Clinical trial NCT03068130
Conditions: Pulmonary Hypertension
Keywords: Pulmonary Arterial Hypertension Pulmonary Hypertension PH PAH Bardoxolone methyl 6-minute walk distance CDDO-ME RTA 402 LARIAT CATALYST RANGER
Sponsor: Biogen
Start date: 2017-04-18; Completion date: 2020-09-30
Enrollment: 261 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in qualified patients with pulmonary hypertension (PH) who previously participated in controlled clinical studies with bardoxolone methyl.

Detailed description:
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in qualified patients with pulmonary hypertension (PH) who previously participated in controlled clinical studies with bardoxolone methyl.

Qualified patients will receive 10 mg of bardoxolone methyl once daily until the drug is available through commercial channels or until patient withdrawal, whichever is sooner. Dose de-escalation (down to 5 mg) is permitted during the study, if indicated clinically.

Arms: arm 1: Bardoxolone methyl will be administered orally once daily at 10 mg until it becomes commercially available. Dose de-escalation (down to 5 mg) is permitted during the study, if indicated clinically.
Interventions: intervention 1: Bardoxolone methyl
Intervention descriptions: intervention 1: Capsules of Bardoxolone methyl

Protocol documents:
SAP_004.pdf: 
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STATISTICAL ANALYSIS PLAN 
RANGER 
VERSION: 2.0 
DATE OF PLAN: 
05-Jun-2020 
 
BASED ON: 
 Protocol Version 3.0 (July 16, 2018)  
 
STUDY DRUG: 
RTA 402, BARDOXOLONE METHYL 
PROTOCOL NUMBER: 
402-C-1602 
STUDY TITLE: 
An Extended Access Program to Access Long-term Safety of Bardoxolone Methyl in Patients 
with Pulmonary Hypertension (“RANGER”) 
 
SPONSOR: 
Reata Pharmaceuticals, Inc. 
2801 Gateway Drive, Suite 150 
Irving, Texas 75063 
(972) 865-2219 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents.  
 


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SIGNATURE PAGE 
 
 
This document has been prepared and/or reviewed by: 
 
This document has been reviewed and accepted by: 
 
 
 
 




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Methodology: This extended access study assesses the long-term safety and tolerability of bardoxolone methyl in 
qualified patients with pulmonary hypertension (PH) who previously participated in controlled clinical studies 
with bardoxolone methyl.  
Qualified patients will start dosing at 10 mg of bardoxolone methyl every other day, then begin once daily dosing 
at Week 4 (unless contraindicated clinically) and continue until the drug is available through commercial 
channels (including reimbursement) or until patient withdrawal, whichever is sooner.  Dose de-escalation (down 
to 5 mg) is permitted during the study, if indicated clinically.    
All patients in the study follow the same visit and assessment schedule.  Patients are scheduled to be assessed in 
person during treatment at Day 1, Week 1, Week 2, Week 4, Week 6, Week 8, Week 24, and every 24 weeks 
thereafter.  Patients are also assessed by telephone contact on Days 3, 10, 21, 31, and 38.  Day 1 for this extended 
access study should occur on the same day as the last visit in the controlled clinical study.  Patient status should 
be carefully monitored by the investigator during the first 8 weeks of study treatment.  Assessments required for 
both the last visit in the controlled study and Day 1 for this study should only be completed once. 
Patients from the CATALYST study: 
Day 1 of this extended access study coincides with the Week 28 follow-up visit for patients from CATALYST 
(402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended access program is not yet open for 
enrollment at the time of a patient’s Week 28 visit, the Day 1 visit (i.e., enrollment) must occur within 30 days of 
site activation.  Exceptions allowing CATALYST patients who have completed 24 weeks of treatment to 
schedule their follow-up assessments prior to Week 28 and still be considered eligible for this open-label study 
should be discussed with the Chief Medical Officer at Reata, or designee, and will be considered on a case-by-
case basis.  
Patients from the LARIAT study:  
Day 1 of this extended access study coincides with the End-of-Study visit for patients from LARIAT (402-C-
1302, NCT02036970). 
Number of Subjects (planned and analyzed): Up to 366 (LARIAT (n ≤ 166); CATALYST (n≤ 200)) 
Diagnosis and main criteria for inclusion (see Protocol Section 8.1):  
Treatment-compliant patients who are participating in qualifying ongoing studies and have completed required 
End-of-Treatment and/or Follow-up visits in a prior clinical study with bardoxolone methyl.   
Test product, dose and mode of administration: 
Bardoxolone methyl capsule will be administered orally (every other day or once daily) at 10 mg until it becomes 
commercially available.  Dose de-escalation (down to 5 mg) is permitted during the study, if indicated clinically. 
Duration of treatment: Until the drug is available through commercial channels, or until patient withdrawal, 
whichever is sooner 
Reference therapy, dose and mode of administration: 
No reference therapy 
Criteria for evaluation (see Protocol Section 6.1): The objective is to provide continuing treatment with 
bardoxolone methyl as part of this extended access program while collecting ongoing safety and tolerability data 
of bardoxolone methyl.   
Statistical methods: The sample size for the RANGER is limited to the number of treatment-compliant patients 
having completed a qualifying clinical study with bardoxolone methyl (i.e., LARIAT or CATALYST).  The 
analysis population includes all enrolled patients (Safety Population).  Since the RANGER is an open-label 
design with no comparator group, all statistical analyses will be descriptive.  No statistical comparisons will be 
performed.  The study was terminated on March 30, 2020. If the treatment end date or study end date are missing, 
the date will be imputed as March 30, 2020. 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
TECHNICAL SUMMARY REPORT (TSR) ..................................................................................3 
1. 
LIST OF ABBREVIATIONS .......................................................................................9 
2. 
INTRODUCTION ......................................................................................................12 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................14 
3.1. 
Study Objectives .........................................................................................................14 
3.1.1. 
Primary Objective .......................................................................................................14 
3.2. 
Study Endpoints ..........................................................................................................14 
3.2.1. 
Primary Safety Endpoints: ..........................................................................................14 
4. 
STUDY DESIGN .......................................................................................................15 
4.1. 
Summary of Study Design ..........................................................................................15 
4.2. 
Definition of Study Drugs ..........................................................................................16 
4.3. 
Sample Size Considerations .......................................................................................16 
4.4. 
Randomization ............................................................................................................16 
4.5. 
Treatment Analysis Group Assignment ......................................................................16 
4.6. 
Clinical Assessments ..................................................................................................17 
5. 
PLANNED ANALYSES ............................................................................................20 
5.1. 
Planned Interim Analyses ...........................................................................................20 
5.2. 
Final Analyses and Reporting .....................................................................................20 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................21 
6.1. 
General Summary Table and Individual Subject Data Listing Considerations ..........21 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................21 
6.3. 
Analysis Populations ..................................................................................................21 
6.3.1. 
Enrolled Population ....................................................................................................22 
6.3.2. 
Safety Population ........................................................................................................22 
6.3.3. 
Subgroups ...................................................................................................................22 
6.4. 
Baseline Definition .....................................................................................................22 
6.5. 
Derived and Transformed Data ..................................................................................22 
6.5.1. 
Connective Tissue Disease (CTD) Etiology ...............................................................22 


