Clinical trial NCT02036970
Conditions: Pulmonary Arterial Hypertension Pulmonary Hypertension Interstitial Lung Disease Idiopathic Interstitial Pneumonia Idiopathic Pulmonary Fibrosis Sarcoidosis Respiratory Bronchiolitis Associated Interstitial Lung Disease Desquamative Interstitial Pneumonia Cryptogenic Organizing Pneumonia Acute Interstitial Pneumonitis Idiopathic Lymphoid Interstitial Pneumonia Idiopathic Pleuroparenchymal Fibroelastosis
Keywords: Pulmonary Arterial Hypertension PAH Bardoxolone methyl 6-minute walk distance CDDO-me RTA 402 Pulmonary Hypertension Interstitial Lung Disease Idiopathic Interstitial Pneumonia Idiopathic Pulmonary Fibrosis Sarcoidosis Respiratory Bronchiolitis Associated ILD Desquamative Interstitial Pneumonia Cryptogenic Organizing Pneumonia Acute Interstitial Pneumonitis Idiopathic Lymphoid Interstitial Pneumonia Idiopathic Pleuroparenchymal Fibroelastosis
Sponsor: Biogen
Start date: 2014-05-31; Completion date: 2018-05-16
Enrollment: 166 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study assesses the safety and efficacy of bardoxolone methyl relative to placebo in patients with pulmonary hypertension to determine the recommended dose range, evaluate the change from baseline in 6-minute walk distance (6MWD) and determine the effect of Bardoxolone methyl in pulmonary hypertension associated with connective tissue disease, interstitial lung disease, and idiopathic etiologies, including subsets of patients with WHO Group III or WHO Group V PH following 16 weeks of study participation.

Detailed description:
The molecular and pharmacological effects of bardoxolone methyl are broad through its induction of Nrf2 and suppression of NF-κB. Bardoxolone methyl may therefore address multiple facets of the pathophysiology of PH because it suppresses activation of proinflammatory mediators, enhances endothelial NO bioavailability, improves metabolic dysfunction, suppresses vascular proliferation, and prevents maladaptive remodeling. Furthermore, while existing therapies primarily target only smooth muscle cells, bardoxolone methyl targets multiple cell types relevant to PH, including endothelial cells, smooth muscle cells, and macrophages.

This is a two-part study.

Part 1: Part 1 of the study will include a dose-ranging phase and a dose-titration phase.

Part 2 (extension period): All patients from Part 1 who complete the 16-week treatment period as planned will be eligible to continue directly into the extension period to evaluate the intermediate and long-term safety and efficacy of bardoxolone methyl.

Arms: arm 1: Participants received bardoxolone methyl 2.5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards) arm 2: Participants received bardoxolone methyl 5 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards) arm 3: Participants received bardoxolone methyl 10 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards) arm 4: Participants received bardoxolone methyl 20 mg once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 continued to receive the same bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards) arm 5: Participants received bardoxolone methyl 2.5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 2.5 mg once-daily in Part 2 (Week 16 and onwards) arm 6: Participants received bardoxolone methyl 5 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 5 mg once-daily in Part 2 (Week 16 and onwards) arm 7: Participants received bardoxolone methyl 10 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 10 mg once-daily in Part 2 (Week 16 and onwards) arm 8: Participants received bardoxolone methyl 20 mg matching placebo capsules once-daily in Part 1 (Day 1 to Week 16). Participants who continued to Part 2 received bardoxolone methyl 20 mg once-daily in Part 2 (Week 16 and onwards) arm 9: Participants in Part 1 started with bardoxolone methyl 5 mg once-daily from Day 1 and escalated to bardoxolone methyl 10 mg once-daily starting at Week 4 thru Week 16. Participants who continued to Part 2 continued to receive the same bardoxolone methyl dose once-daily in Part 2 (Week 16 and onwards) arm 10: Participants in Part 1 received Placebo once-daily from Day 1 thru Week 16. Participants who continued to Part 2 initially received bardoxolone methyl 5 mg once-daily from Week 16 thru Week 20 and bardoxolone methyl 10 mg from week 20 onwards
Interventions: intervention 1: Bardoxolone methyl intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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NCT02036970 
 
RTA 402 
 
402-C-1302 
 
 
 
 
A DOSE-RANGING STUDY OF THE EFFICACY AND 
SAFETY OF BARDOXOLONE METHYL IN 
PATIENTS WITH PULMONARY HYPERTENSION 
 
VERSION 7.0 – 26 JAN 2017 
 
The information contained herein is confidential and the proprietary property of 
Reata Pharmaceuticals, Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of Reata Pharmaceuticals, 
Inc. is expressly prohibited. 




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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for bardoxolone methyl.  I have read 
the 402-C-1302 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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Cohort 3 will consist of two subcohorts, randomized independently within each subcohort using a 
2:1 assignment ratio (bardoxolone methyl:placebo) to be administered once daily for 16 weeks: 
• 
Cohort 3a will consist of WHO Group I connective tissue disease (CTD)-PAH patients; 
• 
Cohort 3b will consist of WHO Group I non-CTD PAH patients.  
Cohort 4 will consist of four subcohorts, randomized independently within each subcohort using a 
2:1 assignment ratio (bardoxolone methyl:placebo) to be administered once daily for 16 weeks: 
• 
Cohort 4a will consist of WHO Group III PH patients with connective tissue disease 
associated interstitial lung disease (CTD-ILD); 
• 
Cohort 4b will consist of WHO Group III PH patients with idiopathic pulmonary fibrosis 
(IPF); 
• 
Cohort 4c will consist of WHO Group III PH patients with nonspecific interstitial 
pneumonia (NSIP) or selected idiopathic interstitial pneumonia (IIP) subtypes;   
• 
Cohort 4d will consist of WHO Group V PH patients with sarcoidosis. 
Based on the variability in 6MWD change from baseline observed for the first 24 patients enrolled in 
each subcohort of Cohort 3 and Cohort 4, the Sponsor may choose to increase the number of patients 
within each subcohort to a maximum of 72 patients.  For Cohort 3b, a maximum of approximately 
24 patients may be enrolled from the United States. 
Patients in Cohorts 3 and 4 will start at 5 mg (or placebo) and will dose escalate to 10 mg at Week 4 
unless a dose-limiting toxicity (DLT) is reported (Section 7.3.1).  Identification of DLTs is left to the 
discretion of the Investigator and may include clinically important changes from baseline in BNP, 
clinical signs of fluid retention, or other adverse events.  Suspected DLTs should be discussed with 
the medical monitor prior to changing dose.  If at any time the patient reports an AE that the 
Investigator considers to be a DLT, the Investigator may choose to decrease the patient’s dose to 
one-half of the prior dose (e.g., 10 mg to 5 mg).  Dose de-escalation can occur more than once, but 
dose reduction is not permitted below a dose of 2.5 mg.  Dose escalation during Part 1 is permitted 
for all patients at Week 4 only. 
All patients in Part 1 of the study (i.e., Cohorts 1, 2, 3a-b, and 4a-d) will follow similar visit and 
assessments schedules.  Selected assessments 
) will be optional for all enrolled patients 
at Sponsor-qualified sites.  Other assessments (e.g., ABPM, 
 
) conducted for Cohorts 1 and 2 will not be conducted for patients in Cohorts 3 and 4.  
Following randomization, patients will be assessed in person during treatment at Weeks 1, 2, 4, 8, 
12, and 16 and by telephone contact on Days 3, 10, and 21.  Patients enrolling in Cohorts 3 and 4 
will have additional assessments in person at Week 6 and additional telephone contact on Days 31, 
38, and 49.  Patients who do not enter Part 2 of the study (i.e., the extension period), either because 
they have discontinued taking study drug during Part 1 or have completed the 16-week treatment 
period as planned but chosen not to continue to Part 2 of the study, will complete an end-of-
treatment visit when patient ends study drug.  In addition, a  follow-up visit should occur four weeks 
after the date of administration of the last dose of study drug.   
Part 2 (extension period):  
Patients who discontinue treatment prematurely in study Part 1 are not eligible to continue into study 
Part 2.  All patients from Part 1 who complete the 16-week treatment period as planned will be 
eligible to continue directly into the extension period to evaluate the intermediate and long-term 
safety and efficacy of bardoxolone methyl.  Day 1 of the extension period will be the same as the 
Week 16 visit for the treatment period.   
Cohort 1 and Cohort 2 patients randomized to placebo in Part 1 of the study will be assigned to 
receive bardoxolone methyl at their group-specific dose in the extension period.  Patients enrolled in 
Cohorts 1 and 2 may dose titrate to the 10 mg dose or de-escalate (minimum dose of 2.5 mg) at 


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scheduled or unscheduled visits.  However, patients who dose escalate must have a telephone call 
1 week after dose escalation and an unscheduled office visit or a home health visit 2 weeks (±3 days) 
after dose escalation to collect clinical chemistry, BNP, and NT-Pro BNP.   
Cohort 3 and 4 patients randomized to placebo in study Part 1 will be assigned to 5 mg of 
bardoxolone methyl, whereas, patients randomized to bardoxolone methyl in study Part 1 will begin 
study Part 2 (Week 16) at the same dose of bardoxolone methyl as they ended with in study Part 1.  
All patients in Cohorts 3 and 4 will have the option to up-titrate their dose at the Week 20 visit, and 
may de-escalate in dose (minimum dose of 2.5 mg) at scheduled or unscheduled visits.  Treatment 
assignment will remain blinded for Cohort 3 and 4 patients through Week 20. 
Treatment-compliant patients who have completed Part 2 of the study are eligible to continue 
receiving bardoxolone methyl through an extended access program (Study 402-C-1602).  After 
Week 32, visits will occur every 24 weeks until bardoxolone methyl is available through the 
extended access program.  Once bardoxolone methyl is available through the extended access 
program, patients in Part 2 who have completed at least 32 weeks of the study will complete an End 
of Treatment Visit.   
Number of patients (planned):  
Approximately 198 patients are expected to be enrolled in Part 1 of the study (38 patients in 
Cohort 1; 16 patients in Cohort 2; and approximately 24 patients in each of Cohorts 3a-b and 4a-d).  
Based on the variability in 6MWD observed in Cohorts 3 and 4, the Sponsor may choose to increase 
the number of patients to a maximum of 72 patients in each of Cohorts 3a-b and 4a-d.  Variability 
for each subcohort will be assessed separately.  The maximum number of patients enrolled will be 
486. 
All eligible patients from Part 1 will be included in Part 2, and no new patients will be randomized 
to Part 2 of the study. 
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 Functional Class II and III; 
4. WHO Group I, III, or V PH according to the following criteria: 
a. If diagnosed with WHO Group I PAH, then one of the following subtypes: 
i. Idiopathic or heritable PAH; 
ii. PAH associated with connective tissue disease; 
iii. PAH associated with simple, congenital systemic-to-pulmonary shunts at 
least 1 year following shunt repair; 
iv. PAH associated with anorexigen or drug-induced toxicity; 
v. PAH associated with human immunodeficiency virus (HIV); or 
b. If WHO Group III PH, then primary diagnosis must be one of the following 
subtypes: 
i. Connective tissue disease associated ILD (CTD-ILD); 
 
 


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ii. Idiopathic pulmonary fibrosis (IPF) according to the American Thoracic 
Society and European Respiratory Society (ATS/ERS) guidelines 
(Raghu 2011); 
iii. Nonspecific interstitial pneumonia (NSIP) or the following idiopathic 
interstitial pneumonia subtypes, according to the American Thoracic 
Society and European Respiratory Society (ATS/ERS) guidelines 
(Travis 2013): 
1. Respiratory bronchiolitis-associated interstitial lung disease;  
2. Desquamative interstitial pneumonia;  
3. Cryptogenic organizing pneumonia;  
4. Acute interstitial pneumonitis; 
5. Idiopathic lymphoid interstitial pneumonia; 
6. Idiopathic pleuroparenchymal fibroelastosis; 
7. Unclassifiable idiopathic interstitial pneumonia, including patients 
who have not had a lung biopsy; or 
c. If WHO Group V PH, then patient must be diagnosed with sarcoidosis; 
5. Had a diagnostic right heart catheterization performed and documented prior to Day 1 that 
confirmed a diagnosis of PH according to all the following criteria:     
a. If diagnosed with WHO Group I PAH, then: 
i. Mean pulmonary artery pressure ≥ 25 mm Hg (at rest); 
ii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; 
iii. Pulmonary vascular resistance > 240 dyn.sec/cm5 or > 3 mm Hg/Liter 
(L)/minute; 
b. If not diagnosed with WHO Group I PAH, then: 
i. Mean pulmonary artery pressure ≥ 21 mm Hg (at rest); 
ii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; 
iii. Pulmonary vascular resistance > 160 dyn.sec/cm5 
6. Has BNP level ≤ 400 pg/mL; 
7. Has an average 6-minute walk distance (6MWDs) ≥ 150 meters on two consecutive tests 
performed on different days prior to randomization, with both tests measuring within 15% of 
one another;   
8. Has been receiving no more than two (2) approved disease-specific PAH therapies.  Cohort 
3b WHO Group I PAH patients enrolled outside the United States must be receiving zero (0) 
or one (1) PAH therapies.  PAH therapy must be at a stable dose for at least 90 days prior to 
Day 1;  
 


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9. If WHO Group III or WHO Group V, disease-specific therapy must be at a stable dose for 
30 days; 
10. Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following 
therapies that may affect PH:  vasodilators (including calcium channel blockers), digoxin, 
L-arginine supplementation, or oxygen supplementation; 
11. If receiving prednisone, has maintained a stable dose of ≤ 20 mg/day (or equivalent dose if 
other corticosteroid) for at least 30 days prior to Day 1.  If receiving treatment for 
connective tissue disease (CTD) with any other drugs, doses should remain stable for the 
duration of the study;   
12. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 that meet the following 
criteria:   
a. For WHO Group I PAH patients with connective tissue disease, total lung capacity 
(TLC) ≥ 65% (predicted); 
b. For all other WHO Group I PAH patients, 
i. Forced expiratory volume in 1 second (FEV1 ) ≥ 65% (predicted); or 
ii. FEV1/forced vital capacity ratio (FEV1/FVC) ≥ 65%;  
c.  For WHO Group III or V PH patients, total lung capacity (TLC) between 50-90% 
(predicted); 
13. For WHO Group I patients, had a ventilation-perfusion (V/Q) lung scan, 
spiral/helical/electron beam computed tomography (CT) or pulmonary angiogram prior to 
Screening 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 disease; 
14. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥ 45 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable 
formula; 
15. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
study procedures; 
16. 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; 
17. For WHO Group III or V PH patients, the presence of ILD must be confirmed by a 
diagnostic high resolution computed tomography (HRCT) scan or biopsy performed and 
documented prior to Day 1. 
Major exclusion criteria: 
1. Participation in other investigational clinical studies involving pharmaceutical 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; 


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2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 3 months 
(90 days) prior to Day 1 or planned initiation during Part 1 of the study;   
3. Stopped receiving any PH chronic therapy within 60 days prior to Day 1; 
4. Requirement for receipt of intravenous inotropes within 30 days prior to Day 1;  
5. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) 
> 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening after a 
period of rest; 
6. Has systolic BP < 90 mm Hg during Screening after a period of rest; 
7. WHO Group III patients with pulmonary hypertension primarily associated with chronic 
obstructive pulmonary disease, sleep-disordered breathing, and/or alveolar hypoventilation 
disorders;  
8. WHO Group III or V patients who at rest require supplemental oxygen at a rate > 4 L/min or 
have peripheral capillary oxygen saturation (SpO2) levels < 92%; 
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 60 days 
of Day 1; 
e. Any current or prior history of symptomatic coronary disease (prior myocardial 
infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, 
or anginal chest pain); 
10. Clinical instability within 8 weeks prior to Day 1, such as hospitalization due to respiratory 
or cardiac symptoms, acutely decompensated heart failure, syncope, or other events that in 
the investigator’s opinion would suggest the patient is an inappropriate candidate for the 
study; 
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; 


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13. Obstructive sleep apnea that is untreated;   
14. For patients with HIV-associated PAH, any of the following: 
a. Concomitant active opportunistic infections within 180 days prior to Screening; 
b. Detectable viral load within 90 days prior to Screening; 
c. Cluster designation 4 (CD4+) T-cell count < 200 mm3 within 90 days prior to 
Screening; 
d. Changes in antiretroviral regimen within 90 days prior to Screening; 
e. Using inhaled pentamidine; 
15. 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); 
16. Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at 
Screening;  
17. Hemoglobin (Hgb) concentration < 10.5 g/dL at Screening; 
18. Diagnosis of Down syndrome; 
19. History of malignancy within 5 years prior to screening, with the exception of localized skin 
or cervical carcinomas; 
20. Active bacterial, fungal, or viral infection, incompatible with the study; 
21. Known or suspected active drug or alcohol abuse, per Investigator judgment; 
22. Major surgery within 30 days prior to Screening or planned to occur during the course of the 
study; 
23. Unwilling to practice 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 due to language problems, poor 
mental development, or impaired cerebral function; 
30. Use of intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues; 
31. Prior exposure to bardoxolone methyl. 






