sit on, discontinue the walk, and note on the worksheet the
distance, the time stopped, and the reason for stopping pre-
maturely.
When the timer is 15 seconds from completion, say this:
“In a moment I’m going to tell you to stop. When I do, just
stop right where you are and I will come to you.”
When the timer rings (or buzzes), say this: “Stop!” Walk
over to the patient. Consider taking the chair if they look
exhausted. Mark the spot where they stopped by placing a
bean bag or a piece of tape on the floor.
 
10. Post-test: Record the postwalk Borg dyspnea and fatigue
levels and ask this: “What, if anything, kept you from walk-
ing farther?”
11. If using a pulse oximeter, measure SpO
 
2
 
 and pulse rate
from the oximeter and then remove the sensor.
12. Record the number of laps from the counter (or tick marks
on the worksheet).
13. Record the additional distance covered (the number of meters
in the final partial lap) using the markers on the wall as dis-
tance guides. Calculate the total distance walked, rounding to
the nearest meter, and record it on the worksheet.
14. Congratulate the patient on good effort and offer a drink
of water.
 
QUALITY ASSURANCE
 
Sources of Variability
 
There are many sources of 6MWD variability (
 
see
 
 Table 3).
The sources of variability caused by the test procedure itself
should be controlled as much as possible. This is done by fol-
lowing the standards found in this document and by using a
quality-assurance program.
 
Practice Tests
 
A practice test is not needed in most clinical settings but
should be considered. If a practice test is done, wait for at least
1 hour before the second test and report the highest 6MWD as
the patient’s 6MWD baseline.
 
Rationale.  
 
The 6MWD is only slightly higher for a second
6MWT performed a day later. The mean reported increase
ranges from 0 to 17% (23, 27, 40, 41, 54, 59). A multicenter
study of 470 highly motivated patients with severe COPD per-
formed two 6MWTs 1 day apart, and on average, the 6MWD
was only 66 ft (5.8%) higher on the second day (54).
Performance (without an intervention) usually reaches a
plateau after two tests done within a week (8, 60). The training
effect may be due to improved coordination, finding optimal
stride length, and overcoming anxiety. The possibility of a
practice or training effect from tests repeated after more than
a month has not been studied or reported; however, it is likely
that the effect of training wears off (does not persist) after a
few weeks.
 
Technician Training and Experience
 
Technicians who perform 6MWTs should be trained using the
standard protocol and then supervised for several tests before
performing them alone. They should also have completed car-
diopulmonary resuscitation training.
 
Rationale.  
 
One multicenter study of older people found
that after correction for many other factors, two of the techni-
cians had mean 6MWDs that were approximately 7% lower
than the other two sites (31).
 
Encouragement
 
Only the standardized phrases for encouragement (as speci-
fied previously here) must be used during the test.
 
Rationale.  
 
Encouragement significantly increases the dis-
tance walked (42). Reproducibility for tests with and without
encouragement is similar. Some studies have used encourage-
ment every 30 seconds, every minute, or every 2 minutes. We
have chosen every minute and standard phrases. Some studies
(53) have instructed patients to walk as fast as possible. Al-
though larger mean 6MWDs may be obtained thereby, we rec-
ommend that such phrases not be used, as they emphasize ini-
tial speed at the expense of earlier fatigue and possible
excessive cardiac stress in some patients with heart disease.
 
TABLE 3. 6MWD SOURCES OF VARIABILITY
 
Factors reducing the 6MWD
Shorter height
Older age
Higher body weight
Female sex
Impaired cognition
A shorter corridor (more turns)
Pulmonary disease (COPD, asthma, cystic fibrosis, interstitial lung disease)
Cardiovascular disease (angina, MI, CHF, stroke, TIA, PVD, AAI)
Musculoskeletal disorders (arthritis, ankle, knee, or hip injuries, muscle wasting, etc.)
Factors increasing the 6MWD
Taller height (longer legs)
Male sex
High motivation
A patient who has previously performed the test
Medication for a disabling disease taken just before the test
Oxygen supplementation in patients with exercise-induced hypoxemia
Definition of abbreviations
 
: COPD 
 

 
 chronic obstructive pulmonary disease; 6MWD 
 

 
 
6-minute walking distance.
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Supplemental Oxygen
 
If oxygen supplementation is needed during the walks and se-
rial tests are planned (after an intervention other than oxygen
therapy), then during all walks by that patient oxygen should
be delivered in the same way with the same flow. If the flow
must be increased during subsequent visits due to worsening
gas exchange, this should be noted on the worksheet and con-
sidered during interpretation of the change noted in 6MWD.
The type of oxygen delivery device should also be noted on
the report: for instance, the patient carried liquid oxygen or
pushed or pulled an oxygen tank, the delivery was pulsed or
continuous, or a technician walked behind the patient with the
oxygen source (not recommended). Measurements of pulse
and SpO
 
2
 
 should be made after waiting at least 10 minutes af-
ter any change in oxygen delivery.
 
Rationale.  
 
For patients with COPD or interstitial lung dis-
ease, oxygen supplementation increases the 6MWD (17, 59,
61, 63). Carrying a portable gas container (but not using it for
supplemental oxygen) reduced the mean 6MWD by 14% in
one study of patients with severe respiratory disability, but us-
ing the container to deliver supplemental oxygen during the
exercise increased the mean 6MWD by 20–35% (59).
 
Medications
 
The type of medication, dose, and number of hours taken be-
fore the test should be noted.
 
Rationale.  
 
Significant improvement in the distance walked,
or the dyspnea scale, after administration of bronchodilators
has been demonstrated in patients with COPD (62, 63), as well
as cardiovascular medications in patients with heart failure (19).
 
INTERPRETATION
 
Most 6MWTs will be done before and after intervention, and
the primary question to be answered after both tests have
been completed is whether the patient has experienced a clini-
cally significant improvement. With a good quality-assurance
program, with patients tested by the same technician, and af-
ter one or two practice tests, short-term reproducibility of the
6MWD is excellent (37). It is not known whether it is best for
clinical purposes to express change in 6MWD as (
 
1
 
) an abso-
lute value, (
 
2
 
) a percentage change, or (
 
3
 
) a change in the per-
centage of predicted value. Until further research is available,
we recommend that change in 6MWD be expressed as an ab-
solute value (e.g., the patient walked 50 m farther).
A statistically significant mean increase in 6MWD in a
group of study participants is often much less than a clinically
significant increase in an individual patient. In one study of
112 patients (half of them women) with stable, severe COPD,
the smallest difference in 6MWD that was associated with a
noticeable clinical difference in the patients’ perception of ex-
ercise performance was a mean of 54 m (95% confidence in-
terval, 37–71 m) (64). This study suggests that for individual
patients with COPD, an improvement of more than 70 m in
the 6MWD after an intervention is necessary to be 95% confi-
dent that the improvement was significant. In an observational
study of 45 older patients with heart failure, the smallest dif-
ference in 6MWD that was associated with a noticeable differ-
ence in their global rating of worsening was a mean of 43 m
(20). The 6MWD was more responsive to deterioration than
to improvement in heart failure symptoms.
 
Reported Mean Changes in 6MWD After Interventions
 
Supplemental oxygen (4 L/min) during exercise in patients with
COPD or interstitial lung disease increased mean 6MWD by
approximately 95 m (36%) in one study (59). Patients taking
 
an inhaled corticosteroid experienced a mean 33 m (8%) in-
crease in 6MWD in an international COPD study (16). Pa-
tients with COPD in a study of the effects of exercise and dia-
phragmatic strength training experienced a mean increase in
6MWD of 50 m (20%) (65). Lung volume reduction surgery in
patients with very severe COPD has been reported to increase
6MWD by a mean of 55 m (20%) (13).
Cardiac rehabilitation in patients referred with various heart
diseases increased 6MWD by a mean of 170 m (15%) in a recent
study (66). In 25 older patients with heart failure, an angiotensin-
converting enzyme inhibitor medication (50 mg captopril per
day) improved 6MWD a mean of 64 m (39%) compared with a
mean increase of only 8% in those receiving a placebo (19).
 
Interpreting Single Measurements of Functional Status
 
Optimal reference equations from healthy population-based
samples using standardized 6MWT methods are not yet avail-
able. In one study, the median 6MWD was approximately 580
m for 117 healthy men and 500 m for 173 healthy women (50).
A mean 6MWD of 630 m was reported by another study of 51
healthy older adults (55). Differences in the population sam-
pled, type and frequency of encouragement, corridor length,
and number of practice tests may account for reported differ-
ences in mean 6MWD in healthy persons. Age, height, weight,
and sex independently affect the 6MWD in healthy adults;
therefore, these factors should be taken into consideration
when interpreting the results of single measurements made to
determine functional status. We encourage investigators to pub-
lish reference equations for healthy persons using the previ-
ously mentioned standardized procedures.
A low 6MWD is nonspecific and nondiagnostic. When the
6MWD is reduced, a thorough search for the cause of the im-
pairment is warranted. The following tests may then be help-
ful: pulmonary function, cardiac function, ankle–arm index,
muscle strength, nutritional status, orthopedic function, and
cognitive function.
 
Conclusions
 
The 6MWT is a useful measure of functional capacity targeted
at people with at least moderately severe impairment. The test
has been widely used for preoperative and postoperative eval-
uation and for measuring the response to therapeutic inter-
ventions for pulmonary and cardiac disease. These guidelines
provide a standardized approach to performing the 6MWT.
The committee hopes that these guidelines will encourage fur-
ther research into the 6MWT and allow direct comparisons
among different studies.
 
This statement was developed by the ATS Committee on Proficiency Stan-
dards for Clinical Pulmonary Function Laboratories.
Members of the committee are:
R
 
OBERT
 
 O. C
 
RAPO
 
, M.D., 
 
Chair
 
*
R
 
ICHARD
 
 C
 
ASABURI
 
, P
 
H
 
.D, M.D.
A
 
LLAN
 
 L. C
 
OATES
 
, M.D.
P
 
AUL
 
 L. E
 
NRIGHT
 
, M.D.*
N
 
EIL
 
 R. M
 
AC
 
I
 
NTYRE
 
, M.D.
R
 
OY
 
 T. M
 
C
 
K
 
AY
 
, P
 
H
 
.D.
D
 
OUGLAS
 
 J
 
OHNSON
 
, M.D.
J
 
ACK
 
 S. W
 
ANGER
 
, M.S.
R. J
 
ORGE
 
 Z
 
EBALLOS
 
, M.D.*
Ad Hoc Committee members are:
V
 
ERA
 
 B
 
ITTNER
 
, M.D.
C
 
ARL
 
 M
 
OTTRAM
 
, R.R.T.
*Writing Committee Members
 
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Thorax
 
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19. DeBock V, Mets T, Romagnoli M, Derde MP. Captopril treatment of
chronic heart failure in the very old. 
 