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6.5.2. 
Baseline Age ...............................................................................................................23 
6.5.3. 
Study Day ...................................................................................................................23 
6.5.4. 
Change from Baseline .................................................................................................23 
6.5.5. 
Visit Windows ............................................................................................................23 
6.6. 
Handling of Missing Data ...........................................................................................24 
6.6.1. 
Missing Data ...............................................................................................................24 
6.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................24 
6.6.3. 
Missing Start and Stop Dates for Adverse Events ......................................................25 
6.6.4. 
Missing Treatment or Study End Date .......................................................................25 
7. 
STUDY POPULATION .............................................................................................26 
7.1. 
Screen Failures ............................................................................................................26 
7.2. 
Subjects Disposition ...................................................................................................26 
7.3. 
Demographic and Baseline Characteristics ................................................................26 
7.4. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................27 
7.5. 
Medical History and Medical Conditions Present at Entry ........................................27 
8. 
EFFICACY .................................................................................................................28 
8.1. 
6-Minute Walk Test ....................................................................................................28 
8.2. 
Borg Dyspnea Index ...................................................................................................28 
8.3. 
WHO/ NYHA Functional Class Assessment .............................................................28 
9. 
SAFETY AND TOLERABILITY ..............................................................................29 
9.1. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............29 
9.1.1. 
Missing and Partial AE Onset Dates ..........................................................................30 
9.1.2. 
Summaries of Adverse Events for Serious Adverse Events (SAE), Adverse 
Event Dropouts, and Death .........................................................................................30 
9.2. 
Exposure and Compliance ..........................................................................................31 
9.3. 
Concomitant and Other Medications ..........................................................................31 
9.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates ..........32 
9.4. 
Summaries of Laboratory Results ..............................................................................32 
9.5. 
Vital Signs ..................................................................................................................32 
9.6. 
Pregnancy ...................................................................................................................32 
10. 
PHARMACOKINETICS ...........................................................................................33 
11. 
CHANGES FROM PROTOCOL ...............................................................................34 
12. 
APPENDIX .................................................................................................................35 


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12.1. 
Programming Specifications .......................................................................................35 
12.2. 
World Health Organization Functional Assessment Classification ............................36 
 
 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................9 
Table 2: 
RANGER Schedule of Assessments ..........................................................................18 
Table 3: 
Analysis Visits ............................................................................................................24 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
AE 
Adverse Event 
ATC 
Anatomical/Therapeutic/Chemical 
ATS 
American Thoracic Society 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
bpm 
Beats per minute 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cm 
Centimeters 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTD 
Connective Tissue Disease 
DBP 
Diastolic blood pressure 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
ERA 
Endothelin Receptor Antagonist 
FC 
Functional Class 
FDA 
Food and Drug Administration (US) 
Hb 
Hemoglobin 


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HLT 
high level term 
hrs 
hours 
ICH 
International Conference on Harmonization 
ICH E9 
International Conference on Harmonization Tripartite Guideline for Good 
Clinical Practice E9 
IRB 
Institutional Review Board 
Kg 
Kilogram 
LLD 
lower Limit of Detection 
LOAEs 
late-onset AEs  
M 
meter 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
min 
minute 
mL 
milliliter 
mm 
millimeter 
mmHg 
millimeter of mercury 
N  
Total Sample Size 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
NYHA FC 
New York Heart Association Functional Classification 
PAH 
pulmonary arterial hypertension 
PH 
pulmonary hypertension 
PD5i 
Phosphodiesterase inhibitors 
pH 
potential of hydrogen 
PK 
Pharmacokinetic 
PT 
Preferred term 


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RTA 402 
BARDOXOLONE METHYL 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SR 
Sustained Release 
TBL 
Total bilirubin 
TEAE 
Treatment Emergent Adverse Events 
ULD 
Upper Limit of Detection 
US 
United States 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol 402-C-1602 (i.e., the 
RANGER trial). 
Protocol Revision Chronology: 
Protocol Version 1 
27-Oct-2016 
Original 
Amendment 1 
(Protocol version 2) 
05-Jan-2017 
• Clinical study manager and contact 
information is updated. 
• Estimated study date is updated. 
• Study schema figure is updated. 
• Weight in clinic collection is added at 
Week 24 and End of Study Visit. 
• Number of dispensed kits are updated. 
• Week 4 visit is made uniform for all 
countries. 
Amendment 2 
(Protocol version 3) 
16-Jul-2018 
• Visit Schedule is revised with additional 
monitoring during first 8 weeks. 
• Dose-titration scheme is changed with 
increased dosing at week 4. 
• Dose Regiment is revised. 
• Clinical chemistries and local chemistry 
are added throughout study. 
• Additional monitoring for fluid status is 
included during first 8 weeks of treatment. 
 