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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
5. 
INTRODUCTION ......................................................................................................26 
5.1. 
Clinical Experience with Bardoxolone Methyl ..........................................................29 
5.1.1. 
Safety and Tolerability ...............................................................................................29 
5.1.2. 
Fluid Overload ............................................................................................................30 
5.1.3. 
Transaminase and GGT Elevations ............................................................................30 
5.1.4. 
Muscle Spasms ...........................................................................................................31 
5.1.5. 
Weight Loss ................................................................................................................31 
5.1.6. 
Hypomagnesaemia ......................................................................................................31 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................33 
6.1. 
Objectives ...................................................................................................................33 
6.2. 
Endpoints ....................................................................................................................33 
6.2.1. 
Primary Efficacy Endpoint .........................................................................................33 
6.2.2. 
Safety Endpoints .........................................................................................................33 
6.2.3. 
Exploratory Endpoint(s) .............................................................................................33 
7. 
INVESTIGATIONAL PLAN .....................................................................................36 
7.1. 
Overall Study Design ..................................................................................................36 
7.2. 
Number of Patients .....................................................................................................38 
7.3. 
Treatment Assignment ................................................................................................38 
7.3.1. 
Criteria for Determining Dose-Limiting Toxicity ......................................................39 
7.4. 
Criteria for Study Termination ...................................................................................39 
7.5. 
Schedule of Assessments ............................................................................................39 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................50 
8.1. 
Patient Inclusion Criteria ............................................................................................50 
8.2. 
Patient Exclusion Criteria ...........................................................................................52 
8.3. 
Patient Re-screening ...................................................................................................54 


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8.4. 
Patient Withdrawal and Discontinuation ....................................................................54 
9. 
TREATMENT OF PATIENTS ..................................................................................56 
9.1. 
Select Management Guidelines ..................................................................................56 
9.1.1. 
Management of Fluid Status .......................................................................................56 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................57 
9.1.3. 
Management of Muscle Spasms .................................................................................57 
9.1.4. 
Weight Loss ................................................................................................................57 
9.1.5. 
Hypomagnesaemia ......................................................................................................57 
9.1.6. 
Nausea .........................................................................................................................57 
9.1.7. 
Anemia ........................................................................................................................58 
9.2. 
Description of Study Drug ..........................................................................................59 
9.3. 
Concomitant Medications ...........................................................................................60 
9.3.1. 
Excluded Medications ................................................................................................60 
9.3.2. 
Permitted Medications ................................................................................................60 
9.4. 
Treatment Compliance ................................................................................................61 
9.5. 
Randomization ............................................................................................................61 
9.6. 
Blinding ......................................................................................................................61 
9.6.1. 
Patient Unblinding ......................................................................................................62 
9.6.2. 
Unblinding for Regulatory Submission ......................................................................62 
9.6.3. 
Protocol Safety Review Committee ............................................................................62 
9.7. 
Unscheduled Visits .....................................................................................................63 
9.8. 
Pregnancy ...................................................................................................................63 
9.8.1. 
Women of Childbearing Potential ..............................................................................63 
9.8.2. 
Methods of Birth Control............................................................................................63 
9.8.3. 
Suspected Pregnancy ..................................................................................................64 
9.9. 
Serious Toxicities .......................................................................................................65 
9.10. 
Study Procedures ........................................................................................................65 
9.10.1. 
Informed Consent .......................................................................................................65 
9.10.2. 
Inclusion/Exclusion ....................................................................................................65 
9.10.3. 
Demographics and Baseline Disease Characteristics .................................................65 
9.10.4. 
Prior and Current Concomitant Medications ..............................................................65 
9.10.5. 
Medical History ..........................................................................................................66 
9.10.6. 
Right Heart Catheterization ........................................................................................66 


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9.10.7. 
Height .........................................................................................................................66 
9.10.8. 
Weight and Body Mass Index (BMI) .........................................................................66 
9.10.9. 
Electrocardiograms (ECG) .........................................................................................66 
9.10.10. 
Vital Sign Measurements ............................................................................................66 
9.10.11. 
Ambulatory Blood Pressure Monitoring (ABPM) .....................................................67 
9.10.12. 
Physical Examination .................................................................................................67 
9.10.13. 
Pregnancy Test ............................................................................................................67 
9.10.14. 
Study Drug Administration.........................................................................................67 
9.10.15. 
Study Drug Dispensation and Collection ...................................................................68 
9.10.16. 
Telephone Contact ......................................................................................................68 
9.10.17. 
Adverse Event Collection ...........................................................................................68 
9.10.18. 
Clinical Chemistry ......................................................................................................68 
9.10.19. 
N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide .................68 
9.10.20. 
Hematology .................................................................................................................69 
9.10.21. 
Urinalysis and Microscopy .........................................................................................69 
9.10.22. 
Virus Serology ............................................................................................................69 
9.10.23. 
6-Minute Walk Test ....................................................................................................69 
9.10.24. 
Echocardiography .......................................................................................................70 
9.10.25. 
MRI .............................................................................................................................70 
9.10.26. 
Pulmonary Function Testing.......................................................................................70 
 
 
 
 
 
 
 
 
 
 
9.10.32. 
Clinical Worsening .....................................................................................................71 
9.10.33. 
WHO/NYHA Functional Class Assessment ..............................................................72 
9.10.34. 
Pharmacokinetic (PK) Blood Samples .......................................................................72 
 
 
 
 
 
 
9.10.38. 
High Resolution Computed Tomography (HRCT) Scan or Biopsy ...........................73 
 
 




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14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................85 
14.1. 
Quality Assurance .......................................................................................................85 
14.2. 
Financial Disclosure ...................................................................................................85 
14.3. 
Sponsor Obligations....................................................................................................85 
14.4. 
Investigator Documentation ........................................................................................85 
14.5. 
Clinical Study Insurance .............................................................................................86 
14.6. 
Use of Information ......................................................................................................86 
15. 
ETHICS ......................................................................................................................87 
15.1. 
Institutional Review Board (IRB) or Ethics Committee Review ...............................87 
15.2. 
Ethical Conduct of the Study ......................................................................................87 
15.3. 
Written Informed Consent ..........................................................................................87 
15.4. 
Confidentiality ............................................................................................................88 
15.5. 
Modification of the Protocol .......................................................................................88 
15.6. 
Protocol Deviations ....................................................................................................89 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................90 
16.1. 
Retention of Records ..................................................................................................90 
16.2. 
Case Report Forms .....................................................................................................90 
17. 
PUBLICATION POLICY ..........................................................................................91 
18. 
REFERENCES ...........................................................................................................92 
19. 
APPENDIX 1:  6-MINUTE WALK TEST INSTRUCTIONS ..................................95 
20. 
APPENDIX 2:  FUNCTIONAL CLASSIFICATION OF PULMONARY 
HYPERTENSION MODIFIED AFTER THE NEW YORK HEART 
ASSOCIATION FUNCTIONAL CLASSIFICATION ACCORDING TO 
THE WHO 1998 (GALIE 2009) ..............................................................................101 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 3: 
Part 1:  Schedule of Assessments for Patients in Cohorts 1 and 2 .............................40 
Table 4: 
Part 1:  Schedule of Assessments for Patients in Cohort 3 and Cohort 4 (PH-
ILD Cohort) ................................................................................................................43 
Table 5: 
Part 2:  Extension Schedule of Assessments for Patients in Cohorts 1 and 2 ............46 
Table 6: 
Part 2: Extension Schedule of Assessments for Patients in Cohorts 3 and 4 .............48 
Table 7: 
Bardoxolone Methyl Drug Product Information ........................................................59 
Table 8: 
Placebo Information ....................................................................................................59 
Table 9: 
SAE Reporting Contact Information ..........................................................................80 
 
LIST OF FIGURES 
Figure 1: 
Bioenergetic Profile of Bardoxolone Methyl Compared with Approved PAH 
Therapies .....................................................................................................................29 
 
 


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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 
ABPM 
Ambulatory blood pressure monitoring 
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 
(ATS/ERS) 
American Thoracic Society and European Respiratory Society  
aPTT 
Activated partial thromboplastin time 
AUC 
Area under the plasma concentration time curve 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CAMPHOR 
Cambridge Pulmonary Hypertension Outcome Review 
CFR 
Code of Federal Regulations (US) 
CKD 
Chronic kidney disease 
CPET 
Cardiopulmonary Exercise Testing  
CPK 
Creatine phosphokinase 
CT 
Computed tomography 
CTD 
Connective Tissue Disease 


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Abbreviation or Specialist Term 
Explanation 
CTD-ILD 
Connective tissue disease associated with interstitial lung 
disease 
CWE 
Clinical Worsening Event  
DLCO 
Diffusion capacity of lung for carbon monoxide 
DLT 
Dose-limiting toxicity 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ERA 
Endothelin receptor antagonist 
FDA 
Food and Drug Administration (US) 
FEV1 
Forced expiratory volume  
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good laboratory practice 
HDL-C 
High density lipoprotein cholesterol 
HDPE 
High-density polyethylene 
HED 
Human equivalent dose 
HIV 
Human immunodeficiency virus 
HRCT 
High-resolution computed tomography 
ICH 
International Conference on Harmonization 
IIP 
Idiopathic interstitial pneumonia 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
IPF 
Idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
LDL-C 
Low density lipoprotein cholesterol 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 


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Abbreviation or Specialist Term 
Explanation 
MCV 
Mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MDSC 
Myeloid derived suppressor cells 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MUGA 
Multiple Gated Acquisition Scan 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B-cells 
NIRS 
Near-infrared spectroscopy 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
NO 
Nitric oxide 
NOAEL 
No observed adverse effect level 
NSIP 
Nonspecific interstitial pneumonia 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
PAH 
Pulmonary arterial hypertension 
PBMC 
Peripheral blood mononuclear cell 
PCWP 
Pulmonary capillary wedge pressure 
PGC1α 
Peroxisome proliferator-activated receptor-gamma coactivator 
(PGC)-1 alpha 
PET/HRCT 
Positron emission tomography/high resolution computed 
tomography 
PH 
Pulmonary hypertension 
PH-ILD 
Pulmonary hypertension associated with interstitial lung 
disease 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PSRC 
Protocol Safety Review Committee 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Qd 
Once daily 
RBC 
Red blood cell 
RHC 
Right heart catheterization 
ROS 
Reactive oxygen species 
RNS 
Reactive nitrogen species 


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Abbreviation or Specialist Term 
Explanation 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
STD10 
Rodent severely toxic dose in 10% of animals 
TAM 
Tumor associated macrophages 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
US 
United States 
VLDL-C 
Very low density lipoprotein 
WBC 
White blood cell 
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 it 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. 
Because of the importance of NF-κB in the growth, invasion, and metastasis of tumors, 
bardoxolone methyl was initially studied in cancer.  Bardoxolone methyl has been shown to 
induce differentiation, inhibit proliferation, and induce apoptosis in cancer cell lines 
(Hong 2012).  Potent single-agent activity has been observed in several animal models of cancer 
with significant inhibitory effects on tumor growth (Place 2003; Deeb 2012), metastasis 
(Deeb 2012), and angiogenesis (Valcarcel-Ares 2012).  In a first-in-human study in patients with 
relapsed and refractory metastatic solid tumors and lymphoid malignancies, bardoxolone methyl 
was shown to significantly increase Nrf2 target genes in peripheral blood mononuclear cells 
(PBMCs) and significantly reduce NF-κB and cyclin D1 levels in biopsies from patients.  In 
addition to the objective responses and disease stabilization that were noted, improvements in 
estimated glomerular filtration rate (eGFR) were observed that appeared to correlate with the 
level of kidney dysfunction. 
Because of the noted improvements in eGFR in cancer patients, bardoxolone methyl and analogs 
have been studied in the setting of kidney disease.  Bardoxolone methyl analogs inhibit 
angiotensin II-induced reductions in volume of intact glomeruli and increase directly-measured 
GFR (inulin clearance) in rodent models of chronic kidney disease (CKD).  In the 5/6 
nephrectomy model of chronic renal failure, a bardoxolone methyl analog improved renal 
function, reduced plasma lipid peroxidation, and restored normal endothelial function.  Seven 
studies have been conducted in patients with CKD and type 2 diabetes.  In all studies, treated 
patients achieved marked improvements in renal function as determined by changes in eGFR, 
BUN, phosphorus, and uric acid.  Improvements in creatinine clearance and markers of 
endothelial dysfunction were also noted in studies that assessed these parameters.  In the largest 
study, conducted in Stage 4 CKD patients (eGFR 15 – 29 mL/min/1.73 m2) with type 2 diabetes, 
a subset of patients with elevated baseline BNP and history of heart failure were shown in post 
hoc analyses to be at risk for fluid retention.  Mechanistic studies subsequently identified 
modulation of the endothelin pathway as the likely pharmacologic effect that precipitated fluid 
retention in this subset of patients at risk.  
As the risk factors for fluid retention with bardoxolone methyl are similar to those with 
endothelin receptor antagonists (ERAs), risk mitigation features, including appropriate eligibility 
criteria, will be used to reduce the risk of fluid retention in subsequent studies.  The bardoxolone 
methyl-mediated hemodynamic effects on renal function, which preclinical data support are 








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5.1.2. 
Fluid Overload 
Similar to 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 
mostly conducted in patients with Stage 3b CKD (eGFR 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.  This current study will 
employ risk mitigation procedures to reduce the potential for bardoxolone methyl-induced fluid 
overload, including exclusion of patients with the identified risk factors and close monitoring for 
fluid retention within the first month of treatment.   
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 and 
have not been 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 and peak approximately two to four weeks later.  In most patients, transaminase elevations 
were mild, but approximately 4 to 11% of patients experienced an elevation to greater than three 
times 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 three times the ULN sometimes required 
additional time to resolve.  While some patients have had elevations to above three times the 
ULN, persistent elevations to above three times the ULN have not been observed, and the 
elevations did not recur once resolved, unless caused by other factors. 
Bardoxolone methyl regulates GGT, a known Nrf2 target gene.  In clinical studies, low level 
GGT elevations during treatment were common, mild, and typically lasted longer than ALT/AST 
elevations.  Bilirubin levels in patients experiencing transaminase or GGT elevations due to 
treatment with bardoxolone methyl either remained at baseline levels or decreased.  The ALT, 
AST, and GGT elevations were generally self-limiting in patients who continued treatment with 
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5.1.4. 
Muscle Spasms 
Muscle spasm was the most frequently reported adverse event in clinical trials of bardoxolone 
methyl in patients with CKD and 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 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 subset of 
patients enrolled in a phase 2a study.  Increases in the whole-body glucose disposal rate were 
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).  To 
date, in those cases where serum creatinine phosphokinase (CPK) levels have been measured, no 
association has been observed between muscle spasms and elevated CPK 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.  
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 and type 2 diabetes.  In the studies of 
patients with CKD and type 2 diabetes, 17% of bardoxolone methyl patients reported the 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 than those of normal or moderately-elevated body-mass 
index.  Patients who reported taste-related adverse events had more weight loss.   
5.1.6. 
Hypomagnesaemia 
Hypomagnesaemia was reported as an adverse event for 15.5% of patients with CKD and type 2 
diabetes who received bardoxolone methyl.  The adverse event of hypomagnesaemia (of any 
relationship) 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 did not show an increase in urinary magnesium levels, indicating 


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that renal loss of magnesium did not account for the reductions in serum magnesium observed 
with bardoxolone methyl treatment in CKD patients.  Notably, in a thorough QT study that tested 
doses of bardoxolone methyl up to 80 mg, bardoxolone methyl did not increase the QT interval.  
 
 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
For patients enrolled in this study, the objectives are as follows: 
• Primary objective   
o To determine the recommended dose range for further study of bardoxolone methyl. 
• Secondary objectives 
o To assess the change from baseline in 6-minute walk distance (6MWD) in those 
patients treated with bardoxolone methyl versus patients given placebo for 16 weeks. 
o To assess the safety and tolerability of 16 weeks of treatment with bardoxolone 
methyl versus 16 weeks of administration of placebo. 
• Exploratory objectives  
o To determine the effect of bardoxolone methyl in pulmonary hypertension associated 
with connective tissue disease, interstitial lung disease and idiopathic etiologies 
including subsets of patients with WHO Group III or WHO Group V PH. 
6.2. 
Endpoints 
6.2.1. 
Primary Efficacy Endpoint 
Change from baseline in 6MWD through Week 16. 
6.2.2. 
Safety Endpoints 
Frequency, intensity, and relationship to study drug of adverse events and serious adverse events, 
concomitant medications, and change from baseline in the following assessments: 
• Physical examinations; 
• Vital sign measurements; 
• 24-hour ambulatory blood pressure monitoring (ABPM) (Cohorts 1 and 2 only); 
• 12-lead electrocardiograms; 
• Clinical laboratory measurements, centrally analyzed; 
• Weight. 
6.2.3. 
Exploratory Endpoint(s) 
  
 
 
 
 
 
 
 
 




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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study consists of two parts: a 16-week double-blind, randomized, placebo-controlled 
treatment period (“Part 1”), followed by an extension period (“Part 2”).  All patients who 
complete treatment in Part 1 may continue to Part 2.  Within Part 1, the study consists of a 
dose-ranging phase and a dose-titration phase.  Qualifying patients with PH in both the 
dose-ranging and dose-titration phases will be followed for safety, tolerability, and efficacy, and 
all patients enrolled in the study will follow a similar schedule of assessments. 
Part 1 
Cohorts 1 and 2: In the dose-ranging phase of Part 1 of the study, up to two independently 
randomized cohorts may be opened at each dose level and patients will be allocated based on 
their baseline 6MWD (i.e., Cohort 1 for 6MWD ≤ 450 m and Cohort 2 for 6MWD > 450 m).  
Once opened for enrollment, each dose group will include the next eight eligible patients 
randomized using a 3:1 assignment ratio (bardoxolone methyl:placebo) to be administered once 
daily for 16 weeks.  Within each cohort type, patients will be enrolled to one dose group at a 
time.  
A Protocol Safety Review Committee (PSRC) will assess the starting dose of 2.5 mg and each 
new dose level of bardoxolone methyl for safety and tolerability based on review of all available 
data for this study at the time of each review.  PSRC reviews will occur after the Week 4 data are 
available for the first eight patients enrolled at each new dose level combined across both 
Cohorts 1 and 2.  The PSRC assessment will include a dose level recommendation for 
subsequent dose groups to escalate to a higher dose, proceed to a lower dose, or maintain the 
current dose.  The PSRC may also recommend stopping dosing for current cohorts.  Upon 
completion of dose ranging, the PSRC will continue to meet at regular intervals (approximately 
quarterly) to monitor safety of all enrolled patients.  
Data from all patients enrolled in Cohort 1 (≤ 450 m patients) and Cohort 2 (> 450 m patients) 
will be used to provide information regarding the optimal dose range for evaluation of safety, 
tolerability, and efficacy, allowing the sponsor to select an appropriate dose of bardoxolone 
methyl for further evaluation in patients with WHO Group I PAH.  Selecting from PSRC-
recommended dose levels, the sponsor will determine the dose level for each subsequent dose 
group.   
Cohorts 3 and 4: Cohort 3 and Cohort 4 will employ a dose titration scheme intended to identify 
an optimal dose for each patient.  Cohort 3 includes additional WHO Group I patients, while 
Cohort 4 (PH-ILD cohort) allows only qualified WHO Group III or WHO Group V patients.   
Cohort 3 will consist of two subcohorts, randomized independently within each subcohort using 
a 2:1 assignment ratio (bardoxolone methyl:placebo) to be administered once daily for 16 weeks: 
• Cohort 3a will consist of WHO Group I connective tissue disease (CTD)-PAH patients; 
• Cohort 3b will consist of WHO Group I non-CTD PAH patients.   
Cohort 4 will consist of four subcohorts, randomized independently within each subcohort using 
a 2:1 assignment ratio (bardoxolone methyl:placebo) to be administered once daily for 16 weeks: 