J Gerontol
 
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20. O’Keeffe ST, Lye M, Donnnellan C, Carmichael DN. Reproducibility
and responsiveness of quality of life assessment and six minute walk
test in elderly heart failure patients. 
 
Heart
 
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21. Bernstein ML, Despars JA, Singh NP, Avalos K, Stansbury DW, Light
RW. Re-analysis of the 12 minute walk in patients with COPD. 
 
Chest
 
1994;105:163–167.
22. Hajiro T, Nishimura K, Tsukino M, Ikeda A, Koyama H, Izumi T. Anal-
ysis of clinical methods used to evaluate dyspnea in patients with
COPD. 
 
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23. Gulmans VAM, vanVeldhoven NHMJ, deMeer K, Helders PJM. The
six-minute walking test in children with cystic fibrosis: reliability and
validity. 
 
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24. Nixon PA, Joswiak ML, Fricker FJ. A six-minute walk test for assessing
exercise tolerance in severely ill children. 
 
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25. Bittner V. Six-minute walk test in patients with cardiac dysfunction. 
 
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diologia
 
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26. Peeters P, Mets T. The 6 minute walk as an appropriate exercise test in
elderly patients with chronic heart failure. 
 
J Gerontol
 
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M147–M151.
27. Zugck C, Kruger C, Durr S, Gerber SH, Haunstetter A, Hornig K,
Kubler W, Haass M. Is the 6-minute walk test a reliable substitute for
peak oxygen uptake in patients with dilated cardiomyopathy? 
 
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28. Montogomery PS, Gardner AW. The clinical utility of a six-minute walk
test in peripheral arterial occlusive disease patients. 
 
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29. Cahan MA, Montgomery P, Otis RB, Clancy R, Flinn W, Gardner A.
The effect of cigarette smoking status on six-minute walk distance in
patients with intermittent claudication. 
 
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30. King S, Wessel J, Bhambhani Y, Maikala R, Sholter D, Maksymowych
W. Validity and reliability of the 6 minute walk in persons with fibro-
myalgia. J Rheumatol 1999;26:2233–2237.
31. Enright PL, McBurnie MA, Bittner V, Tracy RP, McNamara R, New-
man AB, the Cardiovascular Health Study. The six minute walk test: a
quick measure of functional status in elderly adults. Chest (In press)
32. Bittner V, Weiner DH, Yusuf S, Rogers WJ, McIntyre KM, Bangdiwala
SI, Kronenberg MW, Kostis JB, Kohn RM, Guillotte M, et al. Predic-
tion of mortality and morbidity with a 6-minute walk test in patients
with left ventricular dysfunction. JAMA 1993;270:1702–1707.
33. Cahalin LP, Mathier MA, Semigran MJ, Dec GW, DiSalvo TG. The six-
minute walk test predicts peak oxygen uptake and survival in patients
with advanced heart failure. Chest 1996;110:325–332.
34. Cote CG, Celli BR. In patients with COPD, the 6 minute walking dis-
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35. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predic-
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36. Cahalin L, Pappagianopoulos P, Prevost S, Wain J, Ginns L. The relation-
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plant candidates with end-stage lung disease. Chest 1995;108:452–459.
37. Guyatt GH, Thompson PJ, Berman LB, Sullivan MJ, Townsend M,
Jones NL, Pugsley SO. How should we measure function in patients
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39. Niederman MS, Clemente PH, Fein AM, Feinsilver SH, Robinson DA,
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rehabilitation program: improvements are independent of lung func-
tion. Chest 1991;99:798–804.
40. Noseda A, Carpiaux J, Prigogine T, Schmerber J. Lung function, maxi-
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41. Knox AJ, Morrison JF, Muers MF. Reproducibility of walking test re-
sults in chronic obstructive airways disease. Thorax 1988;43:388–392.
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performance. Thorax 1984;39:818–822.
43. Leger LA. A maximal multistage 20-m shuttle run test to predict VO2
max. Eur J Appl Physiol 1982;49:1–12.
44. Singh SJ, Morgan MDL, Scott S, Walters D, Hardman AE. Develop-
ment of a shuttle walking test of disability in patients with chronic air-
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45. Revill SM, Morgan MDL, Singh SJ, Williams J, Hardman AE. The endur-
ance shuttle walk: a new field test for the assessment of endurance capac-
ity in chronic obstructive pulmonary disease. Thorax 1999;54:213–222.
46. Singh SJ, Morgan MDL, Hardman AE, Rowe C, Bardsley PA. Compar-
ison of oxygen uptake during a conventional treadmill test and the
shuttle walking test in chronic airflow limitation. Eur Respir J 1994;7:
2016–2020.
47. Morales FJ, Martinez A, Mendez M, Agarrado A, Ortega F, Fernandez-
Guerra J, Montemayor T, Burgos J. A shuttle walk test for assessment of
functional capacity in chronic heart failure. Am Heart J 1999;138:292–298.
48. Enright PL, Sherrill DL. Reference equations for the six-minute walk in
healthy adults. Am J Respir Crit Care Med 1998;158:1384–1387.
49. Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ. Long WA, Levy PS.
Survival in primary pulmonary hypertension with long-term continu-
ous intravenous prostacyclin. Ann Intern Med 1994;121:409–415.
50. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Na-
kanishi N, Miyatake K. Clinical correlates and prognostic significance
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sion. Am J Respir Crit Care Med 2000;161:487–492.
51. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor
DW, Berman LB. The 6-minute walk: a new measure of exercise ca-
pacity in patients with chronic heart failure. Can Med Assoc J 1985;
132:919–923.
52. Lipkin DP, Scrivin AJ, Crake T, Poole-Wilson PA. Six minute walking
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292:653–655.
53. Troosters T, Gosselink R, Decramer M. Six minute walking distance in
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54. Weiss RA, et al. Six minute walk test in severe COPD: reliability and ef-
fect of walking course layout and length. Paper presented at ACCP
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ison of hallway and treadmill six-minute walk tests. Am J Respir Crit
Care Med 1999;160:1540–1543.
56. Jensen LA, Onyskiw JE, Prasad NGN. Meta-analysis of arterial oxygen
saturation monitoring by pulse oximetry in adults. Heart Lung 1998;
27:387–408.
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JR. Accuracy of pulse oximetry during moderate exercise: a compara-
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59. Leach RM, Davidson AC, Chinn S, Twort CHC, Cameron IR, Batemen
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60. Mungall IPF, Hainsworth R. Assessment of respiratory function in pa-
tients with chronic obstructive airways disease. Thorax 1979;34:254–258.
61. Roberts CM, Bell J, Wedzicha JA. Comparison of the efficacy of a de-
mand oxygen delivery system with continuous low flow oxygen in sub-
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62. Hay JG, Stone P, Carter J, Church S, Eyre-Brook A, Pearson MG,
Woodcock AA, Calverley PM. Bronchodilator reversibility, exercise
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63. Grove A, Lipworth BJ, Reid P, Smith RP, Lamage L, Ingram CG, Jenkins
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64. Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpreting
small differences in functional status: The six minute walk test in chronic
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cumulative effect of long-acting bronchodilators, exercise, and in-
spiratory muscle training on the perception of dyspnea in patients
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66. Bittner V, Sanderson B, Breland J, Adams C, Schuman C. Assessing
functional capacity as an outcome in cardiac rehabilitation: role of the
6 minute walk test. Clinical Exercise Physiology 2000.
APPENDIX
The following elements should be present on the 6MWT worksheet and report:
Lap counter:
__ __ __ __ __
__ __ __ __ __
__ __ __ __ __
Patient name: ____________________
Patient ID# ___________
Walk # ______
Tech ID: _________ Date: __________
Gender: M F
Age: ____
Race: ____
Height: ___ft ____in, ____ meters
Weight: ______ lbs, _____kg
Blood pressure: _____ / _____
Medications taken before the test (dose and time): __________________
Supplemental oxygen during the test: No
Yes, flow ______ L/min, type _____
Baseline
End of Test
Time
___:___
___:___
Heart Rate
_____
_____
Dyspnea
____
____ (Borg scale)
Fatigue
____
____ (Borg scale)
SpO2
____ %
____%
Stopped or paused before 6 minutes? No
Yes, reason: _______________
Other symptoms at end of exercise: angina
dizziness
hip, leg, or calf pain
Number of laps: ____ (60 meters)  final partial lap: _____ meters 
Total distance walked in 6 minutes: ______ meters
Predicted distance: _____ meters
Percent predicted: _____%
Tech comments:
Interpretation (including comparison with a preintervention 6MWD):
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20. 
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF 
PULMONARY HYPERTENSION MODIFIED AFTER THE NEW 
YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ACCORDING TO THE WHO 1998 
(GALIE, 2009) 
World Health Organization functional assessment classification  
Class 
I:  
Patients with pulmonary hypertension (PH) but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, 
or near syncope. 
Class 
II:  
Patients with PH resulting in slight limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near 
syncope. 
Class 
III:  
Patients with PH resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class 
IV:  
Patients with PH with inability to carry out any physical activity without symptoms. 
These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even be 
present at rest. Discomfort is increased by any physical activity. 


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21. 
 
 

SAP_001.pdf: 
Reata Pharmaceuticals, Inc. 
 
402-C-1504 
Statistical Analysis Plan – Protocol v2 
 
May 26, 2020 
Version 2.0 
1 
Confidential 
 
 
Reata Pharmaceuticals, Inc. 
Protocol 402-C-1504 
Protocol Version 2.0 (October 18, 2016) 
CATALYST 
 
A double-blind, randomized, placebo-controlled Phase 3 trial  
to study the safety, tolerability, and efficacy of bardoxolone methyl  
in patients with connective tissue disease-associated pulmonary arterial hypertension 
 
 
 
 
 
Statistical Analysis Plan 
Version 2.0 
Version 2.0: May 26, 2020 
Original: December 19, 2016 




Reata Pharmaceuticals, Inc. 
 