This SAP was developed in accordance with ICH E9 guideline.  All decisions regarding final 
analysis, as defined in this SAP document, will be made prior to the initial Database Lock of the 
study data.  Since the trial is an open-label study, analyses will be re-run based on subsequent 
database locks as needed for regulatory reporting and/or submissions so long as data continue to 
accrue.  Further information can be found in the protocol. 
The statistical analysis plan (SAP) is based on:  
• Protocol No. 402-C-1602 Extension, Version 3, dated July 16, 2018 
• ICH guidelines E4 and E9 (Statistical Principles for Clinical Trials)  


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This SAP describes the study populations, how variables are derived, how missing data are 
handled, and details concerning the statistical methods to be used to analyze the safety and 
efficacy data in the 402-C-1602 study.  Should the SAP and the protocol be inconsistent with 
respect to the planned analyses, the language of the SAP is governing. 
The SAP is finalized, approved by the Sponsor, and placed on file before the initial database 
lock.  This version of the SAP describes the analyses planned prior to the database lock.  Unless 
otherwise specified, these analyses are summarized in the clinical study report (CSR).  Any 
substantive changes made to the SAP after the database lock are clearly identified, and any 
analyses in addition to those specified in the SAP prior to the database lock are considered ad 
hoc.  The CSR will describe any deviations from the planned analyses. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
To provide continuing treatment with bardoxolone methyl as part of this extended access 
program while collecting ongoing safety and tolerability data of bardoxolone methyl. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Safety Endpoints:  
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious 
adverse events (SAEs) and change from baseline in the following assessments: physical 
examinations, vital sign measurements, BNP, N-terminal pro-brain natriuretic peptide 
(NT-proBNP), and weight. 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design  
RANGER examines the long-term safety and tolerability of bardoxolone methyl in qualified 
patients with pulmonary hypertension (PH) following completion of previously controlled 
clinical studies with bardoxolone methyl.  Patients and investigators are not unblinded to study 
treatment from previously controlled clinical studies upon entering the RANGER study.  
Qualified patients receive open label bardoxolone methyl (10 mg) every other day, then begin 
once daily dosing at Week 4 (unless contraindicated clinically) and continue until the drug is 
available through commercial channels or until patient withdrawal, whichever is sooner.  Dose 
de-escalation (down to 5 mg) is permitted during the study if indicated clinically.  Refer to 
Protocol Section 7.3.1 for additional details on dose de-escalation.   
All patients in RANGER follow the same visit and assessment schedule.  RANGER Day 1 is 
defined as the first day treatment is dispensed to the patient for this trial, following completion of 
previously controlled clinical studies.  All other RANGER visits are relative to RANGER Day 1.  
Patients are scheduled for in-person assessments during treatment in RANGER at Day 1, Week 
1, Week 2, Week 4, Week 6, Week 8, Week 24, and every 24 weeks thereafter.  Patients are also 
assessed by telephone contact on Days 3, 10, 21, 31, and 38.   
Since patients from previously controlled clinical studies will be followed continuously within 
the study (i.e., seamless rollover), eligibility for the RANGER study is assessed at the follow-up 
visit or End-of-Treatment visit and a separate screening visit is not required.   
Patients from the CATALYST study: 
Day 1 of this extended access study coincides with the Week 28 follow-up visit for patients from 
CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended access 
program is not yet open for enrollment at the time of a patient’s Week 28 visit, the Day 1 visit 
(i.e., enrollment) must occur within 30 days of site activation.  Exceptions allowing CATALYST 
patients who have completed 24 weeks of treatment to schedule their follow-up assessments 
prior to Week 28 and still be considered eligible for this open-label study should be discussed 
with the Chief Medical Officer at Reata, or designee, and are considered on a case-by-case basis.   
Patients from the LARIAT study: 
Day 1 of this extended access study coincides with the End-of-Treatment visit for patients from 
LARIAT (402-C-1302, NCT02036970).  Treatment-compliant patients who have completed Part 
2 (Week 32) of the study are eligible to continue receiving bardoxolone methyl through an 
extended access program (Study 402-C-1602).  Once bardoxolone methyl is available through 
the extended access program, LARIAT patients in Part 2 who have completed at least 32 weeks 
of the study complete an End of Treatment Visit.   


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RANGER Schema for Patients with Pulmonary Hypertension 
 
 
4.2. 
Definition of Study Drugs  
Capsules containing bardoxolone methyl at the 5 mg and 10 mg strength are used in this study. 
4.3. 
Sample Size Considerations 
The sample size for the RANGER study is limited to the number of patients having completed 
CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24) or LARIAT (402-C-
1302, NCT02036970).  The study is not powered to show efficacy or safety effects, and there is 
no placebo comparator in this open-label trial.  A maximum of 366 patients will be enrolled in 
this study, with 200 from CATALYST and 166 from LARIAT.  
4.4. 
Randomization 
This is the non-randomized, open-label study that includes patients who previously completed 
CATALYST or LARIAT.  As a result, no randomization or blinding is performed, and patients 
enrolled in the RANGER are assigned to bardoxolone methyl 10 mg. 
4.5. 
Treatment Analysis Group Assignment 
While the CATALYST is ongoing, prior treatment for those patients is considered blinded, and 
patients enrolling in RANGER from CATALYST are in the blinded-to-bardoxolone methyl 
treatment analysis group (i.e., “Blinded  BARD”).  Once the CATALYST trial is complete and 
unblinded, patients from CATALYST will be summarized according to their randomized 
treatment in CATALYST (i.e., “BARD  BARD” or “PBO  BARD”). 
Because patients in LARIAT received bardoxolone methyl treatment before enrolling in 
RANGER, all patients enrolling in RANGER from LARIAT are in the bardoxolone methyl study 
group in RANGER (i.e., “BARD  BARD”). 
Therefore, before CATALYST unblinding has occurred, the treatment analysis groups consistent 
of: 
1) Blinded  BARD: blinded patients receiving bardoxolone methyl (patients previously 
enrolled in CATALYST),  
2) BARD  BARD:  bardoxolone methyl patients (patients previously enrolled in 
LARIAT), and 
6-Minute Walk Test
T Telephone Contact
Dose-Titration
(10 mg BARD QOD)
W2
W1
W8
D1
D3
T
D10
T
D21
T
W4
Maintenance
(10 mg BARD QD)
D31
T
D38
T
W6
End of 
Study
W24,
Every 
24 WKs


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After CATALYST is complete and unblinding has occurred, the treatment analysis groups 
consistent of: 
1) PBO  BARD:  placebo-bardoxolone methyl (placebo patients previously enrolled in 
CATALYST),  
2) BARD  BARD:  bardoxolone methyl patients (patients previously enrolled in LARIAT 
and bardoxolone methyl patients previously enrolled in CATALYST)  
4.6. 
Clinical Assessments 
All patients in RANGER follow the same visit and assessment schedule.  RANGER Day 1 is 
defined as the first day treatment is dispensed to the patient for the RANGER, following 
completion of CATALYST or LARIAT.  All other RANGER visits are relative to RANGER 
Day 1.  Patients are scheduled for in-person assessments during treatment in the RANGER at 
Day 1, Week 1, Week 2, Week 4, Week 6, Week 8, Week 24, and every 24 weeks thereafter.  
Patients are also be assessed by telephone contact on Days 3, 10, 21, 31, and 38.   