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• Cohort 4a will consist of WHO Group III PH patients with connective tissue disease 
associated interstitial lung disease (CTD-ILD); 
• Cohort 4b will consist of WHO Group III PH patients with idiopathic pulmonary fibrosis 
(IPF); 
• Cohort 4c will consist of WHO Group III PH patients with nonspecific interstitial 
pneumonia (NSIP) or selected idiopathic interstitial pneumonia (IIP) subtypes;   
• Cohort 4d will consist of WHO Group V PH patients with sarcoidosis. 
Based on the variability in 6MWD change from baseline observed for the first 24 patients 
enrolled in each subcohort of Cohort 3 and Cohort 4, the Sponsor may choose to increase the 
number of patients within each subcohort to a maximum of 72 patients.  For Cohort 3b, a 
maximum of approximately 24 patients may be enrolled from the United States. 
Patients in Cohorts 3 and 4 will start at 5 mg (or placebo) and will dose escalate to 10 mg at 
Week 4 unless a dose-limiting toxicity (DLT) is reported (Section 7.3.1).  Identification of DLTs 
is left to the discretion of the Investigator and may include clinically important changes from 
baseline in BNP, clinical signs of fluid retention, or other adverse events.  Suspected DLTs 
should be discussed with the medical monitor prior to changing dose.  If at any time the patient 
reports an AE that the Investigator considers to be a DLT, the Investigator may choose to 
decrease the patient’s dose to one-half of the prior dose (e.g., 10 mg to 5 mg).  Dose de-
escalation can occur more than once, but dose reduction is not permitted below a dose of 2.5 mg.  
Dose escalation during Part 1 is permitted for all patients at Week 4 only. 
All patients in Part 1 of the study (i.e., Cohorts 1, 2, 3a-b, and 4a-d) will follow similar visit and 
assessments schedules.  Selected assessments 
) will be optional for all enrolled 
patients at Sponsor-qualified sites.  Other assessments (e.g., ABPM, 
 
) conducted for Cohorts 1 and 2 will not be conducted for patients in Cohorts 3 
and 4.  Following randomization, patients will be assessed in person during treatment at 
Weeks 1, 2, 4, 8, 12, and 16 and by telephone contact on Days 3, 10, and 21.  Patients enrolling 
in Cohorts 3 and 4 will have additional assessments in person at Week 6 and additional telephone 
contact on Days 31, 38, and 49.  Patients who do not enter Part 2 of the study (i.e., the extension 
period), either because they have discontinued taking study drug during Part 1 or have completed 
the 16-week treatment period as planned but chosen not to continue to Part 2 of the study, will 
complete an end-of-treatment visit when patient ends study drug.  In addition a follow-up visit 
should occur four weeks after the date of administration of the last dose of study drug.   
Part 2 (extension period):   
Patients who discontinue treatment prematurely in study Part 1 are not eligible to continue into 
study Part 2.  All patients from Part 1 who complete the 16-week treatment period as planned 
will be eligible to continue directly into the extension period to evaluate the intermediate and 
long-term safety and efficacy of bardoxolone methyl.  Day 1 of the extension period will be the 
same as the Week 16 visit for the treatment period.   
Cohort 1 and Cohort 2 patients randomized to placebo in Part 1 of the study will be assigned to 
receive bardoxolone methyl at their group-specific dose in the extension period.  Patients 
enrolled in Cohorts 1 and 2 may dose titrate to the 10 mg dose or de-escalate at scheduled or 
unscheduled visits.  However, patients who dose escalate must have a telephone call 1 week after 


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dose escalation and an unscheduled office visit or a home health visit 2 weeks (±3 days) after 
dose escalation to collect clinical chemistry, BNP, and NT-Pro BNP.   
Cohorts 3 and 4 patients randomized to placebo in study Part 1 will be assigned to 5 mg of 
bardoxolone methyl, whereas, patients randomized to bardoxolone methyl in study Part 1 will 
begin study Part 2 (Week 16) at the same dose of bardoxolone methyl as they ended with in 
study Part 1.  All patients in Cohorts 3 and 4 will have the option to up-titrate their dose at the 
Week 20 visit, and may de-escalate in dose (minimum dose of 2.5 mg) at scheduled or 
unscheduled visits.  Treatment assignment will remain blinded for Cohort 3 and 4 patients 
through Week 20. 
Treatment-compliant patients who have completed Part 2 of the study are eligible to continue 
receiving bardoxolone methyl through an extended access program (Study 402-C-1602).  After 
Week 32, visits will occur every 24 weeks until bardoxolone methyl is available through the 
extended access program.  Once bardoxolone methyl is available through the extended access 
program, patients in Part 2 who have completed at least 32 weeks of the study will complete an 
End of Treatment Visit.  The Week 32 visit may be the same as the End of Treatment Visit.  
Beginning with the Week 32 visit, patients will be seen in the clinic every 24 weeks 
(i.e., Week 56, Week 80, Week 104, etc.) and receive a 6-month supply of study drug at the 
appropriate dose.     
The Sponsor reserves the right to stop the study for a given cohort if development of 
bardoxolone methyl is discontinued for any reason, or if the assessment of available data raises 
concerns about the safety or efficacy of bardoxolone methyl. 
7.2. 
Number of Patients 
Approximately 198 patients are expected to be enrolled in Part 1 of the study (38 patients in 
Cohort 1; 16 patients in Cohort 2; and approximately 24 patients in each of Cohorts 3a-b and 
4a-d).  Based on the variability in 6MWD observed in Cohorts 3 and 4, the Sponsor may choose 
to increase the number of patients to a maximum of 72 patients in each of Cohorts 3a-b and 4a-d.  
Variability in 6MWD for each subcohort will be assessed separately.  The maximum number of 
patients enrolled will be 486. 
All eligible patients from Part 1 will be included in Part 2, and no new patients will be 
randomized to Part 2 of the study.   
7.3. 
Treatment Assignment 
Patients in Cohorts 1 and 2 will be allocated based on their baseline 6MWD (i.e., Cohort 1 for 
6MWD ≤ 450 m and Cohort 2 for 6MWD > 450 m).  Baseline 6MWD for the purpose of cohort 
determination is calculated as the average of 2 assessments collected prior to randomization.  
Patients will be randomized to treatment within each dose group in Part 1 of the study using a 3:1 
assignment ratio to receive bardoxolone methyl or matching placebo in Cohorts 1 and 2.  Patients 
in Cohorts 1 and 2 will continue their randomized treatment throughout Part 1 and 2 (i.e., no 
intra-patient dose escalation).  However, upon qualifying for the extension period (Part 2), 
patients randomized to placebo during the treatment period will begin receiving bardoxolone 
methyl at their group-specific dose.  If the Sponsor decides to continue study Part 2 beyond 


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12 weeks after the last patient enters the extension part of the study all patients may be assigned 
or re-randomized to the dose(s) selected for further development.  
Cohort 3 and Cohort 4 will employ a dose titration scheme intended to identify an optimal dose 
for each patient.  Cohort 3 includes additional WHO Group I patients, while Cohort 4 (PH-ILD 
cohort) allows only qualified WHO Group III or WHO Group V patients.  Cohort 3 will consist 
of two subcohorts randomized independently within each subcohort using a 2:1 assignment ratio 
(bardoxolone methyl:placebo) to be administered once daily for 16 weeks.  Cohort 4 will consist 
of four subcohorts randomized independently within each subcohort using a 2:1 assignment ratio 
(bardoxolone methyl:placebo) to be administered once daily for 16 weeks.  
Patients in Cohorts 3 and 4 will start at 5 mg (or placebo) and will dose escalate to 10 mg at 
Week 4 unless a dose-limiting toxicity (DLT) is reported (Section 7.3.1).  If at any time the 
patient reports an AE that the Investigator considers to be a DLT, the Investigator may choose to 
decrease the patient’s dose to one-half of the prior dose (e.g., 10 mg to 5 mg).  The minimum 
allowed dose is 2.5 mg.  Dose escalation during Part 1 is permitted for all patients at Week 4 
only. 
Cohort 3 and 4 patients randomized to placebo in study Part 1 will be assigned to 5 mg of 
bardoxolone methyl, whereas, patients randomized to bardoxolone methyl in study Part 1 will 
begin study Part 2 (Week 16) at the same dose of bardoxolone methyl as they ended with in 
study Part 1.  All patients in Cohorts 3 and 4 will have the option to up-titrate their dose at the 
Week 20 visit, and may de-escalate in dose at scheduled or unscheduled visits.  Treatment 
assignment will remain blinded for Cohort 3 and 4 patients through Week 20.  Dose escalation 
during the extension period is permitted for all patients at the Week 20 visit only.   
7.3.1. 
Criteria for Determining Dose-
Limiting Toxicity 
The assessment of a DLT (i.e., a side effect serious enough to prevent an increase in dose or to 
warrant a decrease in dose) will be based on the clinical judgment of the Investigator, and may 
include clinically important changes from baseline in BNP, clinical signs of fluid retention,  
and/or serious adverse events associated with study drug administration.  Suspected DLTs should 
be discussed with the medical monitor before dose de-escalation.   
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 treatment 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, Table 4, Table 5, and Table 6 list the overall schedule of assessments for the study. 






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s Prior to randomization, the patient must have a qualified 24-hour ABPM assessment.  If first 24-hour assessment is not qualified, one re-test may be performed prior to randomization. If the second 
test result does not qualify the patient will be considered a screen failure. 
t Pulmonary function tests within 90 days prior to Day 1 may be used to determine eligibility. Right heart catheterization within 36 months prior to Day 1 may be used to determine eligibility. 
u Completed immediately following the completion of the 6MWT. 
v 
   
w  If clinical worsening is suspected, perform unscheduled functional class assessment. 
x Blood samples for PK analysis should be drawn just prior to (0 hour) and after (2 and 4 hours) dose administration for this visit.  Patients should be instructed to not take their study drug prior to 
coming to the clinic at Week 4. 
 
Abbreviations: ECG = electrocardiogram, ECHO = echocardiogram, PK = pharmacokinetic, s = serum, u = urine, WOCBP = women of child-bearing potential, 
 
 6MWT = 6-minute walk test


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Table 4: 
Part 1:  Schedule of Assessments for Patients in Cohort 3 and Cohort 4 (PH-ILD Cohort) 
Study Week 
(Day) 
Assessment 
Screen 
Aa 
Day 1b Week 1 
(Phone) 
Day 3±1 
Week 1c 
Day 7±3 
Week 2 
(Phone) 
Day 
10±1 
Week 2c 
Day 
14±3 
Week 3 
(Phone) 
Day 
21±3 
Week 4 
Day 
28±3 
Week 4 
(Phone) 
Day 
31±3 
Week 5 
(Phone) 
Day 
38±3 
Week 6c 
Day 
42±3 
Week 7 
(Phone ) 
Day 
49±3 
Week 8 
Day 
56±3 
Week 12 
Day 
84±3 
Week 16 or 
End of 
Treatment 
Visitd 
Day 112±3 
F/Ud 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
baseline disease 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight in clinic  
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Weight at homef 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense weight diary 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
 
Collect/review weight 
diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Vital sign measurements 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Physical exam/clinical 
worsening assessmentg 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Pregnancy test for 
WOCBPh 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Study drug administration 
 
X 
-------------------------------------------------------- X ------------------------------------------------ 
 
Dispense study drug 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
Collect study drug 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
Telephone contact 
 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
Adverse event collection 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
BNP and NT-Pro BNPj 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Urinalysis and 
microscopy 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Virus serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-min walk test 
X 
Xl 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Xm 
X 
ECHO 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function 
testingr 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 






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Table 5: Part 2:  Extension Schedule of Assessments for Patients in Cohorts 1 and 2 
Study Week 
Assessment 
Week 16a 
(Day 1) 
(±3 days) 
Week 17 
(Phone) 
(±1 day) 
Week 18b 
(±3 days) 
Week 19 
(Phone) 
(±1 day) 
Week 20 
(±3 days) 
Week 32   
(± 5 days) 
 
Week 56 and 
Every 24 
Weeks 
Thereafter 
(±5 days)c 
End of  
Treatment 
Visitd 
(± 5 days) 
 
Follow-upd 
(± 5 days) 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
Weight in clinic  
 
 
X 
 
X 
X 
X 
X 
X 
Weight at homee 
 
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 
 
ECG 
 
 
 
 
 
X 
 
X 
X 
Vital sign measurements 
 
 
X 
 
X 
X 
X 
X 
X 
Physical exam/clinical worsening assessmentf 
 
 
Xg 
 
X 
X 
X 
X 
X 
Urine Pregnancy test for WOCBPh 
 
 
 
 
 
X 
X 
X 
X 
Study drug administration 
X 
-------------------------------------------------- X -------------------------------------------------- 
 
Dispense study drug 
X 
 
 
 
X 
X 
X 
 
 
Collect study drug 
 
 
 
 
X 
X 
X 
X 
 
Telephone contacti 
 
X 
 
X 
 
 
 
 
 
Adverse event collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistryj 
 
 
X 
 
X 
X 
X 
X 
X 
BNP and NT-Pro BNPj,k 
 
 
X 
 
X 
X 
Xk 
Xk 
X 
Hematology 
 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis and microscopy 
 
 
X 
 
X 
X 
X 
X 
X 
6-min walk test 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional class assessmentm 
 
 
 
 
 
X 
 
X 
X 
PK samplesn 
 
 
 
 
X 
 
 
 
 
a All other Week 16 assessments will be completed as per Table 3 or Table 4.   
b Under delegation of the Investigator and with prior Sponsor approval, a patient may be seen by a home health professional.  The home health professional must have documented study-specific 
training on file prior to the performance of any study-related procedures. 
c Visits beyond Week 32 will only occur until bardoxolone methyl is available through the extended access program. Once bardoxolone methyl is available through the extended access program, 
patients in Part 2 who have completed at least 32 weeks of the study will complete an End of Treatment Visit.  If bardoxolone methyl is available through the extended access program prior to 
Week 32, the End of Treatment visit may coincide with the Week 32 visit.   
d Patients who are discontinued from the study during the extension period for any reason, including Sponsor termination of the study, and patients who are not participating in the extended access 
program must complete all end-of-treatment and follow-up visit assessments.  Patients should complete the end-of-treatment assessments, including the 6MWT, prior to any adjustments being made 
to their PAH-specific treatment regimen.   


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e Weights taken at home by the patient should be taken daily starting at week 16 through and including week 20 and weekly thereafter, preferably at the same time each day and must be recorded in a 
diary and reviewed with the coordinator during telephone contacts and office visits. 
f If clinical worsening is suspected, further clinical evaluations may be required per Section 9.10.32. 
g A limited physical assessment directed to assess for fluid retention and clinical worsening may be performed by a home health professional under the delegation of the Investigator  
h  A serum pregnancy test will be performed at Screen A for WOCBP or at any point in time if a pregnancy is suspected.  All other pregnancy assessments will be urine pregnancy tests.  Additional 
pregnancy assessments will be performed more frequently if required by local law or requested by local regulatory authorities or IRBs/ECs. 
i Patients who dose escalate must be have a telephone call 1 week after dose escalation and an unscheduled office visit or home health 2 weeks (± 3 days) after dose escalation to collect clinical 
chemistry, BNP and NT-Pro BNP, as well as a telephone call.  
j Patients must be allowed to rest for a minimum period 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.  
This sample should be taken with the patient in the same position at all appropriate visits, e.g., sitting or semi-recumbent. 
k After Week 32, only NT-Pro BNP will be collected.  
 
   
m If clinical worsening is suspected, perform unscheduled functional class assessment. 
n Blood samples for PK analysis should be drawn just prior to (0 hour) and after (2 and 4 hours) dose administration for this visit.  Patients should be instructed to not take their study drug prior to 
coming to the clinic at Week 20. 
 
Abbreviations: ECG = electrocardiogram, ECHO = echocardiogram, PK = pharmacokinetic, s = serum, u = urine, WOCBP = women of child-bearing potential, 
 
 
 




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e Weights taken at home by the patient should be taken daily starting at week 16 through and including week 20 and weekly thereafter, preferably at the same time each day and must be recorded in a 
diary and reviewed with the coordinator during telephone contacts and office visits. 
f If clinical worsening is suspected, further clinical evaluations may be required per Section 9.10.32. 
g A limited physical assessment directed to assess for fluid retention and clinical worsening may be performed by a home health professional under the delegation of the Investigator and with prior 
Sponsor approval.  
h A serum pregnancy test will be performed at Screen A for WOCBP or at any point in time if a pregnancy is suspected.  All other pregnancy assessments will be urine pregnancy tests.  Additional 
pregnancy assessments will be performed more frequently if required by local law or requested by local regulatory authorities or IRBs/ECs. 
i Patients must be allowed to rest for a minimum period 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.  
This sample should be taken with the patient in the same position at all appropriate visits, e.g., sitting or semi-recumbent. 
j After Week 32, only NT-Pro BNP will be collected. 
 
   
l If clinical worsening is suspected, perform unscheduled functional class assessment. 
m Blood samples for PK analysis should be drawn just prior to (0 hour) and after (2 and 4 hours) dose administration for this visit.  Patients should be instructed to not take their study drug prior to 
coming to the clinic at Week 20. 
 