402-C-1504 
Statistical Analysis Plan – Protocol v2 
 
May 26, 2020 
Version 2.0 
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Confidential 
CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
CONTENTS .....................................................................................................................................3 
TABLES  ......................................................................................................................................6 
FIGURES  ......................................................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
REVISION HISTORY.....................................................................................................................9 
1. 
INTRODUCTION ......................................................................................................10 
2. 
STUDY DESCRIPTION ............................................................................................10 
2.1. 
Study objectives ..........................................................................................................10 
2.1.1. 
Efficacy .......................................................................................................................10 
2.1.2. 
Safety ..........................................................................................................................10 
2.2. 
Study design ................................................................................................................10 
2.2.1. 
Stratification ...............................................................................................................11 
2.2.2. 
Discontinuation and termination of study patients .....................................................11 
2.2.3. 
Date of last contact .....................................................................................................12 
2.3. 
Study drug ...................................................................................................................12 
2.4. 
Power and sample size ................................................................................................12 
2.5. 
Blinded sample size recalculation ..............................................................................13 
2.6. 
Randomization and blinding .......................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
Intent-to-treat population ............................................................................................13 
3.2. 
Safety population ........................................................................................................13 
4. 
SOFTWARE ...............................................................................................................14 
5. 
GENERAL CONVENTIONS ....................................................................................14 
5.1. 
Definition of baseline .................................................................................................14 
5.2. 
Definition of scheduled post-baseline measurements .................................................15 
5.2.1. 
Laboratory parameters ................................................................................................15 
5.2.2. 
Non-laboratory parameters s .......................................................................................16 
5.2.3. 
Last clinic visit and post-treatment results .................................................................16 
5.3. 
Handling of results of unscheduled tests ....................................................................16 
5.4. 
Definition of time .......................................................................................................16 


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5.5. 
Missing and partial data ..............................................................................................17 
6. 
DATABASE LOCK AND UNBLINDING ...............................................................18 
6.1. 
Final database lock .....................................................................................................18 
6.2. 
Authorization for unblinding ......................................................................................18 
7. 
PATIENT SUMMARIES ...........................................................................................18 
7.1. 
Enrollment ..................................................................................................................18 
7.2. 
Disposition ..................................................................................................................18 
7.3. 
Demographic and baseline characteristics ..................................................................18 
7.4. 
Medical history ...........................................................................................................19 
8. 
STUDY DRUG AND OTHER MEDICATIONS ......................................................20 
8.1. 
Prior and concomitant medications ............................................................................20 
8.2. 
Duration of treatment and exposure to study drug .....................................................20 
9. 
ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) ...............................21 
10. 
EFFICACY OUTCOMES ..........................................................................................21 
10.1. 
Primary efficacy outcome ...........................................................................................21 
10.2. 
Secondary efficacy outcome .......................................................................................21 
10.3. 
Exploratory efficacy outcomes ...................................................................................22 
11. 
STATISTICAL METHODS .......................................................................................24 
11.1. 
Primary efficacy outcome ...........................................................................................24 
11.1.1. 
Primary analysis ..........................................................................................................24 
11.2. 
Secondary efficacy outcome .......................................................................................26 
11.3. 
Exploratory efficacy outcomes ...................................................................................27 
11.3.1. 
Analysis of exploratory change from baseline endpoints ...........................................27 
 
 
11.3.3. 
Analysis of exploratory time-to-event outcomes ........................................................28 
11.3.4. 
Analysis of eGFR changes ..........................................................................................28 
12. 
SAFETY ANALYSES ...............................................................................................29 
12.1. 
Safety variables ...........................................................................................................29 
12.2. 
Adverse events and serious adverse events ................................................................29 
12.3. 
Laboratory determinations ..........................................................................................31 
12.3.1. 
Transaminases .............................................................................................................31 
12.3.2. 
Line plot and Boxplot presentations ...........................................................................32 
12.3.3. 
Shift tables ..................................................................................................................32 


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12.4. 
12-lead Electrocardiogram ..........................................................................................32 
12.5. 
Vital signs and weight ................................................................................................32 
12.5.1. 
Vital signs ...................................................................................................................32 
12.5.2. 
Weight .........................................................................................................................33 
13. 
PHARMACOKINETIC ANALYSES ........................................................................33 
14. 
PROTOCOL DEVIATIONS ......................................................................................33 
14.1. 
Major protocol deviations ...........................................................................................33 
14.2. 
Other protocol deviations ...........................................................................................33 
15. 
OTHER TOPICS ........................................................................................................33 
15.1. 
Analysis by study site .................................................................................................33 
15.2. 
Interim analysis ...........................................................................................................33 
15.3. 
Subgroups analysis .....................................................................................................33 
16. 
ARCHIVING ..............................................................................................................34 
17. 
DEVIATION FROM THE PROTOCOL-SPECIFIED ANALYSIS .........................34 
18. 
REFERENCES ...........................................................................................................35 
APPENDIX A. APPROACH TO ESTIMATING MEANS AND COVARIANCE 
STRUCTURE USED IN THE ORIGINAL SAMPLE SIZE 
CALCULATIONS ......................................................................................................36 
A. 1. 
INTRODUCTION ......................................................................................................36 
A. 2. 
TREATMENT EFFECT OF BARDOXOLONE METHYL ON 6MWT ..................36 
A. 3. 
VARIABILITY OF 6MWT IN OTHER PAH STUDIES ..........................................39 
A. 4. 
SIMULATION STUDY FOR COMPLETE DATA ..................................................41 
A. 5. 
SIMULATION STUDY WITH A MISSING DATA MODEL .................................42 
APPENDIX B. GUIDELINES FOR RECALCULATION OF SAMPLE SIZE ........................44 
B. 1. 
INTRODUCTION ......................................................................................................44 
B. 2. 
STUDY DESIGN ASSUMPTIONS ...........................................................................44 
B. 3. 
RECALCULATION OF PARAMETERS .................................................................45 
B. 4. 
BLINDING PROCEDURES ......................................................................................48 
B. 5. 
SRC: COMPOSITION AND LOGISTICS ................................................................48 
B. 6. 
CALCULATIONS AND DATA SUMMARIES .......................................................49 
B. 7. 
RECOMMENDATION FORM ..................................................................................50 
APPENDIX C. SCHEDULE OF ASSESSMENTS ....................................................................51 
APPENDIX D. CLASSIFICATION OF VISITS .......................................................................52 
APPENDIX E. LIST OF LABORATORY TEST ......................................................................53 




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ABBREVIATIONS 
6MWT 
6-minute walk test 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
ATS 
American Thoracic Society 
BMI 
body mass index 
BNP 
brain natriuretic peptide 
BUN 
blood nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CPK 
creatine phosphokinase 
CSR 
clinical study report 
CTD 
connective tissue disease 
CTD-PAH 
connective tissue disease-associated pulmonary arterial hypertension 
 
 
DSMB 
Data Safety Monitoring Board 
EC 
Ethical Committee 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration rate 
FC 
functional class 
FCS 
fully conditional specification 
FDA 
Food and Drug Administration (US) 
GFR 
glomerular filtration rate 
GGT 
gamma glutamyl transferase 
Hb 
hemoglobin 
HCG 
human chorionic gonadotropin 
HDPE 
high-density polyethylene 
ICH 
International Conference on Harmonization 
IgG 
immunoglobulin G 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
ITT 
intent-to-treat 
LDH 
lactate dehydrogenase 
LLD 
lower limit of detection 
 
 
 


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ABBREVIATIONS, CONTINUED 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
METS 
metabolic equivalent tasks 
MMRM 
mixed model repeated measures 
MNAR 
missing not at random 
NKDEP 
National Kidney Disease Education Program 
PAH 
pulmonary arterial hypertension 
PI 
principal investigator 
PPD 
Pharmaceutical Product Development 
PT 
preferred term 
RBC 
red blood cell 
Reata 
Reata Pharmaceuticals, Inc. 
REB 
Research Ethics Board 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
 
 
SD 
standard deviation 
 
 
SOC 
system organ class 
SRC 
Sample Size Re-calculation Committee 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VCS 
visual contrast sensitivity 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 
 
 


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REVISION HISTORY 
Version 
Date 
Document Owner 
Revision Summary 
1.0 
 
December 19, 2016 
 
Initial version. 
2.0 
May 26, 2020 
 
 
 
Revised definitions of
 
 
clinical improvement 
Updated rules for rounding when taking 
averages 
Removed sensitivity analyses using multiple 
imputation 
Added additional analyses of transaminases  
Added off-treatment safety analyses  
Added medical history analyses 
The analysis plan is based on the information from the following document: 
Protocol Version 2.0, 18 October 2016 
 


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1. 
INTRODUCTION 
Study 402-C-1504 (the CATALYST study) is a randomized, double blind, placebo-controlled 
Phase 3 study designed to compare the safety, tolerability, and efficacy of bardoxolone methyl to 
placebo in patients with connective tissue disease-associated pulmonary arterial hypertension 
(CTD-PAH). This statistical analysis plan (SAP) defines the methods and analyses that Reata 
Pharmaceuticals, Inc. (Reata) will use to analyze data from the CATALYST study.  
This SAP complies with the International Conference on Harmonisation (ICH) guidance and 
relevant Food and Drug Administration (FDA) guidances.  It is based on Version 2 of the study 
protocol dated October 18, 2016.  If the protocol is subsequently amended, this SAP may be 
amended as well.  Should the SAP and the protocol be inconsistent with respect to the planned 
analyses, the language of the SAP is governing.  This version of this SAP describes the analyses 
planned prior to the database lock and supersedes the statistical considerations identified in the 
study protocol.  Reata (the Sponsor) will follow this SAP in analyzing the study data.  Unless 
otherwise specified, these analyses will be summarized in the clinical study report (CSR).  Any 
substantive changes made to the SAP after the database lock will be clearly identified, and any 
analyses in addition to those specified in the SAP after the database lock will be considered ad 
hoc.  The CSR will describe any deviations from the planned analyses. 
2. 
STUDY DESCRIPTION 
2.1. 
Study objectives 
2.1.1. 
Efficacy 
The primary efficacy objective of the CATALYST study is to assess the efficacy of bardoxolone 
methyl relative to placebo in increasing distance in the six-minute walk test (6MWT) from 
baseline to Week 24. 
2.1.2. 
Safety 
The safety objective of the CATALYST study is to assess frequency, intensity, and relationship 
to study drug of adverse events (AEs) and serious adverse events (SAEs), and change from 
baseline in the following assessments: physical examinations, vital sign measurements, 12-lead 
electrocardiograms (ECGs), clinical laboratory measurements, and weight. 
2.2. 
Study design 
The CATALYST study will randomize approximately 130 patients with CTD-PAH.  This 
number may be increased to approximately 200 patients depending on the results of a blinded 
sample size re-calculation. 
Patients who meet all inclusion criteria and no exclusion criterion and have satisfied screening 
evaluations will be randomized 1:1 to receive either placebo or bardoxolone methyl administered 
once daily for 24 weeks.  Patients randomized to placebo will remain on placebo throughout the 
study and undergo sham titration.  Patients randomized to bardoxolone methyl will start at 5 mg 