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Table 2: 
RANGER Schedule of Assessments 
Study Week 
(Day) 
Assessment 
Day 1a 
Week 1  
(Phone) 
Day 3±2 
Week 1  
Day 7±3 
Week 2  
(Phone) 
Day 10±2 
Week 2 
Day 14±3 
Week 3 
(Phone) 
Day 21±2 
Week 4 
Day 28±3 
Week 4 
(Phone) 
Day 31±2 
Week 5  
(Phone) 
 Day 38±2 
Week 6 
Day 42±3 
Week 8 
Day 56±3 
Week 
24±3,  
Every 24 
Weeks  
End of  
Study 
 Visitb 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current background 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight at home 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight in clinic  
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Vital sign measurements 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Physical examination 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Pregnancy testd 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
 
Dispense study drug 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Collect study drug 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Telephone contact 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
Adverse event collection 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistriesf 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
BNP and/or NT-Pro BNP 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
6-min walk test 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
Dyspnea and fatigueg 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
WHO functional class 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro B-type natriuretic peptide; WHO, World Health Organization; AE, adverse event; 6MWT, 6-minute 
walk test 
a On Day 1, all procedures should be performed before study drug administration for patients who are treatment-compliant and have previously participated in clinical studies with 
bardoxolone methyl. 
b After the Week 24 visit, patients will continue to be assessed in person every 24 weeks until bardoxolone methyl becomes commercially available.  The End-of- Study visit 
should occur within 30 days after bardoxolone methyl becomes available through commercial channels.  Patients who will be discontinued from the study prior to commercial 
availability of bardoxolone methyl must also complete all End-of-Study assessments.  
c Day 1 assessments should be performed as part of End-of-Treatment or Follow-up visit procedures from a prior study with bardoxolone methyl.  


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d A serum pregnancy test will be performed 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 health authorities or IRBs/ECs.   
e AE assessments on Day 1 should be performed following study drug administration. 
f Clinical chemistries will be analyzed locally. 
g Dyspnea and fatigue must be assessed prior to beginning and immediately following completion of the 6MWT using the Borg scale. 
 


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5. 
PLANNED ANALYSES 
5.1. 
Planned Interim Analyses  
Interim analyses are based on locked data and performed as appropriate to support commercial 
approval of bardoxolone methyl.  A database lock plan will describe the details of each database 
lock.  All outputs identified in this SAP and planned for the final analysis will be prepared for 
each interim analysis, and an interim CSR will be prepared.   
At the time of each planned interim analysis, no individual patient’s data are considered fully 
locked; therefore, interim results are interpreted as preliminary. 
5.2. 
Final Analyses and Reporting 
All final, planned analyses identified in this SAP will be performed after the last patient has 
completed the study and the database has been locked.  A final CSR will be prepared based on 
the final analyses. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
Results will be summarized by the treatment analysis groups described in Section 4.5.   
Patient listings of all analysis data that support summary tables and figures are provided.    
Measurements from patients excluded from the pre-defined analysis sets are not included in 
summary tables unless specified otherwise, but they are included in the patient listings.  Missing 
data are not imputed, unless otherwise specified.  In general, patient listings are sorted by patient 
number and assessment date (time and parameter, as applicable).   
6.1. 
General Summary Table and Individual Subject Data Listing 
Considerations 
Results of statistical analyses are reported using summary tables, listings, and figures (TLFs).  
All TLFs will use ICH numbering conventions.  
Results will be pulled from RANGER analysis datasets. 
All analyses and summaries are produced using SAS® version 9.3 (or higher). 
6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Unless otherwise specified, descriptive statistics for continuous variables include the number of 
patients with data (N), mean, standard deviation (SD), median, minimum, and maximum.  The 
same number of decimal places as in the observed value are presented when reporting minimum 
and maximum; 1 more decimal place than in the observed value is generally presented when 
reporting mean; and 2 more decimal places than in the observed value are presented when 
reporting SD.  When calculating the minimum and maximum of average baseline values, the 
same number of decimal places as in the observed value will be presented when reporting 
minimum and maximum.  For imputed values and the average of baseline values, the average 
values will be rounded to the same number of decimal places as the source value. 
Categorical (qualitative) data are presented using frequency counts and percentages.  All 
percentages are rounded to 1 decimal place, unless otherwise specified.  Percentages equal to 100 
are presented as 100% and no percentages are presented for zero frequencies.  Where individual 
variable values are missing, summaries of categorical data are based on reduced denominators 
(i.e., only patients with available data are included in the denominators).  For summaries of AEs 
and concomitant medications, the percentages are based on the number of patients who received 
study drug within each summary group. 
6.3. 
Analysis Populations  
Analysis populations defined in this section pertain to patients enrolled in the RANGER portion 
of the trial. 