  
 
Abbreviations: ECG = electrocardiogram, ECHO = echocardiogram, PK = pharmacokinetic, s = serum, u = urine, WOCBP = women of child-bearing potential, 
 
 


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Diagnosis and main criteria for inclusion:  
1. 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 Functional Class II and III; 
4. WHO Group I, III, or V PH according to the following criteria: 
a. If diagnosed with WHO Group I PAH, then one of the following subtypes: 
i. Idiopathic or heritable PAH; 
ii. PAH associated with connective tissue disease; 
iii. PAH associated with simple, congenital systemic-to-pulmonary shunts at 
least 1 year following shunt repair; 
iv. PAH associated with anorexigen or drug-induced toxicity; 
v. PAH associated with human immunodeficiency virus (HIV); or 
b. If WHO Group III PH, then primary diagnosis must be one of the following 
subtypes: 
i. Connective tissue disease associated ILD (CTD-ILD); 
ii. Idiopathic pulmonary fibrosis (IPF), according to the American Thoracic 
Society and European Respiratory Society (ATS/ERS) guidelines 
(Raghu 2011); 
iii. Nonspecific interstitial pneumonia (NSIP) or the following idiopathic 
interstitial pneumonia subtypes, according to the American Thoracic 
Society and European Respiratory Society (ATS/ERS) guidelines 
(Travis 2013): 
1. Respiratory bronchiolitis-associated interstitial lung disease;  
2. Desquamative interstitial pneumonia;  
3. Cryptogenic organizing pneumonia;  
4. Acute interstitial pneumonitis; 
5. Idiopathic lymphoid interstitial pneumonia; 
6. Idiopathic pleuroparenchymal fibroelastosis; 
7. Unclassifiable idiopathic interstitial pneumonia, including patients 
who have not had a lung biopsy; or 
c. If WHO Group V PH, then patient must be diagnosed with sarcoidosis;  


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5. Had a diagnostic right heart catheterization performed and documented prior to Day 1 
that confirmed a diagnosis of PH according to all the following criteria:    
a.  If diagnosed with WHO Group I PAH, then: 
i. Mean pulmonary artery pressure ≥ 25 mm Hg (at rest); 
ii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; 
iii. Pulmonary vascular resistance > 240 dyn.sec/cm5 or > 3 mm Hg/Liter 
(L)/minute; 
b. If not diagnosed with WHO Group I PAH, then: 
i. Mean pulmonary artery pressure ≥ 21 mm Hg (at rest); 
ii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg; 
iii. Pulmonary vascular resistance > 160 dyn.sec/cm5; 
6. Has BNP level ≤ 400 pg/mL; 
7. Has an average 6-minute walk distance (6MWDs) ≥ 150 meters on two consecutive tests 
performed on different days prior to randomization, with both tests measuring within 
15% of one another;   
8. Has been receiving no more than two (2) approved disease-specific PAH therapies.  
Cohort 3b WHO Group I PAH patients enrolled outside the United States must be 
receiving zero (0) or one (1) PAH therapies.  PAH therapy must be at a stable dose for at 
least 90 days prior to Day 1;  
9. If WHO Group III or WHO Group V, disease-specific therapy must be at a stable dose 
for 30 days; 
10. Has maintained a stable dose for 30 days prior to Day 1 if receiving any of the following 
therapies that may affect PH:  vasodilators (including calcium channel blockers), digoxin, 
L-arginine supplementation, or oxygen supplementation; 
11. If receiving prednisone, has maintained a stable dose of ≤ 20 mg/day (or equivalent dose 
if other corticosteroid) for at least 30 days prior to Day 1.  If receiving treatment for 
connective tissue disease (CTD) with any other drugs, doses should remain stable for the 
duration of the study;   
12. Had pulmonary function tests (PFTs) within 90 days prior to Day 1 that meet the 
following criteria:   
a. For WHO Group I PAH patients with connective tissue disease, total lung 
capacity (TLC) ≥ 65% (predicted); 
b. For all other WHO Group I PAH patients, 
i. Forced expiratory volume in 1 second (FEV1 ) ≥ 65% (predicted); or 
ii. FEV1/forced vital capacity ratio (FEV1/FVC) ≥ 65%;  
c. For WHO Group III or V PH patients, total lung capacity (TLC) between 50-90% 
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13. For WHO Group I patients, had a ventilation-perfusion (V/Q) lung scan or 
spiral/helical/electron beam computed tomography (CT) or pulmonary angiogram prior to 
Screening 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 disease; 
14. Has adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥ 45 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 
4-variable formula; 
15. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures; 
16. 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; 
17. For WHO Group III or V PH patients, the presence of ILD must be confirmed by a 
diagnostic high resolution computed tomography (HRCT) scan or biopsy performed and 
documented prior to Day 1. 
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 pharmaceutical products 
being tested or used in a way different from the approved form or when used for an 
unapproved indication within 30 days of Day 1; 
2. Initiation of an exercise program for cardio-pulmonary rehabilitation within 3 months 
(90 days) prior to Day 1 or planned initiation during Part 1 of the study;    
3. Stopped receiving any PH chronic therapy within 60 days prior to Day 1; 
4. Requirement for receipt of intravenous inotropes within 30 days prior to Day 1;  
5. Has uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure 
(BP) > 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening 
after a period of rest; 
6. Has systolic BP < 90 mm Hg during Screening after a period of rest; 
7. WHO Group III patients with pulmonary hypertension primarily associated with chronic 
obstructive pulmonary disease, sleep-disordered breathing, and/or alveolar 
hypoventilation disorders;  
8. WHO Group III or V patients who at rest require supplemental oxygen at a rate 
> 4 L/min or have peripheral capillary oxygen saturation (SpO2) levels <92%; 


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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 
60 days of Day 1; 
e. Any current or prior history of symptomatic coronary disease (prior myocardial 
infarction, percutaneous coronary intervention, coronary artery bypass graft 
surgery, or anginal chest pain); 
10. Clinical instability within 8 weeks prior to Day 1, such as hospitalization due to 
respiratory or cardiac symptoms, acutely decompensated heart failure, syncope, or other 
events that in the investigator’s opinion would suggest the patient is an inappropriate 
candidate for the study; 
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. Obstructive sleep apnea that is untreated; 
14. For patients with HIV-associated PAH, any of the following: 
a. Concomitant active opportunistic infections within 180 days prior to Screening; 
b. Detectable viral load within 90 days prior to Screening; 
c. Cluster designation 4 (CD4+) T-cell count < 200 mm3 within 90 days prior to 
Screening; 
d. Changes in antiretroviral regimen within 90 days prior to Screening; 
e. Using inhaled pentamidine; 
15. 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); 
16. Serum aminotransferase (ALT or AST) levels > 1.5X the upper limit of normal (ULN) at 
Screening;  


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17. Hemoglobin (Hgb) concentration < 10.5 g/dL at Screening; 
18. Diagnosis of Down syndrome; 
19. History of malignancy within 5 years prior to screening, with the exception of localized 
skin or cervical carcinomas; 
20. Active bacterial, fungal, or viral infection, incompatible with the study; 
21. Known or suspected active drug or alcohol abuse, per Investigator judgment; 
22. Major surgery within 30 days prior to Screening or planned to occur during the course of 
the study; 
23. Unwilling to practice 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 due to language problems, 
poor mental development, or impaired cerebral function; 
30. Use of intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogues; 
31. Prior exposure to bardoxolone methyl. 
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 Withdrawal and Discontinuation 
Patients have the right to withdraw from the study at any time for any reason, without prejudice 
to their medical care.  The Investigator may discontinue a patient from the study for any of the 
following reasons: 
• Clinical worsening; 
• Occurrence of an adverse event or change in medical status that leads the Investigator or 
Sponsor to be concerned about the patient’s welfare; 
• Investigator determines the patient is non-compliant with study procedures; 
• Females who become pregnant during the study; 
• Failure to return for follow-up. 


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Patients must be withdrawn from the study 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%); 
• Withdrawal of consent; 
• Death. 
Patients who discontinue from the study will be asked to complete the end-of treatment and 
follow-up procedures noted in Table 3 or Table 4 and Table 5 or Table 6 depending on which 
cohort the patient is enrolled in and whether the patient is Part 1 or 2 of the study.  Patients who 
complete the 16 weeks of Part 1 but choose not to participate in Part 2 (the extension period) 
should complete the follow-up procedures in Table 3 or Table 4 and Table 5 or Table 6.  Patients 
should complete end-of-treatment procedures, including the 6MWT, prior to any adjustments 
being made to their PAH treatment regimen.  Patients who discontinue for elevated transaminase 
levels should complete the End-of-treatment visit, the Follow-up visit and should also be 
followed per Section 9.1.2 if acceptable levels are not reached at the Follow-up visit. 
Every 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(s), request the patient return for end-of-treatment and follow-up visits (if 
applicable), and follow-up with the patient regarding any unresolved AEs.  Patients who 
discontinue participating in the study for any reason may not re-enter the study at any time.   


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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 4 weeks (Cohorts 1 and 2) or 8 weeks 
(Cohorts 3 and 4) 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 Part 1 
and during the first 4 weeks (Cohorts 1 and 2) or 8 weeks (Cohorts 3 and 4) of Part 2 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 may 
not restart their study medication until the Investigator has completed and documented an 
assessment of fluid overload.  
Investigators should also 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, and 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. 
Since placebo patients will be transitioned to active treatment for the extension period (Part 2), 
and the blind will be maintained, all patients entering the extension will be closely monitored for 
weight gain just as they were monitored following randomization into the treatment period.  
Patients will use their Sponsor-provided scale during the first four weeks (Cohorts 1 and 2) or 
eight weeks (Cohorts 3 and 4) of the extension period and will record their weights daily.  As in 
the treatment period (Part 1), patients 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 if they experience a five-pound or greater increase in weight since 
Week 16 (Day 1 of the extension period).   


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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 48-72 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 three times the ULN for 
at least one week or 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 > 2 x 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 
Decreased appetite or anorexia may result from use of bardoxolone methyl.  Weight loss of 
approximately one kilogram per month may be observed, with patients of higher body-mass 
index at baseline losing more than those of normal or moderately-elevated body-mass index.  
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 the patients experience 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.   


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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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9.3. 
Concomitant Medications 
9.3.1. 
Excluded Medications 
Patients taking these medications or treatments will be ineligible for enrollment or continuation 
in the study: 
• Any other investigational drug or device studies; 
• Intravenous (iv) or subcutaneous (sc) prostacyclin/prostacyclin analogue; 
• Intravenous inotropes;  
• Inhaled nitric oxide (excluding acute vasodilator testing during diagnostic cardiac 
catheterization).     
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; 
• Medications intended to manage interstitial lung disease or sarcoidosis in patients 
enrolled in Cohort 4 (PH-ILD cohort), including but not limited to methotrexate, 
prednisone, nintedanib, or pirfenidone; 
• Medications approved for treatment of WHO Group I PAH intended to manage 
pulmonary hypertension in WHO Group III and WHO Group V patients; 
• Oral, implantable, or injectable contraceptives. 
Patients taking medication chronically should be maintained on those same doses and dose 
schedules throughout the study period, as medically feasible.   
The use of the following therapies, which may affect PH, 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, 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; 


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• Agents to treat neuropathic pain associated with peripheral neuropathy (such as 
pregabalin); 
• Oxygen supplementation. 
Corticosteroids are allowed if the patient has been receiving a stable dose of ≤ 20 mg/day of 
prednisone (or equivalent dose, if other corticosteroid) for at least 30 days prior to study Day 1.  
If receiving treatment for CTD with any other drugs, doses should remain stable 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. 
Diuretics may be prescribed as clinically indicated throughout the study.  Any changes to the 
doses of diuretics throughout the course of the study must be recorded in the eCRF.   
Patients who fulfill the requirements, as defined above, should not be withdrawn from the study 
solely on this basis.  Consultation with the medical monitor should occur prior to withdrawing a 
patient from the study. 
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.  A maximum of seven consecutive 
missed doses or no more than 14 missed days are permitted.  Patients must be considered 
treatment compliant to be eligible for the extension period (Part 2).   
9.5. 
Randomization 
Patients will be assigned to cohort based on baseline 6MWD (i.e., ≤ 450 m versus > 450 m) for 
Cohorts 1 and 2, and based on PH classification for Cohorts 3 and 4.  Cohort 3 includes two sub-
cohorts (3a, 3b) and Cohort 4 includes 4 sub-cohorts (4a, 4b, 4c, 4d).  Within each cohort (or 
sub-cohort), patients will be randomized to bardoxolone methyl or placebo for Part 1 of the study 
according to the treatment assignment regimen.  Patients will be assigned to bardoxolone methyl 
in Part 2 according to the study design. 
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.  Appropriate measures will be taken to ensure the blind is maintained for 
the patients and personnel mentioned previously to reduce potential bias.  To maintain the blind, 
Investigators will distribute blinded study drug bottles to patients as directed by the IWRS 
system.     
Treatment assignments will be managed by an IWRS system.  The only people with direct access 
to treatment assignments will be those individuals who develop and maintain the randomization 
code, the individuals involved in the implementation and operation of the IWRS system, and the 
PSRC.  Some Sponsor personnel will be unblinded to individual treatment assignments. 


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Upon starting Part 2 of the study (i.e., the extension phase) all patients will receive bardoxolone 
methyl.   
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 encouraged to contact the medical monitor to discuss situations in which he 
or she believes that the blind should be broken, but the investigator has the right to break the 
blind (e.g., in the event of a serious or life-threatening medical situation).  If unblinding is 
required, the Investigator will utilize the IWRS to perform the unblinding.  If a study drug 
assignment is unblinded, a description of the event that required unblinding must be documented 
by the Investigator 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 early termination 
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) must be provided with unblinded 
information according to the applicable regulatory requirement.  This information must not be 
conveyed to 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. 
Protocol Safety Review Committee 
A Protocol Safety Review Committee (PSRC) will assess the starting dose and each new dose 
level of bardoxolone methyl for safety and tolerability based on review of all available data for 
this study at the time of each review.  PSRC reviews will occur after the Week 4 data are 
available for the first eight patients enrolled at each new dose level combined across Cohorts 1 
and 2 (i.e., the 6MWD ≤  450 m and 6MWD > 450 m cohorts).  Upon completion of the dose 
ranging portion of the study, the PSRC will continue to meet at regular intervals (approximately 
quarterly) to monitor safety of all patients, including those enrolled in Cohorts 3 and 4.     
The PSRC will include at a minimum a Sponsor representative, a cardiologist, and a statistician.  
Should issues arise requiring expertise not represented by the current members, the PSRC may 
appoint additional clinical specialists. 
The PSRC will assess the following to escalate: 


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• Signs and symptoms of fluid overload, including adverse events (edema, dyspnea, etc.), 
weights, and BNP; 
• All other collected safety laboratory test data and vital sign measurements; 
• Pharmacodynamic markers of Nrf2 activation, including transaminase, GGT, and ferritin 
levels. 
Doses or exposures associated with the defined dose levels in this protocol have been studied 
previously in healthy volunteers, oncology patients, patients with hepatic dysfunction, and 
patients with moderate CKD without untoward toxicity.  Therefore, the PSRC will assess for 
general safety and specific signs and symptoms of fluid overload.  The PSRC assessment will 
include a dose level recommendation based on clinical evaluation of the above specified 
assessments for subsequent cohorts to escalate to a higher dose, proceed to a lower dose, or 
maintain the current dose.  The PSRC may also recommend stopping dosing for current cohorts.    
9.7. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
• Assessment of weight gain as 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 for patients enrolled in Cohorts 3 and 4; 
• Dose escalation or dose de-escalation for patients enrolled in Cohorts 1 and 2 in Part 2 of 
the study; 
• Any time the Investigator feels that it is clinically appropriate for patient safety. 
Unscheduled visits may be performed as a home-health visit under the Investigator delegation 
and following prior sponsor approval. 
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 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]); 


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• Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
90 days prior to start of study drug administration; 
• Use of an intrauterine device; 
• Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted.   
During screening, while taking study drug and until 30 days after the final dose of study 
medication is taken, males who have female partners of childbearing potential must practice one 
of the following methods of birth control: 
• Have had a vasectomy (at least 6 months earlier); 
• Use double barrier contraception method defined as male use of a condom and female 
use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, 
diaphragm [always use with spermicidal jelly/cream]); 
• 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 pregnancy is confirmed with 
a serum pregnancy test result, 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: 
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• Stillbirth; 
• Spontaneous miscarriage. 
9.9. 
Serious Toxicities 
In the case of serious toxicities, the Investigator may choose to interrupt treatment with 
bardoxolone methyl.  Dose reductions are permitted for patients enrolled in Cohorts 3 and 4, as 
well as patients enrolled in Part 2 of the study.  Patients who resume therapy after an interruption 
will follow the originally planned study schedule.  If the interruption of treatment with 
bardoxolone methyl exceeds 7 consecutive days or 14 total days, the patients should be 
discontinued from the study as outlined in Section 8.4.   
9.10. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 3 and Table 4 and Table 5 or Table 6.  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 should be reviewed at the times indicated in Table 3 or Table 4.  
Patients must meet all of the inclusion and none of the exclusion criteria for entry in the study.  
Investigators should contact the medical monitor with any questions regarding eligibility prior to 
randomizing the patient on Day 1. 
9.10.3. 
Demographics and Baseline Disease 
Characteristics 
Demographic data including sex, age, race, and ethnicity, will be collected at the times indicated 
in Table 3 or Table 4.  Baseline disease characteristics will be collected at the time point 
indicated in Table 3 or Table 4.   
9.10.4. 
Prior and Current Concomitant 
Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking.  
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug names 
should be used where possible.  Concomitant medications will be reviewed at the times indicated 
in Table 3 or Table 4 or Table 5 or Table 6 and all changes will be recorded. 