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and will dose-escalate to 10 mg at Week 4, unless contraindicated clinically.  Dose de-escalation 
is permitted during the study if indicated clinically. 
2.2.1.
Stratification 
Randomization will be stratified by number of background pulmonary arterial hypertension 
(PAH) therapies into three distinct strata with Stratum 1 consisting of patients with no 
background PAH therapy, Stratum 2 consisting of patients with one background PAH therapy, 
and Stratum 3 consisting of patients with two background PAH therapies. 
All patients in the study will follow the same visit and assessment schedule, shown in Figure 1. 
Following randomization, patients will be scheduled to be assessed in person during treatment at 
Weeks 1, 2, 4, 6, 8, 16, and 24 and by telephone contact on Days 3, 10, 21, 31, 38, 84, and 140.  
Patients will also be scheduled to be assessed at an in-person follow-up visit at Week 28, four 
weeks after the end of treatment.  
Figure 1: 
Schema for study of bardoxolone methyl in patients with CTD-PAH 
 
 
The number of administered doses will be calculated based on date of first dose, date of last 
dose, drug dispensed, and pill counts from drug returned.  Patients who administer at least 126 
doses (i.e., 75% of the 168 expected doses) will be considered treatment compliant.  Patients 
who complete the study (i.e., complete study visits through Week 28), complete treatment 
(i.e., complete study medication through Week 24), and are considered treatment compliant will 
be eligible for a separate open-label extension study. 
2.2.2. 
Discontinuation and termination of study patients 
Patients may discontinue study drug or withdraw from the study at any time for any reason.  
Additionally, the sponsor reserves the right to terminate the study, and the investigator may 
discontinue an individual patient from study drug.  Consultation with the medical monitor should 
occur before discontinuing study drug or withdrawing a patient from the study.  The reason for a 
patient’s discontinuation from study drug or study termination will be recorded in the electronic 
case report form (eCRF). 
Patients who discontinue study drug should remain in the study and undergo all scheduled 
assessments, if possible.  Patients who terminate from the study prior to the Week 24 study visit 
should be brought back to the clinic as soon as possible for early termination assessments (i.e., 
Week 24 Day Prior, and end-of-treatment visits) as well as a follow-up visit four weeks later.  
Patients should complete the end-of-treatment procedures, including the 6MWT, prior to any 
adjustments being made to their PAH treatment regimen. 


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2.2.3. 
Date of last contact 
The last date of contact for each patient is defined as the date of last telephone contact or 
in-person visit at or before the Week 28 follow-up visit, except in the following cases: 
x For those patients who withdraw consent to participate in the study prior to 24 weeks: 
the date of withdrawal of consent 
x For those patients who die prior to 24 weeks: the date of last contact in person or by 
telephone prior to death 
2.3. 
Study drug 
The study drug will be supplied in tamper-evident kits containing two 30-cc high-density 
polyethylene (HDPE) bottles.  Each bottle of study drug will contain 30 capsules of 2.5 mg or 
5 mg strength bardoxolone methyl or the matching placebo capsules.  
2.4. 
Power and sample size 
The primary analysis of the efficacy data will be based on the intent-to-treat (ITT) patient 
population (see Section 3 for a definition of the analysis populations). Primary efficacy is based 
on an estimate of the change from baseline to Week 24 in the 6MWT.  Computation of the 
statistical power of the primary analysis will be based on the difference between change from 
baseline in the bardoxolone methyl and placebo groups.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.5. 
Blinded sample size recalculation 
Since there is uncertainty associated with the values used for the computation of the power, the 
protocol allows recalculation of the sample size when approximately 100 patients have been 
randomized.  Using blinded information, the statisticians responsible for the sample size 
recalculation will reassess relevant baseline and operational parameters and compute the power 
using the simulation approach outlined in Appendix A. Based on the results obtained from this 
recalculation, the study size will be increased, if necessary, to maintain the desired level of 
power.  As no unblinding will occur, the recalculation will have at most a negligible impact on 
the Type 1 error rate for the final analysis.  Appendix B contains details that provide statistical 
and operational guidelines for conducting the planned recalculation of the sample size. 
In the event that the study accrues quickly, so that there is insufficient follow up data for a 
sample size recalculation, the study size may be increased up to 200 subjects. 
2.6. 
Randomization and blinding 
Patients will be randomized in a 1:1 ratio to receive bardoxolone methyl or placebo, and 
randomization will be stratified by number of background PAH medications.  Three strata will 
be used: zero background PAH medications, one background PAH medication, and two 
background PAH medications. 
All patients, investigators, site personnel, laboratories, and Reata personnel with direct 
involvement in the conduct of the study and their designees will be blinded to treatment 
assignments and will remain blinded until after the database is locked and access to the 
randomized treatment codes authorized (Section 6.2). The only individuals with access to 
treatment assignments will be those individuals who develop and maintain the randomization 
code, the Interactive Web Response System (IWRS) group, the Data Safety Monitoring 
Board (DSMB), the external unblinded statistical analysis center providing data to and analyzing 
data for the DSMB, and safety personnel without direct involvement in the conduct of the study 
who are assigned to report unblinded data at the occurrence of unexpected SAEs to regulatory 
authorities as required. 
3. 
ANALYSIS POPULATIONS 
The study has two analysis populations, which are described below.  
3.1. 
Intent-to-treat population 
The ITT population consists of all randomized patients categorized by their assigned treatment 
group regardless of treatment exposure.  Analyses of both the primary and secondary efficacy 
outcomes will use the ITT population.  Some sensitivity and exploratory analyses will also use 
the ITT population. 
3.2. 
Safety population 
The safety population includes all patients who received at least one dose of randomized study 
drug.  Patients who received at least one dose of bardoxolone methyl will be classified in the 


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bardoxolone methyl group.  Patients who received at least one dose of placebo and no 
bardoxolone methyl will be classified in the placebo group.  
4. 
SOFTWARE 
Most statistical analyses will be performed using SAS version 9.3 or later, with SAS program 
code prepared specifically for the project by qualified statisticians and SAS programmers.  Other 
validated programs (e.g., S-Plus, R, CART) may be used for graphs or for specialized analyses. 
5. 
GENERAL CONVENTIONS  
The protocol-specified time windows for a visit (Appendix D) and time of a measurement 
(Section 5.4) determine the visit assignment for each observation.  
Continuous data will be summarized using descriptive statistics: number of observations (n), 
mean, median, standard deviation (SD), minimum, and maximum.  Confidence intervals (CIs) 
will be presented as appropriate.  The same number of decimal places as in the observed value 
will be presented when reporting minimum and maximum; 1 more decimal place than in the 
observed value will be presented when reporting mean and median; and 2 more decimal places 
than in the observed value will be presented when reporting SD. When values are averaged in the 
analysis data (e.g., in the calculation of baseline), the same number of decimal places as in the 
observed value will be presented.  
Frequencies and percentages will summarize categorical data.  Presentations of categorical data 
will generally suppress percentages for items where the count is zero in order to draw attention to 
nonzero counts.  
Confidence intervals will generally be constructed at the 95% level.  For binomial variables, 
exact methods will be employed unless otherwise specified. 
Categorical/qualitative data will be presented using frequency counts and percentages.  All 
percentages will be rounded to 1 decimal place, unless otherwise specified.  Percentages equal to 
100 will be presented as 100% and no percentages will be presented for zero frequencies.   
Summary presentations will classify patients by their randomized treatment group for analyses 
on the ITT population, and actual treatment received for analyses on the safety population, unless 
otherwise specified.  References to treatment group from this point forward in the SAP text 
indicate randomized treatment group, unless stated otherwise. 
5.1. 
Definition of baseline 
This section describes which measurements taken prior to first dose of study drug will be used to 
calculate baseline for each study parameter.  No measurement collected after first dose will be 
used in the calculation of baseline.  The collection date and time of the sample will be compared 
to the date and time of first dose.  Should a patient never receive study drug, only measurements 
collected prior to randomization will be used in the calculation of baseline values. 


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In general, the baseline value for any laboratory or non-laboratory parameter will be calculated 
as the mean of data sampled up until and including Day 1, but not occurring after first dose of 
study drug, except in the following circumstances: 
x Whenever specific visit results (i.e., Screening A, B, or Day 1) are indicated, the 
results will be used regardless of whether the measurements were collected within the 
protocol-specified window of time (Appendix D), as long as they precede first dose. 
x For eligibility purposes, only two 6MWT observations (Screening B and Day 1 
preferred to Screening A and Day 1) will be used to determine eligibility (must be 
within 15% of each other and at least 150 m).  Patients not meeting the eligibility 
criteria are listed. 
x As the covariate in the primary efficacy analysis, the screening 6MWT will be either 
the average of Screening A 6MWT and Screening B 6MWT or the single Screening 
A 6MWT result if Screening B did not occur. 
x For the outcome in primary analysis, the Day 1 6MWT will be subtracted from the 
6MWT observation at each followup time to give the change score.  
x For discrete efficacy outcomes,
 
, the latest assessment will be used 
for analysis purposes. 
x If a scheduled measurement prior to first dose is repeated, baseline calculations will 
use only one result per scheduled measurement (i.e., either the original or repeated).  
The original value will be used, unless it is missing.  The repeated value will only be 
used if the original value is missing, otherwise the repeated value will be ignored. The 
CSR will include listings of all repeated measurements collected prior to first dose, 
indicating whether they were included in the calculation of baseline. 
x For repeated 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.  Otherwise, if the original result is missing 
(e.g., because the laboratory detected an error) but a retest result is available, the 
retested result will be used as the scheduled measurement, and the original result will 
be ignored. 
5.2. 
Definition of scheduled post-baseline measurements 
Instead of relying solely on visit labels in the clinical database for post-baseline values, results 
collected on a date will be attributed to a specific time point by calculating the days relative to 
randomization.  Listings will present all measurements. 
Section 5.4 describes how time is calculated for each assessment. 
5.2.1. 
Laboratory parameters  
Post-baseline laboratory measurements are defined as the scheduled or unscheduled 
measurements collected closest to (or on) the patient’s target visit day (Appendix D), with 
collection date identified in the central laboratory data. If two assessments are equidistant from a 