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6.3.1. 
Enrolled Population 
The enrolled population will include all enrolled patients, regardless of whether a patient took 
any dose of bardoxolone methyl.  A patient is considered enrolled if informed consent form is 
obtained.  The set of enrolled patients will be used for study population summaries. 
6.3.2. 
Safety Population 
The safety population includes all patients who received at least 1 dose of bardoxolone methyl.   
6.3.3. 
Subgroups 
The 6-minute walk test, Borg dyspnea index, and WHO/NYHA functional class assessment are 
summarized separately using the following subgroups: 
 Geographic location: US; Other 
 Sex: female; male  
• Race: (White, Non-White) 
• Ethnicity:  Non-Hispanic/Latino; Hispanic/Latino 
 CTD; non-CTD 
Safety summaries are summarized by CTD; non-CTD. 
6.4. 
Baseline Definition 
Last measurement on or prior to the date of first study drug administration is considered the 
RANGER Day 1 measurement for the calculation of baseline.  If a baseline value is missing, the 
last available value in the LARIAT or CATALYST study will be used as baseline. 
6.5. 
Derived and Transformed Data 
6.5.1. 
Connective Tissue Disease (CTD) Etiology 
Subgroups include summaries by CTD and non-CTD status.  In addition, baseline characteristics 
summaries include connective tissue disease (CTD) etiology (none, scleroderma, lupus, mixed, 
and other).  Patient’s etiology is derived from the baseline characteristics in the prior study in 
which he or she participated (LARIAT or CATALYST).  For patients participating in 
CATALYST or LARIAT, PH etiology values are the values recorded at the CATALYST or 
LARIAT Screening visit.    
Subject’s age in years will be calculated based on date of informed consent date using the 
following formula: 
Age (year) = FLOOR (date of informed consent – date of birth)/365.25*12) 
where FLOOR () function returns the integer part of the result. 


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6.5.2. 
Baseline Age 
Subject’s age in years is defined as the age at RANGER study consent (RANGER Day 1 for 
LARIAT patient, RANGER Day 1for CATALYST patient).  If no date of RANGER study 
consent is present, the age at RANGER Day 1 visit is used.  
Age (year) = Floor ((date of extension study consent – date of birth)/365.25) 
6.5.3. 
Study Day 
Study day is the day relative to the date of first study drug kit dispensation in RANGER study, 
which may precede the date of first dose of study drug.  Day 1 is defined as the date of study 
drug kit dispensation in RANGER study, unless otherwise specified for the calculation of 
baseline (Section 6.4).  
Assessments that occur after RANGER study drug dispensation but before the first study drug 
administration are considered to occur on study Day 1.  Assessments collected on the same date 
as the first date of study drug administration will be considered to occur before the first dose of 
study drug administration. 
For visits (or events) after the date of drug dispensing, day is calculated as: 
• Study day = visit (or event) date - date of drug dispense + 1 
For visits (or events) before the date of drug dispensing, day is calculated as: 
• Study day = visit (or event) date - date of drug dispense 
For listings (such as for adverse events) the quantity ‘days since first (or last dose)’ is defined as: 
• days since first (or last dose) = event date – date of first (or last dose) + 1  
For summaries that present distribution of time expressed in weeks and months, weeks will be 
defined as days divided by seven and months as days divided by 30.4. 
6.5.4. 
Change from Baseline 
Change from baseline is calculated using the baseline value (Section 6.4) and the value closest to 
the target study day, using the rules defined in Section 6.5.5. 
Change from baseline is calculated as (post-baseline result – baseline result). 
Percent change from baseline is calculated as (change from baseline/baseline result * 100). 
If either the baseline or the post-baseline result is missing, the change from baseline and/or 
percentage change from baseline is set to missing as well. 
6.5.5. 
Visit Windows 
Because clinical visits may occur outside protocol-specified windows, instead of relying on visit 
labels in the clinical database, analysis visits and their windows are defined using derived study 
day (Section 6.5.3).  Study day is calculated using the actual date for each scheduled and 
unscheduled assessment and compared to the target study day for each analysis visit.  Data 
analysis and summaries are based on the collection date that is closest to the protocol scheduled 
target study day (Table 3).   


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Table 3: 
Analysis Visits 
Analysis 
Visit 
Label 
Target Study 
Day 
Analysis Window 
0 
Day 1 
1 
1 
1 
Week 1 
7 
2 ≤ Study Day ≤ 10 
2 
Week 2 
14 
11 ≤ Study Day ≤ 21 
4 
Week 4 
28 
22 ≤ Study Day ≤ 35 
6 
Week 6 
42 
36 ≤ Study Day ≤ 49 
8 
Week 8 
56 
50 ≤ Study Day ≤ 70 
24 
Week 24 
168 
140 ≤ Study Day ≤ 196 
48 
Week 48 
336 
308 ≤ Study Day ≤ 364 
72 
Week 72 
504 
476 ≤ Study Day ≤ 532 
96 
Week 96 
672 
644 ≤ Study Day ≤ 700 
120, 144, 
etc. 
Week 120, Week 144, Every 
24 Weeks Thereafter 
Analysis Visit 
x 7 
([Analysis Visit x 7] -28) ≤ Study Day 
≤ ([Analysis Visit x 7] +28) 
FU 
Follow-up 
28 days after 
last dose 
14 ≤ Days after last dose ≤ 35 
 
The safety follow-up is based on days since last dose.  If more than one assessment exists during 
the follow-up after last dose, the one closest to 28 days following the date of the last study drug 
administration is used for analysis and summary. 
If a parameter is assessed or measured more than once within a visit window, the one that is 
closest to the protocol-scheduled time point (or target study day) is used for the purposes of data 
analysis and summary.  If two assessments are equidistant from a target study day, the earlier 
assessment is used.  If the visit used for analysis includes two assessments on the same day, the 
average of the two measurements will be used.  
Records from visits not closest to the target study day, and therefore not used in analyses, are 
presented in by-subject data listings. 
6.6. 
Handling of Missing Data 
6.6.1. 
Missing Data 
Missing data are not imputed. 
6.6.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
Missing start dates for concomitant medications are not imputed.   
Concomitant medications with incomplete end dates are considered concomitant medications if: 