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9.10.5. 
Medical History 
A complete medical history (e.g., per patient report) that includes all medical history within the 
past 5 years must be collected.  Medical history will be recorded at the times indicated in Table 3 
or Table 4.   
9.10.6. 
Right Heart Catheterization 
A right heart catheterization (RHC) completed prior to Day 1 is required.  However, if a patient 
has not had a RHC completed prior to planned Day 1, it should be performed after the patient has 
signed Informed Consent and has passed the Screen A eligibility procedures.   
In addition, data resulting from a RHC performed 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.   
9.10.7. 
Height 
Height should be measured without footwear, head coverings or prosthetics at the time indicated 
in Table 3 or Table 4. 
9.10.8. 
Weight and Body Mass Index (BMI) 
Weight should be measured at the times indicated in Table 3 or Table 4 and Table 5 or Table 6.  
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 capture daily weights.  Weights 
should be taken at the same time each day and recorded in a patient diary.  During the first four 
weeks (Cohort 1 and 2) or first eight weeks (Cohort 3 and 4) of both Part 1 and Part 2, weights 
will be collected daily; weekly weights will be collected thereafter.  Patients will be instructed to 
stop administering study drug and contact the Investigator if their daily weight increases as 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.    
9.10.9. 
Electrocardiograms (ECG) 
A 12-lead ECG will be recorded after the patient has rested for at least 10 minutes in a supine 
position at the times indicated in Table 3 or Table 4 and Table 5 or Table 6.  The heart rate from 
the ECG machine should not be used as part of the vital sign measurements. 
9.10.10. 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), respiration rate, and oral or tympanic 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 at the times indicated Table 3 or Table 4 
and Table 5 or Table 6.  Resting oxygen saturation will be collected for patients enrolled in 
Cohort 3 and Cohort 4 (PH-ILD).  


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9.10.11. 
Ambulatory Blood Pressure 
Monitoring (ABPM) 
ABPM will be performed on all Cohort 1 and Cohort 2 patients only in Part 1 of this study at the 
times indicated in Table 3.  A Sponsor-provided device will be placed on the patient by site 
personnel with the appropriate training.  Participants will wear the ABPM for a minimum of 
24 hours.  Patients should return to the clinic the next day to have the device removed; however, 
with prior sponsor approval, the monitor may be removed at least 24-hours after placement and 
returned to the Investigator.  ABPM will not be collected in patients enrolled in Cohorts 3 and 4 
(PH-ILD cohort). 
9.10.12. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner at the time points indicated in Table 3 or Table 4 and Table 5 or 
Table 6 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, and if abnormal, a description of the abnormality 
must be provided.  Following the examination at Screening, changes must be 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. 
Pregnancy Test 
WOCBP (see Section 9.8) will complete a pregnancy test at the time points indicated in Table 3 
or Table 4 and Table 5 or Table 6, or at any point in 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. 
9.10.14. 
Study Drug Administration 
Patients should self-administer the assigned number of capsules orally once a day in the morning 
at the time points indicated in Table 3 or Table 4 and Table 5 or Table 6.  On days when PK 
samples are collected, patients should not self-administer study drug.  Study staff will administer 
study drug at the clinic following collection of the first PK sample.   
A vomited dose should not be replaced.  Missed doses may be taken in the afternoon or evening 
of the same day.  A double dose (e.g., missed dose from previous day and dose for current day) 
should not be taken. 
For patients enrolled in Cohorts 3 and 4, as well as patients enrolled in Part 2 of the study, dose 
de-escalation may occur any time after a DLT occurs. 


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9.10.15. 
Study Drug Dispensation and 
Collection 
Study drug will be dispensed to the patient and collected from the patient at the time points 
indicated in Table 3 or Table 4 and Table 5 or Table 6.  For patients enrolled in Cohorts 3 and 4, 
dose escalation may occur at Week 4. 
9.10.16. 
Telephone Contact 
Patients will be contacted by telephone at the time points indicated in Table 3 or Table 4 and 
Table 5 or Table 6.  Patients will be asked about their body weight and other signs of fluid 
retention.  If fluid retention is suspected, the patient should be brought into the clinic and 
evaluated by the Investigator as soon as possible, as detailed in Section 9.1.1. 
9.10.17. 
Adverse Event Collection 
Patients should be observed for general appearance, presence of illness or injury, or signs 
indicative of a concurrent illness at the time points indicated in Table 3 or Table 4 and Table 5 or 
Table 6.  Patients should be instructed to volunteer any information regarding AEs at any time 
during the study, 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.  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. 
9.10.18. 
Clinical Chemistry 
Samples will be collected for the following clinical chemistry analyses at the time points 
indicated in Table 3 or Table 4 and Table 5 or Table 6: ferritin, creatine kinase (CK), blood urea 
nitrogen (BUN), creatinine enzymatic, total bilirubin, direct bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, calcium, 
phosphorus, uric acid,  total protein, glucose, albumin, lactate dehydrogenase (LDH), 
magnesium, chloride, bicarbonate, gamma-glutamyl transpeptidase (GGT).  An eGFR using the 
MDRD formula (eGFR = 175 x standardized serum creatinine – 1.154 x age – 0.203 x 1.212 [if black] 
x 0.742 [if female]) will be calculated at the Screen A visit only for eligibility purposes.  Women 
of child-bearing potential will require a serum pregnancy test (hCG-Qual) at Screen A or at any 
point in time if a pregnancy is suspected. 
9.10.19. 
N-Terminal Pro-Brain Natriuretic 
Peptide and Brain Natriuretic Peptide 
Samples will be collected for NT-Pro BNP and BNP at the time points indicated in Table 3 or 
Table 4 and Table 5 or Table 6.  As BNP and NT-Pro BNP may be affected by recent exercise, 
patients must be allowed to rest for a minimum period 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.  This sample should be taken with the patient in the same position at all appropriate 
visits, e.g., sitting or semi-recumbent. 


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After the Week 32 study visit, only NT-Pro BNP should be collected at study visits, as shown in 
Table 5 and Table 6.   
Detailed instructions on collection, storage and shipment of the sample will be provided in the 
central laboratory manual provided to the Investigator.   
9.10.20. 
Hematology 
Samples will be collected for the following hematology assessments at the time points indicated 
in Table 3 or Table 4 and Table 5 or Table 6: 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). 
9.10.21. 
Urinalysis and Microscopy 
Samples will be collected for the following urinalysis and microscopy assessments at the time 
points indicated in Table 3 or Table 4 and Table 5 or Table 6: specific gravity, ketones, pH, 
protein, blood, glucose, clarity, color, leukocytes, nitrite, bilirubin, and a microscopic 
examination (if indicated based on laboratory results). 
9.10.22. 
Virus Serology 
Blood samples will be collected for testing for hepatitis B and hepatitis C at the time point 
indicated in Table 3 or Table 4. 
9.10.23. 
6-Minute Walk Test 
A 6-minute walk test (6MWT) will be administered to patients at the time points indicated  
Table 3 or Table 4 and Table 5 or Table 6.   
The 6MWT is a non-encouraged test that measures the distance walked over 6 minutes.  The 
6MWT must be performed consistently across all patients and sites.  Therefore, each test must be 
performed in strict accordance with the instructions and script provided in Section 19 of 
Appendix 1, which are based on American Thoracic Society (ATS) guidelines [ATS Statement 
2002].  The appropriate language version will be applied for patients with a non-English 
informed consent. 
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 
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 Riociguat 
o The combined occurrence of the events listed below.  If a CWE is confirmed by these 
criteria, then an NT-pro BNP laboratory assessment is required on the day of the 
second 6MWT with the NT-Pro BNP sample obtained after 1 hour of rest:   
1. A decrease in 6MWT by at least 15% from Baseline, confirmed by two 
6MWTs, on different days;  
AND 
2. Increase (worsening) ≥ 1 grade in WHO FC from Baseline;  
AND 
3. Appearance of or worsening of signs/symptoms of right heart failure that did 
not respond to optimized oral diuretic therapy.   
In case of clinical deterioration the Investigator must assess carefully if the deterioration of the 
patient’s condition (e.g., worsening functional class) is related to the underlying pulmonary 
hypertension or can be explained by an alternative cause (e.g., transient infection, 
musculoskeletal disease, surgical or medical intervention other than pulmonary hypertension- 
related, exacerbation of a concomitant lung disease, lacking compliance of medication intake).  
Only persistent clinical deteriorations caused by the underlying pulmonary arterial hypertension 
will be considered a clinical worsening event.  
Time to clinical worsening will be evaluated as the number of days between randomization and 
the occurrence of a predefined clinical worsening event.   
Transient deteriorations of clinical status requiring hospitalization, treatable by, for example,  
short-time application of intravenous diuretics, positive inotropic agents or non-invasive 
ventilation and allowing patients discharge within 48 hours, are not considered to meet the 
criteria for a CWE.  Patients should be discontinued only if any of the above criteria exceed 
48 hours. 
9.10.33. 
WHO/NYHA Functional Class 
Assessment 
WHO functional class assessment (Section 20, Appendix 2) will be made and documented at the 
time points indicated in Table 3 or Table 4 and Table 5 or Table 6 as well as at any time clinical 
worsening is suspected.  WHO/NYHA FC will be assessed.  To the extent feasible, the same 
evaluator should assess WHO/NYHA FC for a particular patient over the entire course of the 
study.  
9.10.34. 
 Pharmacokinetic (PK) Blood Samples 
Blood samples for determination of plasma bardoxolone methyl and potential metabolite 
concentrations will be drawn at the time points indicated in Table 3 or Table 4 and Table 5 or 
Table 6.  Patients will be asked by site personnel to provide the time of their last two study drug 
administrations prior to the blood samples being collected.  This data will be based on patient 
recall and not collected in a patient diary.  Blood sample collection instructions should be 
referenced in the laboratory manual. 






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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 2.5 mg, 5 mg, 10 mg, and 15 mg, and placebos to match, will be 
used in this study. 
10.2. 
Study Drug Packaging and Labeling 
Kits will be dispensed during study Part 1 (Day 1 through Week 12 dispensing).  Either bottles 
containing 30-count or 90-count of capsules or treatment kits will be dispensed during study 
Part 2.  The extension period begins with the Week 16 dispensing.  The blind will be maintained 
until the Week 20 dispensing.   
During study Part 1, the study drug will be supplied in tamper-evident kits containing three 30-cc 
high-density polyethylene (HDPE) bottles and one 60-cc HDPE bottle.  Each bottle will utilize 
foil induction-seal liners and a child-resistant closure.  Each bottle of study drug will contain 
30 count of 2.5 mg, 5 mg, or 15 mg strength bardoxolone methyl or corresponding placebo 
capsules.  Each bottle will also contain a desiccant insert that must not be ingested.  Labeling on 
each kit bottle will contain the following information: 
• Medication ID number; 
• Protocol 402-C-1302; 
• Caution Statement: Limited to Investigational Use. Keep out of sight or reach of 
children; 
• Store at 20° – 25°C (68° – 77°F), excursions allowed to 15° – 30°C (59° – 86°F); 
• Reata Pharmaceuticals, Inc., Irving, TX. 
During study Part 2, the study drug may also be supplied in 30-count or 90-count bottles with 
child-resistant closures.  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 is 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), excursions allowed to 15° – 30°C (59 –86°F).   
10.4. 
Study Drug Administration 
Please refer to Section 9.10.14 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 or Table 4 and Table 5 or Table 6.  Patients must 
be instructed to continue taking study drug once daily up through their Week 16 visits unless 
otherwise instructed by the Investigator or been formally discontinued from the study.  Patients 
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through the end of the study unless otherwise instructed by the Investigator or been formally 
discontinued from the study.  
10.5. 
Study Drug Accountability 
The Investigator, or designee, will maintain a record of all study drug received, dispensed, and 
returned to the Sponsor or its designee.  No study drug shall be destroyed by the clinical site 
unless directed to do so by the Sponsor or its designee.  Study drug bottles and any unused 
capsules should be returned to the study staff. 
10.6. 
Study Drug Handling and Disposal 
At the conclusion of the study, the Sponsor or its designee will direct the site regarding the final 
disposition of any remaining 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, 24-hour ambulatory blood pressure 
monitoring, 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 treatment.  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 or  
Table 4 and Table 5 or Table 6, as appropriate) 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 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 


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Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
which occur during the study (from the time of the first dose of study drug until the final visit 
indicated in Table 3 or Table 4 and Table 5 or Table 6, 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 or Table 4 and Table 5 or Table 6, as 
appropriate), regardless of their relationship to study drug or their clinical significance.  All 
SAEs reported or observed during the study must be followed to resolution or until the 
Investigator deems the event to be chronic or the patient to be stable.  Reata or designee may 
contact the Investigator to obtain additional information on any SAE which has not resolved at 
the time the patient completes the study. 
11.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, non-directed question, such as, “How 
have you been feeling since your last visit?” to elicit any medically related changes in their 
well-being.  They may also be asked if they have been hospitalized, had any accidents, used any 
new medications, or changed concomitant medication regimens (including prescription drugs, 
over-the-counter medications, vitamins, herbal products, and minerals).  Responses must be 
documented in the source documents. 
In addition to patient observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, or ECG 
abnormalities, or from other documents that are relevant to patient safety. 
11.4. 
Assessment of Causality  
The Investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Unrelated: This relationship suggests that there is no association between the study drug and the 
reported event. 
Unlikely: 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. 
Possible: 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. 
Probable: 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. 


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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 30 days following administration of the final dose of study medication, 
regardless of the relationship of the AE to study drug.  Information to be collected includes type 
of event, date of onset, date of resolution, Investigator-specified assessment of severity and 
relationship to study drug, seriousness, as well as any action taken.  
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents, but when documenting the AE, only the total duration and 
greatest severity should be recorded in the eCRF.  AEs characterized as intermittent require 
documentation of onset and duration. 
All drug-related (Possible or Probable, 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 or Table 4 and Table 5 or Table 6, 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 as 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 to be 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. 


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Elective procedures (surgeries or therapies) that were scheduled prior to the start of AE 
collection are not considered AEs.  These elective procedures should not be recorded as AEs, but 
should be documented in the patient’s source documents as elective (e.g., elective periodontal 
surgery).  However, if a pre-planned procedure is performed early (e.g., as an emergency) 
because of a worsening of the preexisting condition, the worsening of the condition should be 
captured as an AE. 
11.7. 
Reporting Serious Adverse Events 
Any AE the Investigator considers serious according to the previously described criteria must be 
reported within 24 hours from the time the site personnel first learn about the event.  
To report the SAE, fax the completed SAE form to Medpace (fax number listed below) within 
24 hours of awareness. 
Table 9: 
SAE Reporting Contact Information 
 
Medpace SAE hotline North America and Australia 
 
Telephone: 
 
Facsimile: 
 
E-mail: 
 
 
Medpace SAE hotline Europe 
Telephone: 
 
Facsimile: 
 
 
For questions regarding SAE reporting, contact your study manager, monitor, or Medpace 
Clinical Safety. 
Follow-Up Reports 
The Investigator must continue to follow the subject until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment) or the 
subject dies. 
Within 24 hours of receipt of new information, the updated follow-up SAE form, along with any 
supporting documentation (e.g., subject discharge summary or autopsy reports), should be faxed 
to Medpace Clinical Safety. 
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 


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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 
• 
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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12.3. 
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 similar 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, standard 
deviation, coefficient of variation, and geometric mean (where applicable).  Categorical data will 
be summarized using frequency counts and percentages. 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
The study monitor, as a representative of the Sponsor, has the obligation to follow the study 
conduct closely.  In doing so, the monitor will visit the principal Investigator and study facilities 
periodically, in addition to maintaining 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 inspection(s), 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), or 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.   
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. 
Any potential Investigator who has a vested financial interest in the success of this study may not 
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; 
• 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 


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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 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 authority(ies), 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, which arise after the approval of the protocol, must be documented as protocol 
amendments.  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.  
If an Electronic Data Capture system (EDC) is used to capture data electronically for all 
randomized patients, it will be 21 CFR Part 11 compliant. 


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17. 
PUBLICATION POLICY 
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 supports 
communication and publication of study results whatever the findings of the study.  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 the 
publications committee for the study. 