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target study day, the earlier assessment is used.  If the visit used for analysis includes two 
assessments on the same day, the average of the two measurements will be used.  As with the 
baseline retest convention, if both the original and a retest result for a scheduled post-baseline 
laboratory are available in the central laboratory data, the original result will be used and the 
second (i.e., ‘retested’) result will be ignored. Otherwise, if the original result is not available 
(e.g., central laboratory detects an error) but a retest result is available, the retested result will be 
used as the scheduled post-baseline measurement. 
5.2.2. 
Non-laboratory parameters s 
Post-baseline measurements of non-laboratory parameters are defined as the measurements 
collected on the day closest to the patient’s target visit day (Appendix D). If two assessments are 
equidistant from a target study day, the earlier assessment is used.  If the visit used for analysis 
includes two assessments on the same day, the average of the two measurements will be used.  
The last clinic visits on and off study drug will be classified according to when they occurred as 
specified in Section 5.2.3. 
5.2.3. 
Last clinic visit and post-treatment results 
Patients who terminate from the study before the Week 24 study visit should be brought back to 
the clinic as soon as possible for early termination assessments as well as a follow-up visit four 
weeks later.  All assessments through Week 24 will be classified according to the time relative to 
randomization, regardless of the patient’s study participation or study drug status.  Post treatment 
assessments will be classified according to the time relative to last dose in Appendix D, for 
example 4 weeks off-treatment is within 7 to 35 days after last dose of the study. 
Patients who discontinue treatment early but continue to be followed until the end of study will 
have their assessments attributed to visits as specified in Section 5.2.1 and Section 5.2.2.  
A listing will indicate when each patient’s visits occurred.  Appendix D indicates how scheduled 
results will be classified. 
5.3. 
Handling of results of unscheduled tests 
As discussed below in Section 5.5, retests will be used for partial 6MWTs stopped for non-
medical reasons and repeated at an unscheduled visit. 
5.4. 
Definition of time 
For visits (or events) that occur on or after randomization, time is calculated in days as: 
time = visit (or event) date – date of randomization + 1 
For visits (or events) that occur prior to randomization, time is calculated in days as: 
time = visit (or event) date – date of randomization 
The quantity ‘days since first dose’ is defined as: 
x days since first dose  = visit (or event) date – date of first  + 1  
The quantity ‘days since last dose’ is defined as: 


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days since last dose = visit (or event) date - date of last dose For summaries that present 
distribution of time expressed in weeks and months, weeks will be defined as days divided by 
seven and months as days divided by 30.4375. 
5.5. 
Missing and partial data 
Early termination of the 6MWT may be due to one of the six American Thoracic Society (ATS) 
immediate stopping criteria, low oxygen, or elective non-medical reasons.  When a partial 
6MWT is caused by non-medical reasons (e.g., a bathroom break), the patient is encouraged to 
return for an unscheduled visit to redo the 6MWT. 
For the analysis of safety variables, only partial dates may be imputed; otherwise, missing data 
will be treated simply as missing.  
The central laboratory uses assays that have lower limits of detection (LLD).  All laboratory 
results below the LLD will be imputed as 1/2 of the LLD.  Results reported as greater than a 
value (i.e., ‘> value’) will be imputed as 1.0 × that value.  In the event that a large percentage (> 
20% of values) of laboratory values are out of the range of the limits of detection, then a footnote 
will be added to indicate that the percentage of values falling outside of the limits of detection is 
greater than 20%. 


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6. 
DATABASE LOCK AND UNBLINDING 
6.1. 
Final database lock 
After the database lock and the authorization for unblinding (Section 6.2), the treatment codes 
will be merged to the analysis datasets. Any change to the clinical database after this time will 
require written authorization, with explanation, by Reata.  In addition, beginning at the time of 
database lock, an audit trail will be maintained of all versions of the analysis datasets that may 
result from refinements of the algorithms for derived variables in the course of the analysis. 
6.2. 
Authorization for unblinding 
After database lock and upon receipt of written authorization from Reata, a blinded study team 
will receive the actual treatment codes directly from the group maintaining the IWRS.  This team 
will generate top-line results and provide them to Reata along with the analysis files containing 
the randomized treatment codes.  Reata will not have direct access to the randomized treatment 
codes until they have been provided the top-line results and datasets. 
Reata’s standard operating procedures dictate how access to the treatment codes will be extended 
within the company and to investigative sites. 
7. 
PATIENT SUMMARIES 
7.1. 
Enrollment 
Enrollment will be summarized by country and geographical region.  A table will present the 
number and percentages of patients in each stratum by treatment group. 
7.2. 
Disposition 
The disposition of patients (number randomized, study drug exposure, duration of follow-up, and 
inclusion in the various study populations) will be tabulated by treatment group in the ITT and 
Safety populations.  Completion of study treatment, completion of study, discontinuation of 
study drug, discontinuation of study, and reason for discontinuation of study drug treatment and 
study will be summarized.  See Section 8.2 for other summaries of treatment exposure.  Time to 
permanent study drug discontinuation will be summarized.  If the treatment end date or study end 
date are missing, the date will be imputed as the Study Drug Termination (SDT).  If the 
treatment end date or study end date are missing and no reason for treatment or study 
discontinuation are included in the CRF, the reason for treatment or study discontinuation will be 
study termination.  
7.3. 
Demographic and baseline characteristics 
Summaries of demographic and other baseline characteristics will be presented by treatment 
group for all analysis populations (Section 3). The two treatment groups will be assessed 
descriptively for comparability of demographic and baseline characteristics for the ITT study 
population.  Demographics and baseline characteristics will be summarized by subgroups. 
Demographics and other baseline characteristics include the following: 


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x age (years) at the date of informed consent, sex, ethnicity, race 
x height, weight, body mass index (BMI) 
x baseline disease characteristics (e.g., WHO functional class, baseline 6MWT, years 
since PAH diagnosis)  
x connective tissue disease (CTD) etiology (scleroderma, lupus, mixed, and other) 
x pulmonary function testing results 
x PAH and CTD medications 
x geographic region 
x baseline eGFR 
x baseline eGFR category 
 
  (ml/min/1.73m2) 
 
60 to < 90 (ml/min/1.73m2) 
 
45 to < 60 (ml/min/1.73m2) 
 
30 to < 45 (ml/min/1.73m2) 
 
15 to < 30 (ml/min/1.73m2) 
 
< 15 (ml/min/1.73m2)  
x other variables of interest 
7.4. 
Medical history 
Medical history is summarized by treatment.  Medical history is coded using MedDRA (Medical 
Dictionary for Regulatory Activities) version 19.0.  Medical history items are summarized by 
MedDRA SOC and PT. 


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8. 
STUDY DRUG AND OTHER MEDICATIONS 
8.1. 
Prior and concomitant medications 
All concomitant medications collected from screening through the end of the study will be 
classified by preferred terms according to the WHO Drug Dictionary (version 01MAR2016, type 
DDE+HD, format B2).  Concomitant medications will be summarized by WHO Drug Dictionary 
classification.  Special groups of medications (e.g. PAH, CTD) will be summarized by treatment 
group, by medical history as appropriate, and dose, if feasible.  
8.2. 
Duration of treatment and exposure to study drug 
The study drug will be supplied in tamper-evident kits containing two 30-cc high-density 
polyethylene (HDPE) bottles.  Each bottle will utilize foil induction-seal liners and a 
child-resistant closure.  Each bottle of study drug will contain 30 capsules of 2.5 mg or 5 mg 
strength bardoxolone methyl or the matching placebo capsules.  Duration of treatment will be 
defined for each patient as the number of days the patient received study medication [(date of last 
dose) – (date of first dose) + 1].  Total number of administered doses will be calculated for each 
patient using duration of treatment minus missed doses.  Missed doses are calculated from 30-
count bottles and number of expected doses based on treatment duration.  For example, a patient 
returning 3 capsules in each bottle after 28 days of treatment is assumed to have administered 27 
doses and missed 1 dose.  Since two bottles are included in each kit, if the number of returned 
capsules in each bottle is not equal, the bottle with the maximum number of returned capsules 
will be used for calculating missed doses.  Total number of doses dispensed and total dose (mg) 
dispensed are calculated from total number of kits (bottles) recorded on the Study Drug 
Dispensation eCRF.  Total number of doses received are calculated from information on the 
eCRF of Study Drug Return and Study Drug Dispensation, as the total number of doses 
dispensed – total number of doses returned.  Study drug compliance (%) is calculated as 100 × 
total number of doses received / total number of doses dispensed.  The proportion of patients 
ZKR KDYH  FRPSOLDQFH LV summarized.  To summarize the actual dose-titration, frequency 
counts and percent of patients on each dose-level (as determined by the dispensed kit strength) 
will be tabulated for each scheduled dispensing visit.  
Standard descriptive statistics will be used to summarize duration of treatment, number of doses 
administered, number of missed doses, percent treatment compliance, and total exposure.  
Descriptive statistics will be calculated and tabulated by treatment group and study completion 
status for the ITT study population, and if warranted, for the other study populations.  All dosing 
information will be listed by treatment group and patient ID. Study drug administration over time 
will be summarized in a listing showing study drug dispensed at each clinic visit.  


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9. 
ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) 
Estimated glomerular filtration rate (eGFR) value will be calculated at the central laboratory and 
used in data analyses.  The equation used to calculate eGFR for each patient will be the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: 
• eGFR (mL/min/1.73 m2   î PLQ6FUț Į î PD[6FUț -1.209 × 0.993Age ×  
1.018 [if female] × 1.159 [if black]. 
:KHUH 6FU LV VHUXP FUHDWLQLQH PJG/ ț LV  IRU IHPDOHV RU  IRU PDOHV DQG Į LV -0.329 for 
females or -0.411 for males, and Age is the age at Screening.  Min indicates the minimum of 
6FUț RU  DQG PD[ LQGLFDWHV WKH PD[LPXP RI 6FUț RU  
Missing eGFR values will not be imputed for the analysis of efficacy.  
10. 
EFFICACY OUTCOMES 
10.1. 
Primary efficacy outcome 
The primary efficacy variable is the change from baseline in 6MWT. 
10.2. 
Secondary efficacy outcome 
The secondary efficacy outcome is the time-to-first persistent clinical improvement event.  To 
declare that clinical improvement has occurred, at least one of the following four criteria must be 
met: 
1. Improvement by at least one WHO functional class coupled with no more than a 15% 
decrease from baseline in 6MWT. 
2. Increase from baseline in 6MWT by at least 10% and stability or improvement in the 
WHO functional class. 
3. Decrease from baseline in creatine kinase (a surrogate biomarker for muscle injury and 
inflammation) by at least 10% and no worsening in WHO functional class and no more 
than a 15% decrease from baseline in 6MWT. 
4. Improvement in estimated JORPHUXODU ILOWUDWLRQ UDWH H*)5  RI EDVHOLQH 
The persistence of the change in WHO functional class, 6MWT, eGFR, or creatine kinase must 
be confirmed by a subsequent assessment that also meets the defined criteria.  The confirmatory 
assessment must occur at least 14 days after the initial assessment, or at the next scheduled 
assessment.  If persistent improvement is confirmed, the date of the event will be considered the 
initial assessment of improved WHO functional class, 6MWT, eGFR, or creatine kinase. 
If confirmatory observation of initial improvement is not available for any reason, such as end of 
study or death, it may or may not be considered an event as defined by the timing of 
improvement as it relates to other study events.  Below is a list of possible reasons for failure to 
obtain a confirmatory observation along with the adjustment to the definition of improvement.   
 