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• Day and month are missing, and the year is equal to or after the year of the first date 
of study drug administration;  
• Day is missing and the year is after the year of the first date of study drug 
administration;  
• Day is missing and the year is equal to the year of the first date of study drug 
administration and the month is equal to or after the month of the first date of study 
drug administration; or 
• Year is missing. 
6.6.3. 
Missing Start and Stop Dates for Adverse Events  
Treatment-emergent adverse events (TEAEs) are events that either: 
• Had a date of onset on or after the date of the date of first dose of study drug and not 
more than 30 days after the date of the last dose of study drug, or  
• Had no recorded date of onset with a stop date after the first dose of study drug, or 
• Had no recorded date of onset or stop date. 
Adverse events with incomplete start dates are considered after the date of first dose if: 
• Day and month are missing, and the year is equal to or after the year of the first date 
of study drug administration;  
• Day is missing and the year is after the year of the first date of study drug 
administration;  
• Day is missing and the year is equal to the year of the first date of study drug 
administration and the month is equal to or after the month of the first date of study 
drug administration; or 
• Year is missing. 
Adverse events with incomplete start dates are considered on or within 30 days of last dose, if: 
• Day and month are missing, and the year is equal to or before the year of the date of 
last dose of study drug plus 30 days; 
• Day is missing and the year is equal to or before the year of the date of last dose of 
study drug plus 30 days, and month is equal to or before the month of the date of last 
dose of study drug plus 30 days; 
• Year is missing. 
6.6.4. 
Missing Treatment or Study End Date 
The study was terminated on March 30, 2020. If the treatment end date or study end date are 
missing, the date will be imputed as March 30, 2020. If the treatment end date or study end date 
are missing and no reason for treatment or study discontinuation are included in the CRF, the 
reason for treatment or study discontinuation will be study termination.  


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7. 
STUDY POPULATION 
Data are summarized for the safety population (Section 6.3.2).   
7.1. 
Screen Failures 
Screen failures are not summarized.  
7.2. 
Subjects Disposition 
A disposition summary includes the number and percentage of patients in the following 
categories: 
• Patients with prior participation in LARIAT 
• Patients with prior participation in CATALYST and randomized to placebo (only 
summarized when unbinding of CATALYST has occurred) 
• Patients with prior participation in CATALYST and randomized to bardoxolone 
methyl (only summarized when unblinding of CATALYST has occurred) 
• Continuing (or complete) treatment 
• Terminate from the study  
− Reason for terminating study 
Results will be summarized by analysis population (Section 6.3).  A listing of disposition is 
provided for all enrolled patients.   
7.3. 
Demographic and Baseline Characteristics 
Summaries of demographic and other baseline characteristics summaries are presented by 
treatment analysis group (Section 4.5) for all analysis populations.  Derivation of demographic 
and other baseline characteristics are described in Section 6.5. 
Demographic and other baseline characteristics include the following: 
• Age (years) at the date of informed consent  
• Sex: female; male  
• Race 
• Ethnicity:  Non-Hispanic/Latino; Hispanic/Latino 
• Weight, body mass index (BMI)  
• Geographic location: US; Other 
• Baseline disease characteristics (WHO functional class, baseline 6MWT)  
• Connective tissue disease (CTD) etiology (none, scleroderma, lupus, mixed, and 
other)  
• Number of background medications 


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• Background medication class (endothelin receptor antagonist, phosphodiesterase 
type-5 inhibitors, soluble guanylate cyclase, prostacyclins) 
− Background medications (e.g., ambrisentan, bosentan, riociguat, etc.) 
7.4. 
Listing of Subject Inclusion and Exclusion Criteria 
A listing of enrolled patients who did not meet inclusion or exclusion criteria is generated. 
7.5. 
Medical History and Medical Conditions Present at Entry 
Medical history is summarized by treatment analysis group (Section 4.5, as well as all patients 
combined).  For patients participating in CATALYST or LARIAT, medical history values are 
the values recorded at the CATALYST or LARIAT Screening visit.  Medical history is coded 
using MedDRA (Medical Dictionary for Regulatory Activities) version 19.0.  Medical history 
items are summarized by MedDRA SOC and PT.  Patient listings are also provided.   


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8. 
EFFICACY 
Analyses of 6MWT, Borg dyspnea scale include only summary statistics by visit window 
(Section 6.5.5) Summary statistics for observed values and change from baseline are presented.   
8.1. 
6-Minute Walk Test  
The change from baseline in 6MWT score is summarized by visit and treatment analysis group 
(Section 4.5).  Summary statistics for observed values and change from baseline are presented by 
visit window (Section 6.5.5).  Line plots of change from baseline of 6MWT by visit and 
treatment analysis group (including overall patients) are generated up to and including study 
Week 120. 
8.2. 
Borg Dyspnea Index 
The change in Dyspnea scale is summarized by visit and treatment analysis group (Section 4.5).  
Summary statistics for observed values and change from baseline are presented by visit window 
(Section 6.5.5).   
8.3. 
WHO/ NYHA Functional Class Assessment 
WHO functional class assessment values collected at each visit using the appropriate analysis 
windows (Section 6.5.5) will be used.  The number of patients in each class Section 12.2) is 
summarized at each analysis visit by treatment analysis group (Section 4.5).  The categorical 
summaries for shift from baseline to highest and lowest WHO/ NYHA Functional Class are 
presented.  The shift from baseline values includes WHO/ NYHA Functional Class I, II, III, IV 
and a category for missing data. 


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9. 
SAFETY AND TOLERABILITY 
Safety data (including AEs, vital signs, BNP, and NT-proBNP) are listed and summarized for 
patients in the safety population (Section 6.3.2) by treatment analysis group (Section 4.5).   
The analysis visit windows (Section 6.5.5) are used for all safety analyses.  Any results not 
included in summaries based on analysis visit window definitions are presented in data listings. 
9.1. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
AEs are summarized by treatment analysis group as defined by the safety analysis set.  General 
considerations for AE summaries and calculations are: 
• Multiple events by preferred term (PT) and system organ class (SOC) are counted 
once only per patient for each treatment analysis group. 
• For summaries by severity, only the most severe event is counted per patient for each 
treatment analysis group. 
• For summaries by relationship, for frequency counts by patient, only the most related 
event is counted per patient for each treatment analysis group. 
• An AE with a missing resolution date or incomplete date that is not identified as 
continuing is assumed to be continuing and no duration is calculated. 
• Only treatment-emergent adverse events (TEAEs) are included in summaries. 
AEs are coded using MedDRA (Medical Dictionary for Regulatory Activities) version 19.0.  In 
MedDRA, each verbatim term is mapped to a preferred term and high level term (HLT), which is 
then mapped to a system organ class.  Tables and listings present data at the SOC and PT level. 
Treatment-emergent adverse events (TEAEs) are events that either: 
• Had a date of onset on or after the date of the date of first dose in the RANGER study 
and not more than 30 days after the date of the last dose of study drug in the 
RANGER study, or  
• Had no recorded date of onset with a stop date after the first dose of study drug, or 
• Had no recorded date of onset or stop date. 
Adverse events with a date of onset in LARIAT or CATALYST that continued during the 
RANGER study are not considered TEAEs. 
In addition, adverse events which occurred >30 days after the date of last dose of study drug are 
listed as late-onset AEs (LOAEs).  These are adverse events that had a date of onset more than 
30 day after the date of the last dose of study drug.  
The investigator grades the severity of the AEs as mild, moderate, or severe as defined in the 
study protocol Section 11.5. 
Association or relatedness to the study medication are graded by the investigator according to 
criteria specified in Section 11.4 of the study protocol.  