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18. 
REFERENCES 
Wu QQ; Wang Y; Senitko M; Meyer C; Wigley WC; Ferguson DA; Grossman E; Chen J; Zhou 
XJ; Hartono J; Winterberg P; Chen B; Agarwal A, & Lu CY. Bardoxolone methyl 
(BARD) ameliorates ischemic AKI and increases expression of protective genes 
Nrf2, PPARgamma, and HO-1. American Journal of Physiology - Renal Physiology. 
(2011). 300, F1180-F1192. 
Rojas-Rivera J; Ortiz A, & Egido J. Antioxidants in kidney diseases: The impact of bardoxolone 
methyl. International Journal of Nephrology. (2012). 2012, 1-11. 
Lee D-F; Kuo H-P; Liu M; Chou C-K; Xia W; Du Y; Shen J; Chen C-T; Huo L; Hsu M-C; Li C-
W; Ding Q; Liao T-L; Lai C-C; Lin A-C; Chang Y-H; Tsai S-F; Li L-Y, & Hung M-
C. KEAP1 E3 ligase-mediated downregulation of NF-kB signaling by targeting 
IKKß. Molecular Cell. (2009). 36, 131-140. 
Dinkova-Kostova AT; Liby KT; Stephenson KK; Holtzclaw WD; Gao X; Suh N; Williams C; 
Risingsong R; Honda T; Gribble GW; Sporn MB, & Talalay P. Extremely potent 
triterpenoid inducers of the phase 2 response: Correlations of protection against 
oxidant and inflammatory stress. Proceedings of the National Academy of Sciences. 
(2005). 102, 4584-4589. 
Osburn WO & Kensler TW. Nrf2 signaling: An adaptive response pathway for protection against 
environmental toxic insults. Mutation Research / Reviews in Mutation Research. 
(2008). 669, 31-39. 
Hong DS; Kurzrock R; Supko JG; He X; Naing A; Wheler J; Lawrence D; Eder JP; Meyer CJ; 
Ferguson DA; Mier J; Konopleva M; Konoplev S; Andreeff M; Kufe D; Lazarus H; 
Shapiro GI, & Dezube BJ. A phase I first-in-human trial of bardoxolone methyl in 
patients with advanced solid tumors and lymphomas. Clinical Cancer Research. 
(2012). 18, 3396-3406. 
Place AE; Suh N; Williams CR; Risingsong R; Honda T; Honda Y; Gribble GW; Leesnitzer LM; 
Stimmel JB; Willson TM; Rosen E, & Sporn MB. The novel synthetic triterpenoid, 
CDDO-Imidazolide, inhibits inflammatory response and tumor growth in vivo. 
Clinical Cancer Research. (2003). 9, 2798-2806. 
Deeb D; Gao X; Liu Y; Jiang D; Divine GW; Arbab AS; Dulchavsky SA, & Gautam SC. 
Synthetic triterpenoid CDDO prevents the progression and metastasis of prostate 
cancer in TRAMP mice by inhibiting survival signaling. Carcinogenesis. (2012). 32, 
757-764. 
Valcarcel-Ares MN; Gautam T; Warrington JP; Bailey-Downs L; Sosnowska D; de Cabo R; 
Losonczy G; Sonntag WE; Ungvari Z, & Csiszar A. Disruption of Nrf2 signaling 
impairs angiogenic capacity of endothelial cells: Implications for microvascular 
aging. Journal of Gerontology: Biological Sciences. (2012). 67, 821-829. 


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Eba S; Hoshikawa Y; Moriguchi T; Mitsuishi Y; Satoh H; Ishida K; Watanabe T; Shimizu T; 
Shimokawa H; Okada Y; Yamamoto M, & Kondo T. The Nrf2 activator oltipraz 
attenuates chronic hypoxia-induced cardiopulmonary alterations in mice. American 
Journal of Respiratory Cell and Molecular Biology. (2013). 49 , 324-333. 
Pugh, ME; Robbins, IM; Rice, TW; West, J; Newoman, JH; Hemnes AR. Uncrecognized 
glucose intolerance is common in pulmonary arterial hypertension. J Heart Lung 
Transplant. (2011). 30 (8), 904-911. 
Sutendra G, Michelakis ED. The metabolic basis of pulmonary arterial hypertension. Cell 
Metabolism. (2014). 19, 558-573.  
Mainguy V, Maltais F, Saey D, Gagnon P, Martel S, Simon M, Provencher S. Peripheral muscle 
dysfunction in idiopathic pulmonary hypertension. Thorax. (2010). 65, 113-117.  
Batt J, Ahmed SS, Correa J, Bain A, Granton J. Skeletal muscle dysfunction in idiopathic 
pulmonary arterial hypertension. American Journal of Respiratory Cell and 
Molecular Bioolgy. (2014). 50, 74-86. 
Malenfant S, Potus F, Fournier F, Breulis-Bonnet S, Pflieger A, Bourassa S, Tremblay E, Nehme 
B, Droit A, Bonnet S, Provencher S. Skeletal muscle proteomic signature and 
metabolic impairment in pulmonary hypertension. Journal of Molecular Medicine.  
(2015). 93, 573-584.  
Vescovo G, Ravara B, Gobbo V, Angelini A, Libera LD. Skeletal muscle fibres synthesis in 
heart failure: Role of PGC-1α, calcineurin and GH. International Journal of 
Cardiology. (2005). 104, 298-306.  
Saha P; Reddy V; Konopleva M; Andreeff M; Chan L. 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, 40581-40592. 
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. 
Patel AS, Siegert R, Creamer D, Larkin G, Maher TM, Renzoni EA, Wells AU, Higginson IJ, 
Birring SS. The development and validation of the King’s Sarcoidosis Questionnaire 
for the assessment of health status. Thorax. (2013). 68, 57-65. 
Judson MA, Baughman RP, Teirstein AS, Terrin ML, Yeager H Jr. Defining organ involvement 
in sarcoidosis: the ACCESS proposed instrument. ACCESS Research Group. A Case 
Control Etiologic Study of Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. (1999). 
16, 75-86.  
Raghu G,  Collard HR, Egan JJ, Martinez FJ, Behr J, et al. An Official ATS/ERS/JRS/ALAT 
Statement: Idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis 
and Management. American Journal of Respiratory and Critical Care Medicine. 
(2011). 183, 788-824.  


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Travis WD, Costabel U, Hansell DM, King TE, Lynch DA, et al. An Official American Thoracic 
Society/European Respiratory Society Statement: Update of the International 
Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias. American 
Journal of Respiratory and Critical Care Medicine. (2013). 188, 733-748. 
 
 
 


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19. 
APPENDIX 1:  6-MINUTE WALK TEST INSTRUCTIONS 
(Modified from American Thoracic Society (ATS) Statement: Guidelines for the Six-Minute 
Walk Test. [ATS Statement 2002])  
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 protocol, 
outlines safety measures, describes proper patient preparation and procedures, and offers 
guidelines for clinical interpretation of results.  
STUDY SPECIFIC REQUIREMENTS 
The assessor of the 6MWT must not provide the patient with the results of the assessment once 
complete. 
BACKGROUND  
The 6MWT is a practical simple test that requires a 98-ft (30 meter) 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 distance that a patient can walk 
on a flat, hard surface in a period of 6-minutes (the 6MWT).  It evaluates the global and 
integrated 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 information 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 
capacity 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 6MWT may better reflect the functional exercise level for 
daily physical activities.  
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the 
previous month and myocardial infarction during the previous month.  Relative contraindications 
include a resting HR of more than 120, a sBP of more than 180 mmHg, and a dBP of more than 
100 mmHg.  
Patients with any of these findings should be referred to the physician ordering or supervising the 
test for individual clinical 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.  Stable 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.  


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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 and thousands of patients with heart failure or cardiomyopathy without serious 
adverse events.  The contraindications 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 adverse 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 appropriate 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).  
3. A telephone or other means should be in place to enable a call for help.  
4. The technician should be certified in cardiopulmonary resuscitation with a minimum of 
Basic Life Support by an American Health Association–approved cardiopulmonary 
resuscitation course.  Advanced cardiac life support certification is desirable.  Training, 
experience, and certification in related health care fields (registered nurse, registered 
respiratory therapist, certified pulmonary function technician, etc.) are also desirable.  A 
certified individual should be readily available to respond if needed.  
5. 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.  
6. 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 following: (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 appropriate 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: BP, 
pulse rate, oxygen saturation, and a physician evaluation.  Oxygen should be administered as 
appropriate.  
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.  The walking course must be 15-30m in length. An 
approximate 49 to 98-ft hallway is, therefore, required.  The length of the corridor should be 
marked every 3 meters.  The turnaround points should be marked with a cone (such as an orange 


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traffic cone).  A starting line, which marks the beginning and end of each 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 6MWT.  
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.  A notation should be made in the patient’s 
source documentation of which shoes the patient wore for the first test.  Prior to each clinic 
visit the patient should be called/reminded to ensure they wear this same pair of shoes. 
3. Patients should use their usual walking aids during the test (cane, walker, etc.).  NOTE – if 
a patient uses a walking aid for the first test this same aide should be used during all 
subsequent test whether needed or not.  
4. The patient's usual medical regimen should be continued.  The patient should continue to 
take doses of study drug prior to the test. 
5. A light meal is acceptable before early morning or early afternoon 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 at the starting position, for at least 10 
minutes before the test starts.  During this time, check for contraindications, measure pulse 
and BP, and make sure that clothing and shoes are appropriate.  Also, note the patient’s 
general conditions and ailments (i.e. physical or mental) on this day that may potentially 
influence the results of the test.  Complete the first portion of the course document 
worksheet.   
4. Pulse oximetry is optional.  If it is performed, measure and record baseline HR and pulse 
oximetry oxygen saturation (SpO2) and follow manufacturer's instructions to maximize the 


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signal and to minimize motion artifact.  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 although the distance is the primary 
outcome measure, improvement during serial evaluations may be manifest either by an increased 
distance or by reduced symptoms with the same distance walked.  The SpO2 should not be used 
for constant monitoring during the exercise.  The technician must not walk with the patient to 
observe the SpO2.  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.  
1. Set the lap counter to zero and the timer to 6-minutes.  Assemble all necessary equipment 
(lap counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point.  
2. 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 yourself. You will 
probably get out of breath or become exhausted.  You are permitted to slow down, to stop, and to 
rest as necessary.  You may lean against the wall while resting, 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 POSSIBLE for 6-minutes, but don't run or jog.  Start now, or whenever you 
are ready."  
1. 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.  
2. Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  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.  Exaggerate the 
click using body language, like using a stopwatch at a race.  
3. Investigators or appropriate 6MWT administrators should not walk with the patient 
during the test. 
After the first minute, tell the patient the following (in even tones): "You are doing well.  You 
have 5-minutes to go."  


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When the timer shows 4-minutes remaining, tell the patient the following: "Keep up the 
good work.  You have 4-minutes to go."  
When the timer shows 3-minutes remaining, tell the patient the following: "You are doing 
well.  You are halfway done."  
When the timer shows 2-minutes remaining, tell the patient the following: "Keep up the 
good work.  You have only 2-minutes left."  
When the timer shows only 1-minute remaining, tell the patient the following: "You are 
doing well.  You have only 1-minute to go."  
Do not use other words of encouragement (or body language 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 prematurely.  
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.  
1. Post-test: Record the post-walk Borg dyspnea and fatigue levels and ask this: "What, if 
anything, kept you from walking farther?"  
2. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then remove 
the sensor.  
3. Record the number of laps from the counter (or tick marks on the worksheet).  
4. Record the additional distance covered (the number of meters in the final, partial lap) using 
the markers on the wall as distance guides.  
5. Calculate the total distance walked, rounding to the nearest meter (i.e. 251.3 meters is 251 
meters or 251.5 meters is 252 meters), and record it on the worksheet.  
6. Congratulate the patient on good effort and offer a drink of water.  
QUALITY ASSURANCE  
Sources of Variability 
There are many sources of 6MWT variability.  The sources of variability caused by the test 
procedure itself should be controlled as much as possible.  This is done by following the 
standards found in this document and by using a quality-assurance program.  
Technician Training and Experience 
Technicians who perform 6MWT should be trained using the standard protocol and then 


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supervised for several tests before performing them alone.  They should also have completed 
cardiopulmonary resuscitation training.  
Encouragement 
Only standardized phrases for encouragement (as outlined above) must be used during the 
test.  
Rationale 
Encouragement significantly increases the distance walked.  Reproducibility for tests with and 
without encouragement is similar.  We have chosen every minute and standard phrases.  
Supplemental Oxygen 
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.  Measurements of pulse and SpO2 should be made after waiting at least 10-minutes 
after any change in oxygen delivery.  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. 
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).   
Pulse Oximetry 
Patients should not carry the pulse oximeter during the 6MWT; instead, pulse oximetry is to be 
collected at the beginning and end of the 6MWT using a headband, ear or finger probe. For 
patients with scleroderma in cohorts 3a and 4a, a finger probe pulse oximeter should not be used.  
 


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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. 
 
 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A DOSE-RANGING STUDY OF THE EFFICACY AND 
SAFETY OF BARDOXOLONE METHYL IN PATIENTS 
WITH PULMONARY ARTERIAL HYPERTENSION 
 
 
Name of Test Drug: 
Bardoxolone Methyl 
 
 
Sponsor: 
Reata Pharmaceuticals, Inc 
 
 
Protocol No.: 
402-C-1302 
 
 
Protocol Version/Date 
26-Jan-2017 (Protocol Version 7.0) 
 
 
Author Biostatistician: 
Megan O’Grady, PhD 
 
 
Analysis Plan Version/Date: 
Version 3.0 / 14-June-2018 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 


RTA 402-C-1302 
Statistical Analysis Plan Version 3 
 
 
CONFIDENTIAL 
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SPONSOR APPROVAL 
A DOSE-RANGING STUDY OF THE EFFICACY AND SAFETY 
OF BARDOXOLONE METHYL IN PATIENTS WITH 
PULMONARY ARTERIAL HYPERTENSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
1. 
INTRODUCTION ......................................................................................................................................... 6 
1.1 
Study Objectives ............................................................................................................................... 7 
1.1.1 
Primary Objectives .......................................................................................................... 7 
1.1.2 
Secondary Objectives ...................................................................................................... 7 
1.2 
Endpoints .......................................................................................................................................... 7 
1.2.1 
Primary Efficacy Endpoint .............................................................................................. 7 
1.2.2 
Exploratory Endpoints ..................................................................................................... 7 
1.2.3 
Pharmacokinetic Endpoints ............................................................................................. 9 
1.2.4 
Safety Endpoints ............................................................................................................. 9 
1.3 
Determination of Sample Size ........................................................................................................... 9 
1.4 
Study Cohorts .................................................................................................................................... 9 
1.5 
Timing of Analysis .......................................................................................................................... 10 
1.5.1 
Protocol Safety Review Committee .............................................................................. 10 
1.5.2 
Part 1 (placebo-controlled period) Results .................................................................... 10 
1.5.3 
Part 2 (extension period) Results ................................................................................... 10 
1.6 
Changes from Protocol .................................................................................................................... 10 
2. 
STUDY CONDUCT .................................................................................................................................... 11 
2.1 
Randomization ................................................................................................................................ 11 
2.2 
Data Monitoring .............................................................................................................................. 11 
2.3 
Data Sources ................................................................................................................................... 11 
3. 
STATISTICAL METHODS ........................................................................................................................ 12 
3.1 
Analysis Populations ....................................................................................................................... 12 
3.1.1 
Intent-to-treat (ITT) Population ..................................................................................... 12 
3.1.2 
Modified Intent-to-treat (mITT) Population .................................................................. 12 
3.1.3 
Safety Population .......................................................................................................... 13 
3.2 
Analysis of Study Conduct .............................................................................................................. 14 
3.3 
Analysis of Treatment Group Comparability .................................................................................. 14 
3.4 
Analysis of Part 1 ............................................................................................................................ 14 
3.4.1 
Exposure of Study Medication and Patient Adherence ................................................. 14 
3.4.2 
Concomitant Medications .............................................................................................. 15 
3.4.3 
Efficacy Analysis .......................................................................................................... 15 
3.4.4 
Safety Analysis .............................................................................................................. 21 
3.5 
Analysis of Part 2 ............................................................................................................................ 24 
3.5.1 
Patient characteristics and exposure .............................................................................. 25 
3.5.2 
Concomitant Medications .............................................................................................. 25 


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3.5.3 
Efficacy ......................................................................................................................... 25 
3.5.4 
Safety............................................................................................................................. 26 
3.6 
Pharmacokinetic Analysis ............................................................................................................... 26 
3.7 
Missing and Partial Data ................................................................................................................. 26 
3.7.1 
Analysis Windows for Part 1 ......................................................................................... 26 
3.7.2 
Analysis Windows for Part 2 ......................................................................................... 27 
3.7.3 
Analysis Windows for Unscheduled and End of Treatment Visits (Part 1) .................. 28 
4. 
REFERENCES ............................................................................................................................................ 29 
5. 
APPENDICES ............................................................................................................................................. 30 
5.1 
Appendix A: Ambulatory Blood Pressure Monitoring (ABPM) ..................................................... 30 
5.2 
Appendix B: Listing of Tables Included for Part 2 Analysis .......................................................... 31 
5.3 
Appendix C: Imputation Rules for Missing Dates .......................................................................... 32 
 
 
 
 


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Rationale for Version 3.0 
The changes from Version 2.0 to Version 3.0 of the Statistical Analysis Plan were motivated by 
additional protocol amendments subsequent to the finalization of Version 1 of the SAP. Version 
2 was finalized 24 Sept 2015 under protocol Version 5, which included larger expansion cohorts 
which would be the focus of efficacy analyses. The protocol has been amended two times since 
Version 2 of the SAP (Protocol Version 6, 01 Jun 2016, and Protocol Version 7, 26 Jan 2017).  
Additional modifications were made to provide clarity to the statistical methods used in the 
planned analysis. 
In general, the notable modifications include: 
 
• Clarification of a modified Intent-to-Treat subset of patients to exclude patients without 
sufficient treatment or who have no post-baseline data for the primary endpoint, patients 
who did not have at least 28 doses of study treatment, or who had a heart or lung 
transplant over the course of the 16 week study 
• Clarify that the primary object of this study is to identify appropriate doses to be used for 
further study, and that this will be done through assessing the totality of data rather than a 
single endpoint 
• Provide more guidance associated with the methods used in the primary efficacy analysis 
• Specify the pooling strategy for the primary analysis 
• Specify additional subgroup analyses of 6MWD 
• Updated visit windows for unscheduled and end of treatment visits 
• Added visit windows for unscheduled and end of treatment visits in Part 2 
• Updated appendices to only include information not found in external documentation  
• Added specifications for calculating estimated glomerular filtration rate (eGFR) 
 
 








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1.6.4 Pharmacokinetic Endpoints 
Analysis of PK data will be described in a separate PK analysis plan and presented in a 
standalone PK report. 
1.6.5 Safety Endpoints 
The safety endpoints include frequency, intensity, and relationship to study drug of adverse 
events and serious adverse events, concomitant medications, and change from baseline in the 
following assessments: 
• Physical examinations; 
• Vital sign measurements; 
• 24-hour ambulatory blood pressure monitoring (ABPM); 
• 12-lead electrocardiograms; 
• Clinical laboratory measurements; 
• Weight. 
1.7 
Determination of Sample Size 
A sample size of 8 patients randomized at a 3:1 (bardoxolone methyl : placebo) assignment ratio 
in each dose level within cohort includes 6 patients treated with bardoxolone methyl for 
identification of gross safety signals. A small number of patients at each dose is not expected to 
fully characterize safety, therefore issues of concern identified in only 1 of 6 patients (16%) 
treated with bardoxolone methyl may suggest the need to collect additional information before 
escalating the dose, by either adding more patients at the current dose level or a lower dose as 
determined by the PSRC. Each additional dose level enrolled at selected doses adds 6 more 
patients treated with bardoxolone methyl to further characterize safety, tolerability, and efficacy. 
 