 


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These reasons are as follows: 
1. Last visit: If the improvement is observed at the last scheduled assessment, the 
requirement for an additional assessment after 14 days is waived, and the patient is 
classified as satisfying the criteria for improvement.  In the absence of study end date, 
Study Drug Termination (SDT) is used. 
2. Death: If the patient’s death occurs before the confirmatory observation, then the patient 
is classified as not satisfying the criteria for improvement. 
3. Study termination: If the patient terminates the study for reasons of “lost to follow-up” or 
“withdrawal of consent”, then the patient is classified as not satisfying the criteria for 
improvement. 
4. Patient starts new PAH drug: If a patient decides to stop study drug and switch to a new 
PAH drug, then the patient is classified as not satisfying the criteria for improvement. 
5. Patient discontinues study drug: If a patient discontinues the study drug due to an AE and 
improvement is confirmed, then the patient is classified as satisfying the criteria for 
improvement.  If improvement is not confirmed or if the patient has no follow-up 
measurement, then the patient is classified as not satisfying the criteria for improvement. 
10.3. 
Exploratory efficacy outcomes 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11. 
STATISTICAL METHODS 
11.1. 
Primary efficacy outcome 
11.1.1. 
Primary analysis 
This section describes the methods planned for the primary analysis, which is based on the 
primary efficacy outcome, the change from baseline in 6MWT.  The analysis will compare the 
mean change in the bardoxolone methyl group relative to placebo at Week 24.  A mixed model 
will be fit with this outcome using the following PROC MIXED code in SAS, where ID is the 
patient identifier, SCR_6MWT and DELT_6MWT are the screening values for the 6MWT and 
change from baseline, respectively, in the primary outcome at each visit (VOBS) by treatment 
group (GRP), and N_PAH_MEDS is the fixed number of background PAH therapies for a patient. 
Below is example code used to estimate the treatment effect:  
proc mixed data = &DAT. method=reml alpha=0.05 covtest; 
   class  ID GRP (ref="plc") VOBS (ref=LAST)  
     N_PAH_MEDS; 
   model DELT_6MWT = SCR_6MWT  
 
 
 
 
N_PAH_MEDS 
GRP  
 
 
 
 
VOBS  
GRP * VOBS  
VOBS * SCR_6MWT Hb / s ddfm=kr; 
   repeated VOBS / subject = ID type = UN r; 
   lsmeans  VOBS * GRP / diff om cl e; 
run; 
 
The model will have the following characteristics: 
x The response variable will be the vector of observed change in the primary efficacy 
outcome from baseline at each study visit where the 6MWT is measured (Week 4, 
Week 8, Week 16, and Week 24).  The outcome will consist of the following four 
repeated measures: Week 4 6MWT – baseline 6MWT, Week 8 6MWT – baseline 
6MWT, Week 16 6MWT – baseline 6MWT, and Week 24 6MWT (averaged over 
both measurements made at Week 24) – baseline 6MWT.  
 
 6MWT values collected after 
the date of clinical worsening will be treated as missing for analysis of 6MWT. 
x Repeated post-baseline measurements from each patient will be identified by patient 
identifier (ID). 
x Within-patient correlations will be modeled using an unstructured covariance 
structure.  In the unlikely situation that this model does not converge (i.e., the study 
has too few observations for the number of parameters estimated), the model will use 
the heterogeneous Toeplitz structure, which assumes the correlation between two 
repeated measurements depends solely on their lag in visit number, and that the 
variance of the outcome may differ over time. If the model still does not converge 


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with the heterogeneous Toeplitz structure, the model will use a homogeneous 
Toeplitz structure.  Finally, if the model using the homogeneous Toeplitz structure 
does not converge, the model will use a compound symmetry structure which 
assumes equal correlation for a patient’s measurements, regardless of how far apart in 
time they were taken. 
x The models will include the following covariates: 
 Time defined as a categorical variable (i.e., no restriction is imposed on the 
trajectory of the mean outcome over time) (VOBS) 
 Treatment group (GRP) 
 N_PAH_MEDS (stratification variable for number of background PAH therapies) 
 Screening 6MWT (SCR_6MWT) 
 Screening 6MWT by time interaction (VOBS * SCR_6MWT) 
 Day 1 hemoglobin (Hb) 
 Time by treatment group interaction (GRP * VOBS) 
The MMRM, as defined above, uses the screening value of the 6MWT as a covariate and the 
baseline value of the 6MWT for the computation of the outcome (the change from baseline).  
This allows adjustment for the “baseline” value between groups while providing the ability to 
provide valid estimates of the placebo-adjusted treatment effect. 
In the event the MMRM model with an unstructured covariance structure does not converge, the 
following covariance structures are substituted, in the order listed.  Each subsequent covariance 
structure is used only if each previous covariance structure is used and no previous model 
converged. 
1. Heterogeneous Toeplitz covariance structure (assuming different variances at each time 
point and that measurements taken closer together in time are more highly correlated than 
those taken farther apart). 
2. Toeplitz covariance structure (assuming measurements taken closer together in time are 
more highly correlated than those taken farther apart). 
3. First order auto-regressive [AR(1)] covariance structure (assuming measurements taken 
closer together in time are more highly correlated than those taken farther apart, but the 
correlation is more constrained than the Toeplitz structure). 
4. Compound symmetry covariance structure (assuming equal correlation for measurements 
from a patient, regardless of how far apart in time they were taken).  A compound 
symmetry covariance structure was assumed in the sample size calculation. 
 
Results of MMRM are summarized in tables and line plots.  Additionally, line plots of 
6MWT change from baseline, labeled by treatment group up to and including Week 24 are 
generated 


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11.2. 
Secondary efficacy outcome 
The secondary efficacy outcome, the time to clinical improvement, will be analyzed using 
methods for a censored time-to-event outcome.  All analyses will be stratified using number of 
background PAH medications at baseline to define the strata. 
Summary tables will present median time to first clinical improvement and associated 95% CIs 
for each treatment group as well as hazard ratios and 95% CIs for each comparison of 
bardoxolone methyl to placebo.  Median duration with appropriate 95% CIs, as well as the 
proportion of patients remaining event-free at times of interest, will be estimated using Kaplan-
Meier methods with the product limit estimator computed using PROC LIFETEST in SAS.  
PROC PHREG in SAS will be used to estimate hazard ratios, mean and standard error time -to-
event, and their 95% CIs by Cox regression models.  
 
 
 
 
In the event that the number of events across strata is too small, the strata consisting of zero 
background PAH medications and one background PAH medication will be collapsed.  
 
 
     
  
 
 
 
 
 
 
 
 
 
Treatment group comparisons will use the Type 3 Chi-square test and unadjusted two-sided p-
value associated with the treatment group variable in the Cox proportional hazards model.  Time-
to-event analyses will use Breslow’s method of handling ties in event times [1], which is the 
default method used in PROC PHREG. The TEST statement in PROC LIFETEST will be used to 
include the strata and the STRATA statement will be used in PROC PHREG. 
Kaplan-Meier plots will supplement these presentations.  The number of patients within each 
treatment group at risk of an event at regular time points will appear at the bottom of these 
figures. 
The secondary outcome is important in understanding the effectiveness of bardoxolone methyl 
and its ability to improve function.  


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11.3. 
Exploratory efficacy outcomes 
 
  
11.3.1. 
Analysis of exploratory change from baseline endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
11.3.2. 
 
 
 
 
 
 
 
 
 
 
 


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11.3.3. 
Analysis of exploratory time-to-event outcomes 
 
 
 
11.3.4. 
 
 
 
 
 
 
 
 
 
   
 
   
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 


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12. 
SAFETY ANALYSES 
12.1. 
Safety variables  
Safety variables will include physical examinations, vital sign measurements, ECG, clinical 
laboratory measurements, concomitant medications, AEs, and SAEs.  The safety analyses will 
include all results collected from randomization through the end of the study.  The safety 
analyses will include only patients in the safety population, with patients classified by whether 
they received any dose of bardoxolone methyl or not.  For laboratory data, vital signs, and ECG 
data, On-treatment values will be summarized according to the analysis study windows and off-
treatment values will be summarized according to the analysis study windows in Appendix D . 
12.2. 
Adverse events and serious adverse events 
Each treatment emergent AE (TEAE) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA version 19.0).  An AE is defined as any untoward medical occurrence in a 
patient regardless of its causal relationship to study treatment.  A TEAE must have an onset or 
worsen in severity on or after the first dose of study drug and not more than 30 days after the 
date of the last dose of study drug.  AEs with an onset greater than 30 days after the last dose of 
study drug, and therefore not treatment-emergent AEs (TEAEs), are classified as off-treatment 
AEs (OTAEs).  Analyses described for TEAEs are also performed for OTAEs and tabulated 
separately.   
A SAE is defined as an adverse event 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 the offspring of a patient taking the study drug, or is an important 
medical event. Important medical events are defined as events that may jeopardize the patient or 
result in medical or surgical intervention to prevent one of the outcomes listed above.  The term 
“life-threatening” refers to an event in which the patient was at immediate risk of death at the 
time of the event.  
Adverse events resulting from concurrent illnesses, reactions to concurrent medications, or 
progression of disease states will be reported.  Conditions existing prior to the start of the AE 
collection period are considered concurrent medical conditions and are not recorded as AEs.  If 
the patient experiences a worsening or complication of a concurrent medical condition, the 
worsening or complication will be recorded as an AE. 
Each AE will be recorded as a single diagnosis.  Accompanying signs and symptoms will not be 
recorded as additional AEs.  Signs and symptoms will only be recorded if the diagnosis is not 
determined.  Changes in laboratory tests values or ECG parameters will be recorded if they are 
determined to be clinically significant; however, abnormal test values or ECG findings will not 
be reported as AEs if they are the result of pathology for which there is an overall diagnosis. 
Elective procedures performed to manage or treat conditions existing prior to the patient’s 
enrollment in the study are recorded in the patient’s source documents but not in the AE records.  
If a planned procedure is performed early because the pre-existing condition worsens, the 
worsening should be documented as an AE.  