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As defined in the protocol and captured on the CRF, a serious adverse event (SAE) is an adverse 
event that results in any of the following: 
• Death; 
• A life-threatening adverse drug experience; 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Results in a congenital anomaly or birth defect in an offspring of a patient taking 
study drug; 
• Is an important medical event. 
9.1.1. 
Missing and Partial AE Onset Dates 
Rules for handling missing partial AE Onset Dates are included in Section 6.6.3. 
9.1.2. 
Summaries of Adverse Events for Serious Adverse Events (SAE), Adverse Event 
Dropouts, and Death 
Treatment-emergent AEs are summarized by treatment analysis group at onset of the AEs.  For 
each treatment analysis group, SOC, and PT, the number and percentage of patients reporting an 
event are calculated.  For subgroups, the number and percentage of patients reporting an event 
within a subgroup are calculated.  In summary tables, SOC are presented alphabetically and 
events within SOC are presented by decreasing frequency count.  
Summary tables (number and percentage of patients) of AEs (by SOC and PT) are provided by 
treatment analysis group as follows: 
• All treatment-emergent AEs 
• All treatment-emergent related AEs (definitely, probably, or possibly related) 
• All treatment-emergent AEs by severity 
• All treatment-emergent serious adverse events (including deaths) 
• All related treatment-emergent serious adverse events (including deaths) 
• All treatment-emergent adverse events leading to permanent discontinuation of study 
drug. 
Listings are provided showing: 
• All AEs 
• Serious adverse events (including deaths) 
• AEs leading to discontinuation of study drug. 


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9.2. 
Exposure and Compliance 
The duration of study drug exposure is defined as the number of days on treatment analysis 
group from the first dose of study drug until the last dose of study drug 
(last dose - first dose + 1).  Study drug exposure is summarized by descriptive statistics.  
Summaries include the total dose (mg) received (based on the number of pills returned), study 
drug compliance, the number and percentage of patients receiving study drug by scheduled 
dispense visit (reference visit window table), and duration (days) of exposure during the study 
treatment period.   
In addition, a summary of the number and percentage of patients on bardoxolone methyl by visit 
and dose (5 mg, 10 mg) is generated.  
Total number of doses dispensed and total dose (mg) dispensed are calculated from total number 
of kits (bottles) recorded on the Study Drug Dispensation eCRF.  Total number of doses received 
are calculated from information on the eCRF of Study Drug Return and Study Drug 
Dispensation, as the total number of doses dispensed – total number of doses returned.  Study 
drug compliance (%) is calculated as 100 × total number of doses received / total number of 
doses dispensed.  For patients who remain on study treatment at the time of an interim or final 
data cut, the last kit dispensed date is considered the date of last dose. 
9.3. 
Concomitant and Other Medications 
Concomitant medications are coded using the World Health Organization (WHO) drug 
dictionary (1 Mar 2016 DDE+HD B2) for anatomical therapeutic chemical classification (ATC) 
and preferred drug name.  A patient who used multiple medications are counted only once for 
each ATC and preferred drug name.  ATC and preferred drug name within each ATC are sorted 
alphabetically.  Coded concomitant medications are summarized by treatment analysis group 
(Section 4.5).  Percentages are based on the number of patients in the safety analysis set.   
A concomitant medication is any medication taken at the time of first study treatment during the 
RANGER study or a medication that was started after the start of RANGER study drug dosing.  
Specifically, concomitant medications are medications 
• that are continued from CATALYST or LARIAT and continued after the first study 
drug dosing, or 
• that have start dates or stop dates within the treatment period. 
Concomitant medications are summarized for each treatment analysis group by WHO ATC class 
and preferred name.  Patients may have more than one medication per ATC class and preferred 
name.  At each level of patient summarization, a patient is counted once if he/she reported one or 
more medications at that level.  Each summary is ordered by descending order of incidence of 
ATC class and preferred name within each ATC class. 
Concomitant medications include those with an end date after the first study drug administration 
as well as medications without an end date.  Medications with an end date on the date of first 
study drug administration are not be considered concomitant medications.  


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9.3.1. 
Missing and Partial Concomitant and Other Medication Start and Stop Dates 
Missing and partial concomitant medication start and stop dates are detailed in Section 6.6.2. 
9.4. 
Summaries of Laboratory Results 
Laboratory data are summarized at baseline and at each time point by treatment analysis group 
(Section 4.5).  Only values obtained within analysis study windows (Section 6.5.5) are included 
in by-visit summary statistics 
Patients falling into the following four clinical meaningful categories are listed. 
In addition, the number and percentage of patients in the following four clinical meaningful 
categories is summarized at each analysis visit by treatment analysis group (Section 4.5).  
• BNP > 200 pg/mL 
• BNP increase from baseline > 100% 
• NT-proBNP > 1000 pg/mL 
• NT-proBNP increase from baseline > 100% 
9.5. 
Vital Signs 
Vital signs assessments include systolic blood pressure (SBP, mmHg) and diastolic blood 
pressure (DBP, mmHg), body temperature (°C), heart rate (HR, bpm), weight (kg), and BMI 
(kg/m2).  Only values obtained within analysis study windows (Section 6.5.5) are included in by-
visit summary statistics.  Vital signs are summarized at baseline and at each time point along 
with the change from baseline by treatment analysis group (Section 4.5).  All data are listed. 
Line plots of change from baseline of vital signs by visit and treatment analysis group (including 
overall patients) are generated up to and including study Week 120.  In addition, line plots are 
generated by: CTD; non-CTD. 
Vital signs are summarized by: CTD; non-CTD. 
9.6. 
Pregnancy 
A patient listing is provided for all on-study pregnancies. 