 
 
 
 
 
 
All eligible patients from Part 1 will be included in Part 2, and no new patients will be 
randomized to Part 2 of the study. 
1.8 
Study Cohorts 
As described in Section 1, this study includes 2 cohorts in the dose-ranging phase and 6 sub-
cohorts (within 2 overarching cohorts) in the dose-titration phase.  Analyses described in this 
SAP may be performed separately by cohort.  The Part 1 and Part 2 safety and efficacy analyses 
will be summarized by randomized treatment, pooling all placebo patients and all active patients 
into various subgroups: 
• 
All PAH patients (Cohorts 1, 2, 3a, and 3b patients) 
• 
All CTD-PAH patients (CTD-PAH patients in Cohorts 1, 2, and 3a) 


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• 
All Non-CTD PAH patients (Non-CTD PAH patients in Cohorts 1, 2, and 3b) 
• 
All PH patients (Cohorts 4a, 4b, 4c, 4d)  
In addition to the subgroups listed above, the eGFR, six-minute walk test, and pulmonary 
function testing results will be summarized by individual cohort.  
All patients enrolled in the study will follow the same schedule of assessments, including a 
placebo-controlled period (Part 1) followed by an extension period (Part 2). 
1.9 
Timing of Analysis 
Analyses of Part 1 and Part 2 may be performed as data accumulate to allow for planning of 
future studies. Timing of analyses will be determined solely by the Sponsor. As this is an 
exploratory study, no statistical adjustments will be made for repeating an analysis. 
1.9.2 Protocol Safety Review Committee 
A Protocol Safety Review Committee (PSRC) will assess the starting dose and each new dose 
level of bardoxolone methyl for safety and tolerability based on review of all available data for 
this study at the time of each review.  PSRC reviews will occur after the Week 4 data are 
available for the first eight patients enrolled at each new dose level combined across both the 
≤ 450 m and > 450 m cohorts.  
1.9.3 Part 1 (placebo-controlled period) Results 
For a particular cohort, the primary analysis of Part 1 will be performed after all patients enrolled 
in that cohort have completed Part 1. 
1.9.4 Part 2 (extension period) Results 
In addition to the final reporting of Part 2 data for each cohort, analysis of Part 2 data will be 
performed for regulatory interactions as determined by the Sponsor. The final analysis of Part 2 
data for a particular cohort will be performed after all enrolled patients complete their last Part 2 
visit. 
1.10 Changes from Protocol 
The primary efficacy endpoint was defined in Version 1 of the protocol as change from baseline 
in 6MWD at Week 16.  The primary objective of this longitudinal phase 2 study is to identify the 
appropriate dose range for further study of bardoxolone methyl in PAH patients.  Each dose level 
includes 6 active and 2 placebo patients within each cohort.  Therefore, to maximize the 
information attained from each patient in the estimate of treatment effect on an endpoint known 
to have large variability, the primary efficacy endpoint was modified.  The original endpoint as 
defined in the protocol (i.e., treatment effect at Week 16) will also be estimated, along with 
estimates at other timepoints.  The totality of the results will be considered in dose range 
selection for future studies. 
Quality of life, oxygen use and pulse oximetry were not defined in the protocol as exploratory 
endpoints. These four endpoints will be analyzed using approaches described later in this SAP.  


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2. STUDY CONDUCT 
2.1 
Randomization 
Eligible patients in Cohorts 1 and 2 will be assigned a dose cohort type based on baseline 
6MWD, as described in the study design section in the protocol.  Eligible patients in Cohorts 
3and 4 will be assigned a dose cohort type based on PAH etiology, as described in the study 
design section in the protocol.  Based on the determined cohort, patients will be randomized to 
bardoxolone methyl or placebo for Part 1 of the study according to the treatment assignment 
regimen. 
In this double-blind study, all patients, investigators, site personnel, laboratories and central 
readers with direct involvement in the conduct of the study and their designees will be blinded to 
treatment assignments. Appropriate measures will be taken to ensure the blind is maintained for 
the patients and personnel mentioned previously to reduce potential bias. To maintain the blind, 
investigators will distribute blinded study drug kits to patients as directed by the IWRS system. 
Treatment assignments will be managed by an IWRS system. The only people with direct access 
to treatment assignments will be those individuals who develop and maintain the randomization 
code, the individuals involved in the implementation and operation of the IWRS system, and the 
PSRC. Some Sponsor personnel will be unblinded to individual treatment assignments. 
Upon starting Part 2 of the study (i.e., the extension phase) all patients will receive bardoxolone 
methyl. 
2.2 
Data Monitoring 
Refer to the PSRC plan for details around the timing and conduct of PSRC meetings. The PSRC 
will be used to evaluate interim analysis results and to determine dose escalation. All 
summaries/analyses by treatment arm for the PSRC review will be prepared by an Independent 
Data Coordinating Center (IDCC) 
. During the study the PSRC will review, 
in an unblinded manner, available safety data through at least Week 4 for all patients in each 
recently opened cohort and available data from prior cohorts in order to determine if escalation 
to the next highest dose is warranted. 
2.3 
Data Sources 
Refer to the data management plan for Electronic Case Report Form (eCRF) data specifications 
and the non-eCRF guidelines for details around data sources external to the eCRF. All data 
collected in the eCRF and external data sources will be presented in by-patient data listings. 


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3. STATISTICAL METHODS 
The analyses outlined in this SAP will supersede those specified in the protocol for the purpose 
of a regulatory filing. 
Screen failure patients will be summarized by reason for screen failure. Screen failure patients 
will not be included in any other analyses described in this document.  Statistical methods in 
study Part 1 (Section 3.4) and study Part 2 (Section 3.5) are described separately. 
All analyses will be presented by cohort. There are no pre-planned analyses to combine same 
dose levels across multiple cohorts. Titration cohorts (cohort 3 and cohort 4) will not examine 
individual dose levels.  Summaries of titration cohorts will be grouped according to the 
randomized treatment: bardoxolone methyl or placebo.   
3.1 
Analysis Populations 
Populations for primary analyses of efficacy and safety from Part 1 of the study are described 
below. Based on results of the primary analyses, additional populations for sensitivity analyses 
may be performed as post-hoc analyses.  
3.1.2 Intent-to-treat (ITT) Population 
The ITT population includes all randomized patients. The ITT analysis will be done by 
randomized treatment, pooling all placebo patients within each cohort.  No data will be imputed 
for ITT analyses. The ITT population will be used for analyses of exploratory endpoints except 
6MWD.  The ITT analysis will be summarized by randomized treatment, pooling all placebo 
patients and all active patients into various subgroups: 
• All PAH patients (Cohorts 1, 2, 3a, and 3b patients) 
• All CTD-PAH patients (CTD-PAH patients in Cohorts 1, 2, and 3a) 
• All Non-CTD PAH patients (Non-CTD PAH patients in Cohorts 1, 2, and 3b) 
• All PH patients (Cohorts 4a, 4b, 4c, 4d) 
In addition to the subgroups listed above, the eGFR and pulmonary function testing results will 
be summarized by individual cohort.  
All 6MWD analyses will use the mITT population. 
3.1.3 Modified Intent-to-treat (mITT) Population 
The purpose of this Phase 2 study is to estimate the treatment effect of bardoxolone methyl on 
6MWD in patients with PAH, and to identify an appropriate dose for further development.  
Estimated treatment effect from this study will be used to power future trials of bardoxolone 
methyl in PAH patients.     
The mITT population will include all randomized patients who received at least 28 doses of 
study treatment, did not undergo heart or lung transplantation during the treatment period, and 
performed at least one post-baseline 6MWT assessment. The primary population for efficacy 
analyses of the primary endpoint will be the mITT population. The mITT analysis will be done 
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Since treatment effect is expected to be observed within the first few weeks of treatment and 
sustained over time, missing data will be imputed using last observation carried forward (LOCF) 
for mITT analyses.  Missing data will only be imputed for the 6MWD analysis. 
3.1.4 Safety Population 
The safety population includes all randomized patients who were dispensed any dose of study 
drug during the study treatment period.  Patients who received one or more doses of bardoxolone 
methyl will be assigned to the corresponding bardoxolone methyl treatment arm even if it was 
given in error. If a patient is dispensed bardoxolone methyl at more than one dose, the patient 
will be included in the safety population at the highest dose dispensed.  All safety data will be 
analyzed for the safety population according to the medication actually dispensed. 
 


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3.2 
Analysis of Study Conduct 
Study enrollment, study treatment exposure and compliance, reasons for study termination will 
be summarized by treatment arm for all randomized patients within each cohort. Major protocol 
deviations, including violations of inclusion/exclusion criteria, based on information captured in 
the eCRFs will be reported and summarized by treatment arm.  Any inclusion/exclusion 
violations will be listed separately, and will only be summarized if it is considered a major 
protocol deviation. 
3.3 
Analysis of Treatment Group Comparability 
Demographic information (age, sex, ethnicity, race), baseline characteristics (baseline BMI, 
weight) and baseline disease characteristics (including PAH classification and details, time since 
diagnosis, baseline PAH concomitant medications, thromboembolic disease assessment, 
pulmonary function testing, oxygen use during 6MWTs and available baseline right heart 
catheterization data) will be summarized by treatment arm for all randomized patients.  
Descriptive baseline summaries of continuous data will present the group mean, standard 
deviation, median, minima, and maxima. Descriptive summaries of discrete data will present the 
category counts as frequencies and percentages.   
Unless otherwise stated, the baseline value of any variable will be defined as the last available 
value recorded prior to the first administration of bardoxolone methyl/placebo. Missing values 
will not be imputed, unless otherwise noted, and will be tabulated as missing. 
3.4 
Analysis of Part 1 
Part 1 data will be analyzed using the analysis populations defined in Section 3.1. Separate 
analyses will be performed by each cohort.  Part 1 analyses will only include data from the 
placebo controlled portion of the study.  If a subject does not complete Part 1, or chooses not to 
enter Part 2, then all their data will be used in Part 1.  If a subject enters Part 2, then all data up to 
and including the Week 16 visit will be included in Part 1. 
3.4.2 Exposure of Study Medication and Patient Adherence 
Patient disposition, study treatment exposure, and compliance will be summarized for each 
treatment arm with descriptive statistics.  
The overall exposure (days) is calculated as [(Week 16 visit date ) – (date of first dose)  + 1].   
If a subject discontinues treatment prior to Week 16, the date of last dose will be used for 
calculating overall exposure. 
Each study drug kit contains 4 bottles (Bottle A, B, C, D).  Each bottle contains 30 capsules at 
the time of dispensing, and the number of capsules remaining in each bottle is recorded in the 
drug return CRF.  Administered doses will be estimated for each bottle based on the number of 
capsules dispensed minus the number returned.  The compliance is calculated for each bottle 
(bottle ‘X’) as:  [((Total number of kits dispensed in Part 1) x 30) – (Total Bottle ‘X’ capsules 
returned)] / (Study part exposure days) 
For the disposition summary, a patient who completes part 1 is defined as any patient who 
completes the Week 16 visit while taking study treatment (i.e., end-of-treatment page is blank or 
date of last dose is within 2 weeks before Week 16 visit date). 
 


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3.4.3 Concomitant Medications 
The WHO Drug Dictionary will be used to classify all medications recorded during this study. 
Medications taken from 28 days prior to the administration of the first dose of bardoxolone 
methyl/placebo through the final follow-up visit will be recorded in the concomitant medication 
forms. The numbers and percentages of patients who had taken any baseline concomitant 
medications (i.e., start date on or before study Day 1 and stop date after Day 1) will be 
summarized by medication for each treatment arm. The numbers and percentages of patients who 
had started taking any post-baseline concomitant medications during Part 1 (i.e., start date after 
study Day 1 through Week 16) will be summarized by medication for each treatment arm.  Study 
medications with start date after Week 16 will be excluded from the Part 1 summaries of 
concomitant medications, unless the patient did not continue into Part 2.   
In the presence of partial dates, the available data (month and/or year) will be compared to the 
appropriate study reference dates to identify the most likely study period. 
3.4.4 Efficacy Analysis 
Analysis of the 6MWD will be performed using the mITT analysis set on all available data.  
Missing 6MWD data in Part 1 will be imputed using LOCF as described in Section 3.1.2. No 
imputation will be performed for missing 6MWD data in Part 2. 
The CRF nominal study visits (i.e., Week 4, Week 8, Week 12, and Week 16) will be used for all 
6MWT efficacy analyses. For subjects that prematurely discontinue treatment before Week 16 
with a 6MWT recorded at the End of Treatment (EOT) assessment, that EOT 6MWD will be 
used in analysis for the nominal protocol visit most closely matching the subject’s visit schedule. 
For all other efficacy analyses, the value closest to the target study day should be used (Section 
3.7.2). In Part 1, LOCF will be applied to impute missing 6MWD values after analysis values are 
obtained taking into consideration the End of Treatment assessment, if applicable. For all other 
efficacy variables besides 6MWD, LOCF should not be used, and no imputation for missing data 
should be performed.  
Analysis will pool all active doses within cohort for comparison with placebo in Part 1.   
The analyses will be repeated for subgroups defined by PAH etiology in Part 1 (i.e., connective 
tissue disease vs non-connective tissue disease). 
Given the exploratory nature of this study, sensitivity analysis may be performed in an ad hoc 
manner. 
Plots will be generated to summarize 6MWT results by randomized treatment, pooling all 
placebo patients and all active patients into various subgroups: 
• 
All PAH patients (Cohorts 1, 2, 3a, and 3b patients) 
• 
All CTD-PAH patients (CTD-PAH patients in Cohorts 1, 2, and 3a) 
• 
All Non-CTD PAH patients (Non-CTD PAH patients in Cohorts 1, 2, and 3b) 
• 
All PH patients (Cohorts 4a, 4b, 4c, 4d)  
 


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3.4.4.1 Primary Efficacy Endpoint 
The primary measure of efficacy is the overall treatment effect across Week 4, Week 8, Week 
12, and Week 16 for change from baseline in exercise capacity, as measured by the 6MWD, for 
bardoxolone methyl compared to placebo. The difference in mean overall change from baseline 
through Week 16 (active – placebo) will be used to assess the effect of bardoxolone methyl on 
6MWD in patients with PAH.  A lower 6MWD reflects greater PAH severity thus, a positive 
change from baseline suggests an improvement.   
As supportive analysis to the primary endpoint, the mean change from baseline and treatment 
differences will be estimated for each visit. The actual values and changes from baseline in 
6MWD will be summarized using descriptive statistics at each scheduled visit. Walk distances 
collected at any duration other than 6 minutes will not be included in the analysis of 6MWD 
unless the reason for not walking 6 minutes is one listed in the ATS guidelines as a reason for 
stopping the test immediately (i.e., chest pain, intolerable dyspnea, leg cramps, staggering, 
diaphoresis, and pale or ashen appearance).   
Baseline for 6MWD will be the average of scheduled predose assessments (e.g., Screen A and 
Day 1) collected prior to the first administration of study drug. Similarly, two 6MWD 
measurements collected at Week 4 and again at Week 16.  Multiple measures are within the 
Week 4 and Week 16 visits, and the 6MWD value used as at these visits is the calculated average 
within these visits. 
The mean overall treatment effect across all visits for change from baseline in 6MWD will be 
estimated and compared with placebo through 16 weeks of treatment by mixed-model repeated 
measures (MMRM), with treatment group, visit, and the interaction between treatment and visit 
as fixed factors. Visits at Weeks 4, 8, 12, and 16 will be used. A compound symmetry covariance 
matrix will be assumed. Point estimates and 95% confidence intervals for the mean change from 
baseline for each treatment as well as the treatment difference (active-placebo) will be provided 
overall and at each protocol scheduled timepoint. 
Separate mixed models will be used to compare (1) pooled bardoxolone methyl doses with 
placebo and (2) individual dose levels with placebo.  The first model contains two treatment 
groups with data at four timepoints. Example SAS code to obtain estimated treatment differences 
is provided below. 
Proc Mixed data=x order=data; 
  
Class usubjid trt week; 
  
model cfb =  trt week trt*week /s; 
  
repeated week / sub = usubjid type = cs; 
 
Lsmeans trt / diff cl; 
 
Lsmeans trt*week / diff cl; 
Run; 
SAS ODS output datasets (DIFFS and LSMEANS) can be used to obtain estimated treatment 
differences overall and at each week.   
If the Pearson correlation between baseline BMI and Week 16 change from baseline 6MWD is 
significant, then baseline BMI will be included as a covariate. Baseline BMI is defined as the last 
non-missing observation prior to initial dose. Baseline BMI should only be used as a covariate if 