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The investigator must report all SAEs observed or reported by the patient to Reata or designee, 
regardless of their relationship to the study drug or their clinical significance.  SAEs must be 
followed to resolution or until the investigator deems the event to be chronic or the patient to be 
stable. 
Causality of AE is classified according to the following criteria: 
x Unrelated: This relationship suggests that the study drug and the event are not 
associated. 
x Unlikely: This relationship suggests that the association between the study drug and 
the event is unlikely. 
x Possible: This relationship suggests that treatment with study drug might have caused 
or contributed to the AE.  That is, the event follows a reasonable temporal sequence 
from the time of study drug administration or follows a known response pattern to the 
study drug, but could have been produced by other factors. 
x Probable: This relationship suggests that a reasonable temporal sequence of the event 
with the 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 the study drug administration seems likely. 
x Definite: This relationship suggests a definite causal relationship between the study 
drug administration and the AE, and other conditions (concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event.  
Severity is assessed according to the following criteria 
x Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
x Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
x Severe: Symptoms causing inability to perform usual social and functional activities 
The MedDRA dictionary will be used to classify all AEs reported during the study by system 
organ class (SOC) and preferred term (PT).  All summary tables will include counts of patients 
with treatment-emergent adverse events (TEAEs).  TEAEs are defined as those AEs that have an 
onset time either at or after the start of study drug administration and no more than 30 days after 
the last dose of study drug is administered.  Furthermore, TEAEs may be AEs ongoing at the 
time of study drug initiation that increase in severity or become closer in relationship to study 
drug administration during the treatment period.  AEs with missing start dates, but with stop 
dates either overlapping into the treatment period or missing, will be considered TEAEs.  
An overall summary of TEAEs will be presented with the number and percentage of patients 
having a TEAE, a serious TEAE, a TEAE leading to study discontinuation, a TEAE with an 
outcome of death, a TEAE related to study drug (definitely, probably, or possibly related), or a 
severe TEAE. The overall incidence of TEAEs will be summarized by SOC and by SOC and PT 


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using the number and percentage of patients reporting an event and the number of events 
reported.  The incidence of serious TEAEs and TEAEs leading to study discontinuation will be 
summarized in a similar manner.  TEAEs will also be summarized by maximum severity (mild, 
moderate, or severe) and assessed relationship to study drug with the percentage of patients in 
each category.  A TEAE with missing severity or relationship will be considered severe or 
related, respectively.  If more than one TEAE is recorded for a patient within any SOC or PT, the 
patient will only be counted once.  Serious TEAEs, TEAEs leading to study discontinuation, and 
TEAEs with an outcome of death will be presented in separate listings. 
12.3. 
Laboratory determinations  
Actual values and change from baseline values for continuous data from laboratory 
determinations will be summarized descriptively by received study drug at all scheduled study 
visits (Sections 5.1 - 5.3, unless otherwise specified). The laboratory tests is listed in 
Appendix E.  
12.3.1. 
Transaminases 
Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plots are generated for ALT and 
AST versus TBL  
The number and percentage of patients meeting the following thresholds, which are consistent 
with FDA guidance, are summarized by the maximum dosage received: 
Table 1: 
Pre-Specified Threshold Levels for Transaminases 
Lab Parameter 
Threshold 
ALT, AST 
 
 3 × upper limit of normal (ULN) and < 5 × ULN 
 5 × ULN and < 10 × ULN 
 10 × ULN and < 20 × ULN 
 20 × ULN 
 5 × ULN for more than 2 weeks 
TBL 
 8/1 DQG   î 8/1 
> 1.5 × 8/1 DQG   î 8/1 
> 2 × ULN 
ALT, /AST, TBL 
ALT or AST > 3×ULN and Total bilirubin > 1.5×ULN 
ALT or AST > 3×ULN and Total bilirubin > 2×ULN 
ALT, AST, TBL, 
INR 
> 3 × ULN and (TBL > 2 × ULN or INR > 1.5) 


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Lab Parameter 
Threshold 
ALP 
> 1.5 × ULN 
      
A summary table that includes frequencies and percentages of patients that meet any of the 
above criteria at any time during the study is provided.  A listing of subjects with abnormal ALT, 
AST, or TBL will also be provided. 
12.3.2. 
Line plot and Boxplot presentations 
Boxplot figures will present the distribution of laboratory values (both observed and change from 
baseline) over time by treatment group.  Additionally line plots of change from baseline of 
laboratory values, vital signs and ECG by visit and treatment analysis group will be generated up 
to and including study week 28. 
12.3.3. 
Shift tables 
Clinical laboratory test results categorized as in or out of the limits of the normal range will be 
summarized using “worst case shift tables,” that is, by cross-tabulating baseline result categories 
(high, normal, low) with worst case results during the treatment period. Shift tables will not be 
limited to results collected at scheduled visits, but will use all available results.  
In addition, for ALT, AST and TBL, shift table summarizing (1) baseline to end of treatment, (2) 
baseline to worst on-treatment, (3) baseline to worst off-treatment, and (4) worst on-treatment to 
worst off-treatment will be presented. 
12.4. 
12-lead Electrocardiogram 
All ECG measurements including ventricular rate, QT interval, Corrected QT interval - 
Fridericia’s formula (QTcF), and the overall interpretation will be displayed in a data listing.  
Only QTcF will be summarized.  The QTcF will be calculated based on the following formula: 
x QTcF = QT / cube-root (RR interval) 
x RR interval = 60 / heart rate 
A summary table of the actual values and change from baseline will be presentated for QTcF by 
treatment group.  In addition, the categories for QTcF of:   450 msec, > 450 - 480 msec, 
> 480 - 500 msec, and > 500 msec, and categories of change from baseline IRU 47F) RI  30 
PVHF DQG  60 msec will be summarized by visit and treatment group. 
12.5. 
Vital signs and weight 
Actual values and changes from baseline values for vital signs and weight will be summarized 
descriptively by treatment group at all scheduled study visits.  Vital sign measurements will 
include blood pressure, heart rate, temperature, and respiratory rate. 
12.5.1. 
Vital signs 
Changes in blood pressure and other vital signs will be summarized by baseline quartile. 


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12.5.2. 
Weight 
Weight change from baseline will be summarized by baseline BMI category (< 18.5, 18.5 to 
< 25.0, 25.0 to < 30.0, 30.0 or greater). 
13. 
PHARMACOKINETIC ANALYSES 
The planned pharmacokinetic analyses are described in a separate document. 
14. 
PROTOCOL DEVIATIONS 
The Principal Investigator (PI) or designee must document any protocol deviation or violation 
and report them to the appropriate Institutional Review Board (IRB), Ethical Committee (EC), or 
Research Ethics Board (REB).  The PI must follow the applicable IRB, EC, or REB guidelines. 
If there is an immediate hazard to a patient, the PI may deviate from the protocol without prior 
Sponsor and IRB, EC, or REB approval.  Notification to Reata, the IRB, EC, or REB is 
necessary for the deviation.  
14.1. 
Major protocol deviations 
Major protocol deviations from entry criteria and treatment compliance will be listed. 
14.2. 
Other protocol deviations 
Protocol deviations that are not major are termed “other” will not be listed but will be included in 
the analysis data. 
15. 
OTHER TOPICS 
15.1. 
Analysis by study site 
Because the number of patients at each site is likely to be small, no analyses will be performed 
by study site. 
15.2. 
Interim analysis 
A DSMB will be reviewing data from the study to ensure patient safety.  The DSMB charter 
describes the interim reviews of safety.  No interim analyses for efficacy are planned.  
15.3. 
Subgroups analysis   
Safety and efficacy outcomes will be analyzed for the subgroups of interest listed below.  The 
following subgroup analyses will be tabulated using summary statistics: 
x Geographic region: US; non US 
x Age by median (above and below equal median)  
x Sex: female; male 


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x Race: White; Non-White 
x Ethnicity: Non-Hispanic/Latino; Hispanic/Latino  
x Number of PAH medications at baseline: 0-1; 2 
x CTD type: scleroderma; no scleroderma 
x Baseline FC: II; III 
x Baseline 6MWT: < 450 m;   m 
x On ERA (PAH med): yes; no 
x On PD5i (PAH med): yes; no 
x %DVHOLQH +E   JG/   JG/ 
x Baseline BMI: < 30;   
x End-of-treatment dose:  10 mg; <10 mg; placebo 
16. 
ARCHIVING 
After finalization of the analysis, the following will be archived: 
x SAP 
x All computer code used in creating the analysis datasets, in generating the tables and 
figures, and in analyzing the data 
x Tables, listings, and figures as included in the CSR 
x SAS datasets 
17. 
DEVIATION FROM THE PROTOCOL-SPECIFIED ANALYSIS 
The protocol-defined secondary efficacy outcome is the time-to-first persistent clinical 
improvement event.  To declare that clinical improvement has occurred per the language in the 
protocol, at least one of the following three criteria must be met: 
1. Improvement by at least one WHO functional class coupled with no more than a 15% 
decrease from baseline in 6MWT. 
2. Increase from baseline in 6MWT by at least 10% and stability or improvement in the 
WHO functional class. 
3. Decrease from baseline in creatine kinase (a surrogate biomarker for muscle injury and 
inflammation) by at least 10% and no worsening in WHO functional class and no more 
than a 15% decrease from baseline in 6MWT. 
However, a persistent improvement in estimated glomerular filtratiRQ UDWH H*)5  RI
baseline was added to this criteria. 


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18. 
REFERENCES 
[1] 
Klein J, Moeschberger M. Survival Analysis: Techniques for Censored and Truncated 
Data. New York: Springer-Verlag New York, Inc.; 2003 
[2] 
Pugh M, Buchowski M, Robbins, I et al. Physical Activity Limitation as Measured by 
Accelerometry in Pulmonary Arterial Hypertension. CHEST, 2012; 142:1391-1398. 
 