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the p-value between Week 16 change from baseline 6MWD and baseline BMI is <0.05. Example 
SAS code to obtain correlation coefficients and p-values is provided below:  
proc corr data=x pearson; 
where visit='Week 16'; 
var bmi cfb; 
ods output PearsonCorr = bmi_corr; 
run; 
Modifications to contrast statements will be required for the model containing individual dose 
levels. However, ODS output datasets may also be used without modification of SAS code. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.4.5 Safety Analysis 
Safety data will be summarized using the safety population.  Missing data will not be imputed 
for safety analyses. With the exception of adverse events, safety results will be summarized by 
the CRF nominal study visits (i.e., Week 1, Week 2, Week 4, Week 8, Week 12, and Week 16). 
For subjects that prematurely discontinue treatment before Week 16 with an End of Treatment 
(EOT) assessment, that EOT will be used in analysis for the nominal protocol visit most closely 
matching the subject’s visit schedule. Similarly, for patients with safety results at an unscheduled 
visit that unscheduled visit will be used in analysis for the nominal protocol visit most closely 
matching the subject’s visit schedule. For all safety listings except adverse events, if a safety 
result does not fall within a scheduled visit window, that result will be included in the safety 
listings but not the safety table summaries.  
Moreover, if retest values are available, all safety analyses should use the results closest to the 
target study day (e.g., Day 28 for Week 4, Day 56 for Week 8, etc.). If two values are equidistant 
from the target study day, the earliest of those values will be used in all safety analyses.  
3.4.5.1 Part 1 Treatment Emergent Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used to classify 
all adverse events reported during the study by system organ class (SOC) and preferred term 


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(PT). Analysis of treatment-emergent adverse events from Part 1 (Part 1 TEAE) will include all 
new or worsening adverse events with date of onset during or after the date of first study drug 
administration through the end of Part 1.  Part 1 TEAE summaries will exclude adverse events 
with date of onset after the Week 16 visit date or date of onset more than 30 days after the date 
of last study drug administration for patients who discontinue treatment.   Part 2 TEAE 
summaries will exclude adverse events with date of onset more than 30 days after the date of last 
study drug administration for patients who discontinue treatment.   Adverse events will be 
summarized by SOC and PT. Tables and listings will summarize adverse events occurring in Part 
1 and 2 separately. Drug-related AEs, SAEs, and serious drug-related AEs will be summarized 
accordingly. Multiple occurrences of the same event will be counted once for each patient at the 
level of SOC and the level of PT. 
Adverse events by SOC, PT, and severity will also be summarized.  Multiple occurrences of the 
same event will be counted once for each patient by preferred term under the highest severity. 
In the presence of partial dates, the available data (month and/or year) will be compared to the 
appropriate study reference dates to identify the most likely study period. 
3.4.5.2 Laboratory Data 
Laboratory test results include clinical chemistry, hematology, and urinalysis. Continuous lab 
data, including actual values and changes from baseline, will be summarized using descriptive 
statistics (including mean, standard deviation, quartiles, median, minima and maxima) for 
chemistry and hematology parameters. If the scheduled assessment is missing, use the recheck 
measurement closest in time to scheduled visit (if available). 
If a Day 1 laboratory collection occurred after the first dose of study drug, that lab value should 
not be used as the baseline lab value. The baseline lab value is the last laboratory value collected 
before study drug administration. 
Shift tables will be provided to assess changes from normal to abnormal shifts from baseline to 
Week 16 for chemistry and hematology parameters.  
3.4.5.3 Estimated Glomerular Filtration Rate  
For calculation of the eGFR, the 4-variable MDRD equation must be used.  The equation is as 
follows: 
eGFR = 175 x standardized serum creatinine (mg/dL) –1.154 x age –0.203 x 1.212 [if black] x 
0.742 [if female] 
The patient’s age utilized in the eGFR calculation will be the age by visit listed in the laboratory 
dataset.  
For the eGFR analysis, the value closest to the target study day should be used (Section 3.7.2). 
Patients randomized to placebo and converted to bardoxolone methyl in Part 2 should use the 
Week 16 eGFR value as baseline.  
The eGFR analyses will not include eGFR values >=14 days after the patient’s last dose of 
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3.4.5.4 Physical Exam Data 
Physical examination data is collected as normal/abnormal categories at each time point by body 
system. Abnormal physical examinations will be listed by patient, body system and visit. 
3.4.5.5 Vital Sign Measurement 
Vital sign measurements include patient’s heart rate, respiration rate, and temperature, weight, 
BMI, and blood pressure (systolic and diastolic). Actual values and changes from baseline values 
for vital signs and weight will be summarized using descriptive statistics (including mean, 
standard deviation, quartiles, median, minima and maxima) by treatment group at all scheduled 
study visits. If the scheduled assessment is missing, use the recheck measurement closest in time 
to scheduled visit (if available). 
 


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3.4.5.6 24 Hour Ambulatory Blood Pressure Monitoring 
Systolic blood pressure, diastolic blood pressure, pulse pressure and heart rate are collected 
during the 24-hour ambulatory blood pressure monitoring (ABPM) 
 
. 
Actual values and changes from baseline values for these four parameters will be summarized 
using descriptive statistics (including mean, standard deviation, quartiles, median, minima, 
maxima, and 95% confidence interval) by treatment group at all scheduled study visits. If the 
scheduled assessment is missing, the recheck measurement closest in time to scheduled visit will 
be used (if available).  
The overall (24 hour) mean for each measure, the day time mean, and the night time mean will 
be summarized. Appendix A provides more detail of the planned analyses of the 24-hour ABPM 
data. 
3.4.5.7 ECG 
Actual values for the 12-lead ECGs collected at each visit and changes from baseline in ECG 
measures (i.e., RR, PR, QRS, QT/QTc interval) at post-baseline visits will be summarized. 
Additionally, frequency counts for ECG results (normal, abnormal not clinically significant, 
abnormal clinically significant, or unable to evaluate) will be summarized at each visit. If the 
scheduled assessment is missing, use the recheck measurement closest in time to scheduled visit 
(if available). 
3.5 
Analysis of Part 2 
All patients in Part 2 will receive an active dose of bardoxolone methyl.  Patients must be 
compliant with dosing and complete Part 1 according to the protocol to be eligible for 
continuation into the extension period (Part 2).  Therefore, separate populations for safety and 
efficacy will not be defined for Part 2 analyses. 
The Part 2 safety and efficacy analyses will be summarized by randomized treatment, pooling all 
placebo patients and all active patients into various subgroups: 
• 
All PAH patients (Cohorts 1, 2, 3a, and 3b patients) 
• 
All CTD-PAH patients (CTD-PAH patients in Cohorts 1, 2, and 3a) 
• 
All Non-CTD PAH patients (Non-CTD PAH patients in Cohorts 1, 2, and 3b) 
• 
All PH patients (Cohorts 4a, 4b, 4c, 4d)  
Due to the ongoing nature of this study, summary of Part 2 data will be strictly by patients 
initially randomized to active versus placebo patients that transition to active therapy.  The 
groups will be labeled as BARD or PBO-BARD. All patients randomized to an active dose of 
bardoxolone methyl in Part 1 will be summarized with the BARD group in Part 2 analyses.  All 
patients randomized to placebo in Part 1 will be summarized with the PBO-BARD group in Part 
2 analyses. 
Additional by-dose level results may be presented to explore long term trends by dose level, but 
will be included in an ad hoc manner. 


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3.5.2 Patient characteristics and exposure 
Demographics and baseline disease characteristics will be summarized for patients who continue 
into study Part 2. 
Exposure will be summarized using the Part 2 treatment groups (BARD, PBO-BARD) for the 
following: 
• Total time in Part 2: ([last dose date] – [Week 16 visit date] + 1)  
• Total time in study:  ([last dose date] – [first dose date] + 1) 
Discontinuations in Part 2 prior to study termination will be listed. 
3.5.3 Concomitant Medications 
The WHO Drug Dictionary will be used to classify all medications recorded during this study. 
The numbers and percentages of patients who had started taking any post-baseline concomitant 
medications during Part 1 (i.e., start date after study Day 1 through Week 16) or Part 2 will be 
summarized by medication for each treatment arm.   
In the presence of partial dates, the available data (month and/or year) will be compared to the 
appropriate study reference dates to identify the most likely study period. 
3.5.4 Efficacy 
Efficacy analyses described in Section 3.4.3 will not be performed on available data from Part 2.  
Instead, 6MWD will be summarized using descriptive statistics only (include 95% confidence 
interval for change from baseline at each visit) using the Part 2 treatment groups (BARD, PBO-
BARD)   Patients randomized to placebo and converted to bardoxolone methyl in Part 2 should 
use the Week 16 eGFR value as baseline. If the Week 16 eGFR lab collection occurs after the 
date and time of first dose at Week 16, then the closest value prior to Week 16 should be used as 
baseline for patients randomized to placebo and converted to bardoxolone methyl. No inferential 
statistics will be provided for Part 2 data and missing 6MWD will not be imputed in Part 2. 
3.5.4.1 Part 2 Changes from Baseline in 6MWD 
Due to the ongoing nature of this study, summary of Part 2 data will be strictly by patients 
initially randomized to active versus placebo patients that transition to active therapy.  The 
groups will be labeled as BARD or PBO-BARD. All patients randomized to an active dose of 
bardoxolone methyl in Part 1 will be summarized with the BARD group in Part 2 analyses.  All 
patients randomized to placebo in Part 1 will be summarized with the PBO-BARD group in Part 
2 analyses. 
In the Part 2 (open-label) portion of LARIAT, all active doses within a cohort will be pooled 
(including placebo patients randomized to active in Part 2). All active doses within a cohort, the 
BARD group, and PBO-BARD group will be compared to baseline 6MWD.  
Actual values and changes from baseline will be summarized using descriptive statistics 
(including mean, standard deviation, quartiles, median, minima and maxima). 
 


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3.5.5 Safety 
Safety analyses described in Section 3.4.4 will be performed on available safety data from Part 2 
using the Part 2 treatment groups (BARD, PBO-BARD).  Change from baseline summaries of 
safety described in 3.4.3 will include both change from baseline (Part 1) and change from the end 
of Part 1 (Week 16) for Part 2. 
Analyses of adverse events will count only Part 2 treatment-emergent adverse events (TEAEs), 
defined as new or worsened events after the Week 16 visit.  New or worsened events after Week 
16 visit are those events with an AE start date after the Week 16 study visit, or previously 
recorded AEs with an adverse change in severity (e.g., went from mild to moderate or moderate 
to serious) after the Week 16 study visit. Similarly, only new onset concomitant medications 
(date of first dose after the Week 16 visit) will be included in Part 2 summaries.   
Shift tables will be provided to assess changes from normal to abnormal shifts from Week 16 to 
each nominal visit for chemistry and hematology parameters.  
Additional details will be provided in the mock Tables, Listings, and Figures. 
3.6 
Pharmacokinetic Analysis 
A separate document contains details regarding the planned pharmacokinetic analyses. 
3.7 
Missing and Partial Data 
For the analysis of safety variables, partial dates may be imputed; otherwise, missing data will be 
treated simply as missing. However, if an AE onset date is missing, it will be imputed (see 
Appendix C). The algorithms for imputation of partial dates depend upon the parameter (see 
Appendix C). The central laboratory uses assays that have lower limits of detection (LLD). 
Continuous laboratory data results which are less than the lower limit of detection or above the 
upper limit of quantification will be imputed to the value of the lower or upper limit plus or 
minus one significant digit, respectively (e.g., if the result of a continuous laboratory test is < 20, 
a value of 19 will be assigned).  
Imputation for missing efficacy data (i.e., 6MWD) is described with the efficacy analysis 
Section 3.4.4. 
3.7.2 Analysis Windows for Part 1 
For all Part 1 analyses of 6MWD, scheduled visits will be used regardless of study day, as well 
as any unscheduled or end of treatment visits within the visit windows listed in  Section 3.7.4. If 
an unscheduled or EOT visit falls within the same window as a nominal study visit, the average 
of the two will be used. For subjects that prematurely discontinue treatment before Week 16 with 
a 6MWT recorded at the End of Treatment (EOT) assessment, that EOT 6MWD will be used in 
analysis for the nominal protocol visit most closely matching the subject’s visit schedule.   
For all other Part 1 efficacy and safety analyses, if multiple assessments fall within the same 
analysis visit, the assessment closest to the target study day specified in the protocol will be used. 
If two assessments are equidistant from a post-baseline target visit day, the earlier assessment 
will be used.  Visits that do not occur in all versions of the protocol (i.e., Week 6) should be 
treated as unscheduled assessments.  


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3.7.3 Analysis Windows for Part 2 
Part 2 assessments will be used in efficacy and safety analyses if the assessment was collected 
within the scheduled window below. Study day will be calculated for each assessment and 
compared to the protocol defined study day for each visit.  In general, analysis in Part 2 will be 
defined as follows: 
Table 1. Visit Windows in Part 2 
Analysis Visit 
Study Day 
Analysis Window 
Week 18 
126 
123 ≤ Study Day ≤ 132 
Week 20 
140 
133 ≤ Study Day ≤ 147 
Week 22 
154 
148 ≤ Study Day ≤ 161 
Week 24 
168 
162 ≤ Study Day ≤ 182 
Week 32 
224 
210 ≤ Study Day ≤ 238 
Week 56 and 
every 24 weeks 
thereafter 
392, every 168 
days thereafter 
Study Day – 14 days ≤ 
Study Day ≤ Study Day + 14 
days 
Records from unscheduled or end of treatment visits that do not fall within an analysis window 
will be listed, but will not be analyzed. For the 6MWT analysis, if use of the visit windows 
yields more than one value for a particular visit, the average of the two or more values will be 
used for analysis.  For all other analyses, including the eGFR and safety analyses, the value 
closest to the target study day should be used Visits that do not occur in all versions of the 
protocol (i.e., Part 2 visits past week 32 that were changed to phone visits) should be treated as 
unscheduled assessments. 
 


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3.7.4 Analysis Windows for Unscheduled and End of Treatment Visits (Part 1) 
Additionally, unscheduled assessments and end of treatment assessments will be used in efficacy 
and safety analyses if the unscheduled assessment was collected within the scheduled window 
below. Study day will be calculated for each unscheduled assessment and compared to the 
protocol defined study day for each visit.  In general, analysis windows for unscheduled and end 
of treatment visits in Part 1 will be defined as follows: 
Table 2. Visit Windows for Unscheduled and End of Treatment Visits in Part 1 
Analysis Visit 
Study Day 
Analysis Window 
Day 1 
1 
Study Day ≤1 
Week 1 
7 
2 ≤ Study Day ≤ 10 
Week 2 
14 
11 ≤ Study Day ≤ 20 
Week 4 
28 
21 ≤ Study Day ≤ 42 
Week 8 
56 
43 ≤ Study Day ≤ 70 
Week 12 
84 
71 ≤ Study Day  ≤ 98 
Week 16 
112 
99 ≤ Study Day ≤ 119 
Records from unscheduled or end of treatment visits that do not fall within an analysis window 
will be listed, but will not be analyzed. Per Section 3.4.4, for the 6MWT analysis, if use of the 
visit windows yields more than one value for a particular visit, the average of the two or more 
values will be used for analysis.  For all other analyses, including the eGFR and safety analyses, 
the value closest to the target study day should be used (Table 2). 
 


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4. REFERENCES 
1. QualityMetric Health Outcomes(tm) Scoring Software 
2. http://www2.sas.com/proceedings/sugi29/188-29.pdf 


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5. APPENDICES 
5.1 Appendix A: Ambulatory Blood Pressure Monitoring (ABPM) 
Throughout this section, “ambulatory blood pressure” refers to the systolic and diastolic 
pressures, pulse pressure, and heart rate as collected via 24-hour ABPM. If multiple 24-hour 
APBM collections occur for a nominal study visit, the last 24-hour APBM collection will be 
used in the analysis.  
Three ambulatory blood pressure parameters will be calculated for each patient using the 24-
hour ABPM data. 
1. A patient’s mean 24-hour ambulatory blood pressure is calculated as the average of all 
valid measurements taken from the patient’s ambulatory blood pressure monitoring 
device. 
2. A patient’s mean daytime ambulatory blood pressure is calculated as the average of all 
valid measurements taken from 6 am to 10 pm. 
3. A patient’s mean nighttime ambulatory blood pressure is calculated as the average of all 
valid measurements taken from 10 pm to 6 am next day. 
For a given 24-hour period average, the numerator is the sum of all valid ambulatory blood 
pressure measurements, while the denominator is the number of all valid blood pressure 
measurements.  
Using each of the three ambulatory blood pressure parameters (24-hour, daytime, nighttime) 
calculated for each patient, actual values and change from baseline values will be summarized 
descriptively by received study drug at all scheduled study visits for all four ambulatory blood 
pressure assessments (systolic blood pressure, diastolic blood pressure, pulse pressure, heart 
rate). Descriptive summaries will include confidence intervals for each treatment group as well 
as the difference between the treatment group’s means. Additionally, blood pressure analyses 
described in Section 5.1will be performed using the ABPM measurements. 
 


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5.2 Appendix B: Listing of Tables Included for Part 2 Analysis 
A subset of TLFs in Part 1 will be used in Part 2. Minor modifications are anticipated due to 
the combined dose levels (BARD vs PBO-BARD).  All TLFs in Part 2 will only include data 
associated with Part 2 of the study. No cumulative summaries or listings will be provided. 
Efficacy summaries that include a change from baseline will summarize both change from 
original baseline as well as change from Week 16. No inferential statistics will be provided for 
Part 2 data. 
 


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5.3 Appendix C: Imputation Rules for Missing Dates 
Incomplete diagnosis or treatment date  
• If day is missing, day will be set to 15th of the month.  
• If month and day are missing, month and day will be set to July 1st.  
• If year and month and day are missing, date will be set to missing.  
Adverse Event  
• If onset date is completely missing, onset date is set to date of first dose.  
• 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 31st.  
o If year > year of first dose, then set month and day to January 1st.  
• 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 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.  
 


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Concomitant Medications  
• If start date is completely missing, start date will not be imputed.  
• 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.  
• If year and month are present and day is missing, set day to 1st day of month.  
• If end date is completely missing, end date will not be imputed.  
• 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.