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APPENDIX A. APPROACH TO ESTIMATING MEANS AND 
COVARIANCE STRUCTURE USED IN THE ORIGINAL 
SAMPLE SIZE CALCULATIONS 
A. 1. INTRODUCTION 
The primary efficacy analysis will use a MMRM with the change from baseline in 6MWT as the 
outcome variable (Section 10.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. 2. TREATMENT EFFECT OF BARDOXOLONE METHYL ON 6MWT 
 
  
 
 
 
 


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A. 3. VARIABILITY OF 6MWT IN OTHER PAH STUDIES 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 


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Figure A 2. 
Observed variance, covariance, and correlation in LARIAT data
 
 


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Table A 1. 
Variance-covariance and correlation structure for simulation study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. 4. SIMULATION STUDY FOR COMPLETE DATA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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Table A 2. 
Power by sample size and variance-covariance of complete data  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 5. SIMULATION STUDY WITH A MISSING DATA MODEL 
 
 
 
 
  
 


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Table A 3. 
Power by sample size and variance-covariance with a missing data model 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX B. GUIDELINES FOR RECALCULATION OF SAMPLE 
SIZE 
B. 1. INTRODUCTION 
The design of the CATALYST study is based on assumptions, as described in Appendix A of 
this SAP, regarding the mean trajectory of 6MWT in the treated and placebo groups and the 
correlation structure of the outcome. As is typical of a Phase 3 randomized clinical trial, these 
parameters were estimated from data that came from previous studies.  Because of the 
uncertainty of these estimates, the protocol for the CATALYST study allows recalculation of the 
sample size at an intermediate point in the study.  This recalculation will be based on blinded 
information, that is, data pooled across treatment groups.  Because no unblinding will occur, 
recalculation will have at most a negligible impact on the Type 1 error rate for the final data 
analysis.  See Section 2.6 for further details on blinding procedures. 
The recalculation will be performed when approximately 100 patients have been randomized.  At 
this point, relevant baseline and operational parameters will be reassessed and the study size 
increased if necessary to maintain desired power. A sample size re-calculation committee (SRC), 
composed of members from Reata and 
 will review blinded 
data at the time of recalculation and make a formal recommendation about study size to Reata.  
 The remaining sections of this Appendix summarize the current assumptions underlying the 
sample size and describe the planned recalculation.  This appendix will have been finalized and 
submitted to the FDA as part of the full SAP prior to the sample size recalculation.  
B. 2. STUDY DESIGN ASSUMPTIONS 
As described in the protocol and in the main body of the SAP, the CATALYST study will assess 
efficacy based on the primary outcome, the change from baseline in 6MWT relative to placebo at 
Week 24.  The study design calls for randomizing approximately 130 patients (65 in each group) 
and for assessing 6MWT at baseline and again at Weeks 4, 8, 16, and 24. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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B. 3. RECALCULATION OF PARAMETERS 
When approximately 100 patients have been randomized, a pooled dataset will be constructed 
with baseline and available follow-up data.  Table B 1 details the original assumptions that will 
be checked at the time of the recalculation.  At that time, 
 will rerun the sample size 
simulations based on the updated values for the parameters.  Note that all computations will be 
based on the CATALYST data that is available at the time of the recalculation. 
 


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Table B 1. 
Tables available at time of the recalculation of parameters needed for power estimates 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figures will be provided for visual representation of data presented in the source tables.  
 
 


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Table B 2. 
Graphical presentations 
Number 
Title 
Description 
 
 
 
 
 
In addition to the sample size calculations noted above, the SRC will review data summaries listed in Table B 1 and Table B 2. Using 
all available data, the SRC will decide whether to recommend increasing the sample size up to 200.  


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B. 4. BLINDING PROCEDURES 
All measures in place to ensure blinding to treatment assignments, as discussed in the protocol 
(Section 6.2) and this SAP (Section 2.6), will be maintained through the sample size 
recalculation. Specifically, 
x The only individuals with access to treatment assignments will be the unblinded 
statistical group 
, the DSMB, and the unblinded IWRS group.  No additional 
access to treatment codes will be granted for the sample size recalculation described 
in this Appendix. 
x All members of the SRC as well as all patients, investigators, site personnel, 
laboratories, and Reata personnel (regardless of their involvement in the conduct of 
the study) and their designees
 will be blinded to treatment 
assignments and will remain blinded until after the database is locked and formal 
access to the randomized treatment codes is authorized by Reata. 
x The recalculation will be performed using aggregate data pooled for all patients; no 
treatment assignments will be provided.  
x All available data for the relevant clinical parameters specified in this Appendix will 
be considered in recalculating sample size. 
x SRC recommendations will be based on information limited to the package of data 
described in this Appendix.  
B. 5. SRC: COMPOSITION AND LOGISTICS 
The SRC will perform these evaluations and make recommendations to Reata’s senior 
management.  The committee, which will be blinded to treatment allocation, will act by 
consensus.  
, its chair, will serve the SRC as the statistical representative for 
Reata.  
The other members of the SRC will be representatives from Reata who played significant roles 
in developing the original sample size assumptions:
 
 
 
After the recalculation, the SRC will provide a formal recommendation for change or no change 
with details and rationale to Reata’s senior management, who will make the final decision about 
whether to accept the recommendation.  The SRC will use the attached recommendation form 
(Appendix B. 7) after the recalculation.  
Should the SRC and Reata’s senior management agree that a sample size increase is warranted 
after the recalculation, Reata will document the increase in a note to file to the clinical sites and, 
as needed, to the EC/IRB/REB and the DSMB. If a change in sample size is implemented, a 
protocol amendment will not be required because the current protocol includes a provision for 
the sample size recalculation. 


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B. 6. CALCULATIONS AND DATA SUMMARIES 
 will provide the SRC with the set of predefined tables and figures 
presented in Table B 1 and Table B 2. 
The SRC will review the materials and provide 
 with updated assumptions for the 
recalculations.  
 will detail the updated assumptions, methodology, and document results of 
the sample size and event recalculations documented in a report provided to the SRC and 
ultimately to Reata’s senior management.  


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B. 7. RECOMMENDATION FORM 
CATALYST Trial Sample-size Recalculation Committee (SRC) Recommendation Report 
Meeting Date:  ___________________________________ 
Sample Size Recalculation Ƒ  
Meeting Attendees:  
 
 
The SRC charged with the review of sample size for the CATALYST Trial reviewed data 
summaries dated [_________]. 
As a result, the SRC recommendation is: 
Ƒ To continue the trial unmodified. 
Ƒ To continue the trial and amend the study design as checked:     
Ƒ To increase sample size to [_____________] due to: 
 
 
Ƒ higher variability than expected 
Ƒ higher rate of drop-outs than expected 
Ƒ lower correlation than expected 
Ƒ faster enrollment and limited ability to test assumptions 
 
Comments: 
 
 
 
 
 
 
 (SRC Chair) 
 
 
 
 
 
Date 


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APPENDIX C. SCHEDULE OF ASSESSMENTS 
The schedule of assessments is available in the protocol.


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APPENDIX D. CLASSIFICATION OF VISITS 
Table D 1. 
Classification of on treatment visits 
Timing of assessment 
(days relative to first 
dose of study druga) 
Target day 
Visit associated with 
assessment 
1 
1 
Day 1 a 
2 to 10 
7 
Week 1 
11 to 21 
14 
Week 2 
22 to 35 
28 
Week 4 
36 to 49 
42 
Week 6 
50 to 84 
56 
 Week 8 
85 to 139 
112 
Week 16 
140 to 182 
7 <= Days after last 
dose <=35 
168 
28 
 Week 24 a 
 Week 28 c 
 
a Day 1 is the day of first dose of study drug. 
b. Week 24 values is the average of the two values closest to target date. 
c  Week 28 is only applicable to eGFR change from baseline efficacy 
analysis 
 
 
Table D 2: 
Analysis Visits for Post-Treatment Safety Analysis 
Analysis Visit 
Label 
Target Study Day 
(Reference Day is 
Days After Last Dose) 
Analysis Window 
40 
4-weeks – Off 
Treatment 
28 
7  6WXG\ 'D\   
80 
8-weeks – Off 
Treatment 
56 
  6WXG\ 'D\   
120 
12-weeks– Off 
Treatment 
84 
  6WXG\ 'D\   
240 
24-weeks– Off 
Treatment 
168 
  6WXG\ 'D\   
 
 


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APPENDIX E. LIST OF LABORATORY TEST  
Blood samples are collected throughout the study for hematology, chemistry, and urinalysis for 
clinical laboratory evaluation.  Test panels include the following lab tests plus additional collected 
lab assessments based on availability:   
Table E1: 
List of Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
HbA1C 
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) 
Mean corpuscular hemoglobin 
concentration (MCHC) 
Reticulocytes/Erythrocytes 
 
Blood urea nitrogen (BUN) 
Creatinine 
Total bilirubin 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALP) 
Ferritin 
Sodium 
Potassium 
Calcium 
Inorganic phosphorus 
Magnesium 
Chloride 
Bicarbonate 
Uric acid 
Cholesterol 
Total protein 
Glucose 
Triglycerides 
Albumin 
Creatine phosphokinase (CPK) 
Lactate dehydrogenase (LDH) 
High-density lipoprotein cholesterol 
(HDL-C) 
Low-density lipoprotein cholesterol 
(LDL-C) 
Very-low-density lipoprotein 
cholesterol (VLDL-C) 
Gama-glutamyl transpeptidase (GGT) 
Estimated glomerular filtration rate 
(eGFR) using the CKD-EPI / 
Schwartz Bedside Equation 
Specific gravity 
Ketones 
pH 
Protein 
Blood 
Glucose 
Urobilinogen 
Bilirubin 
 
 


Reata Pharmaceuticals, Inc. 
402-C-1504
Statistical Analysis Plan – Protocol v2 
May 26, 2020 
Version 2.0 
54 
Confidential
APPENDIX F. IMPUATATION RULES FOR MISSING DATES 
Incomplete diagnosis or treatment date 
x If day is missing, day will be set to 15th of the month. 
x If month is missing, month and day will be set to July 1.
 If year is missing, date will be set to missing. 
The imputed dates must be logical. 
Adverse Event  
x If onset date is completely missing, onset date is set to date of first dose. 
x If year is present and month and day are missing or year and day are present and 
month is missing: 
o 
If year = year of first dose, then set month and day to month and day of 
first dose 
o 
If year < year of first dose, then set month and day to December 31. 
o 
If year > year of first dose, then set month and day to January 1. 
x If month and year are present and day is missing: 
o 
If year = year of first dose and 
month = month of first dose then set day to day of first dose date 
month < month of first dose then set day to last day of month 
month > month of first dose then set day to first day of month 
o 
If year < year of first dose then set day to last day of month 
o 
If year > year of first dose then set day to first day of month 
 For all other cases, set onset date to date of first dose. 
Concomitant Medications 
x If start date is completely missing, start date will not be imputed. 
x If year is present and month and day are missing or year and day are present and 
month is missing, set month and day to January 1. 
x If year and month are present and day is missing, set day to 1st day of month. 
x If end date is completely missing, end date will not be imputed. 
x If year is present and month and day are missing or year and day are present and 
month is missing, set month and day to December 31. 
 If year and month are present and day is missing, set day to last day of the month.