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10. 
PHARMACOKINETICS 
There are no pharmacokinetic samples collected in RANGER study. 


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11. 
CHANGES FROM PROTOCOL 
Synopsis in the protocol doesn’t indicate patients are scheduled to be assessed in person during 
treatment at Week 1.  This SAP includes Week 1 in Section 4.6  Clinical Assessment and Table 3  
Analysis Visits to follow protocol Table 3 Schedule of Assessments. 


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12. 
APPENDIX 
12.1. 
Programming Specifications 
Continuous data are listed corresponding to the precision measured or calculated.  Measures of 
central tendency are presented using one more decimal place than the precision of the data.  
Summaries of variability are presented using two significant digits more than the precision of the 
underlying data.  Median, Minimum, and the maximum are presented using the precision of the 
data.  For instance, if the raw data are rounded to the 0.001 decimal place, the derived values 
must be rounded to the 0.0001 decimal place.  
All percentages are to be expressed as integers with one decimal place.  The convention for 
rounding percentages is as follows: 
• Values greater than or equal to x.x5% are rounded up 
• Values between 0 and x.x5% are rounded down 


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12.2. 
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 Pulmonary Hypertension 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 Pulmonary Hypertension 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 Pulmonary Hypertension 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. 
 

Prot_003.pdf: 
Protocol 402-C-1602 
Reata Pharmaceuticals, Inc. 
Confidential 
Version 3.2 Germany 
1 
 
BARDOXOLONE METHYL (RTA 402) 
402-C-1602
 
EUDRACT NUMBER: 2016-004365-16 
AN EXTENDED ACCESS PROGRAM TO ASSESS 
LONG-TERM SAFETY OF BARDOXOLONE METHYL 
IN PATIENTS WITH PULMONARY HYPERTENSION 
VERSION 3.2 – 11 JULY 2019 
GERMANY 
Protocol History 
Version 1.0 – 27 October 2016 
Version 2.0 – 05 January 2017 
Version 2.2 – 23 June 2017 
Version 3.1 – 16 July 2018 
The information contained herein is confidential and the proprietary property of 
Reata Pharmaceuticals, Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of Reata Pharmaceuticals, 
Inc. is expressly prohibited. 




Protocol 402-C-1602 
Reata Pharmaceuticals, Inc. 
Confidential 
Version 3.2 Germany 
3 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for bardoxolone methyl.  I have read the 
402-C-1602 clinical study protocol and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


Protocol 402-C-1602 
Reata Pharmaceuticals, Inc. 
Confidential 
Version 3.2 Germany 
4 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Medical and Scientific 
Leader 
 
 
 
 
 
 
 
 
Clinical Study 
Manager 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
SAE Reporting 
 
 
 
 
 
 
 
 
 
 
Non-North American sites will use access codes specific to their country.  
Numbers for non-North American sites for SAE reporting will be provided 
by the clinical team directly to the sites for reporting and submitting SAE 
information to 
.  
 
 


Protocol 402-C-1602 
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Version 3.2 Germany 
5 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Product: 
Bardoxolone methyl 
Title of Study:  
An Extended Access Program to Assess Long-Term Safety of Bardoxolone Methyl in Patients with 
Pulmonary Hypertension  
Study center(s): Approximately 150 study centers  
Studied period: 60 months 
Estimated date first patient enrolled in Germany:  
July 2017 
Estimated date last patient completed in Germany: July 2023 
The study duration may be extended beyond 60 months in a 
future protocol amendment subject to all applicable 
regulatory and ethics approvals.  
The end of the study is defined as the last visit of the last 
patient. 
Phase of development:  
3a 
Primary Objectives:   
To provide continuing open-label treatment with bardoxolone methyl as part of this extended access 
program while collecting ongoing safety and tolerability data of bardoxolone methyl.   
Primary Safety Endpoint: 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse events 
(SAEs), and change from baseline in the following assessments: physical examinations, vital sign 
measurements, B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), 
and weight. 
Methodology:  
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in 
qualified patients with pulmonary hypertension (PH) who previously participated in controlled clinical 
studies with bardoxolone methyl.  
Qualified patients will start dosing at 10 mg of bardoxolone methyl every other day, then begin once daily 
dosing at Week 4 (unless contraindicated clinically) and continue the drug for up to 5 years or until 
patient withdrawal, whichever is sooner.  The treatment duration may be extended in a future protocol 
amendment subject to all applicable regulatory and ethics approvals.  Dose de-escalation (down to 5 mg) 
is permitted during the study, if indicated clinically.    
All patients in the study will follow the same visit and assessment schedule.  Patients will be scheduled to 
be assessed in person during treatment at Day 1, Week 2, Week 4, Week 6, Week 8, Week 24, and every 
24 weeks thereafter.  Patients will also be assessed by telephone contact on Days 3, 10, 21, 31, and 38.  
Day 1 for this extended access study should occur on the same day as the last visit in the controlled 
clinical study.  Patient status should be carefully monitored by the investigator during the first 8 weeks of 
study treatment.  Assessments required for both the last visit in the controlled study and Day 1 for this 
study should only be completed once. 


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Patients from the CATALYST study: 
Day 1 of this extended access study will coincide with the Week 28 follow-up visit for patients from 
CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended access program 
is not yet open for enrollment at the time of a patient’s Week 28 visit, the Day 1 visit (i.e., enrollment) 
must occur within 30 days of site activation.  Exceptions allowing CATALYST patients who have 
completed 24 weeks of treatment to schedule their follow-up assessments prior to Week 28 and still be 
considered eligible for this open-label study should be discussed with the Chief Medical Officer at Reata, 
or designee, and will be considered on a case-by-case basis.  
Patients from the LARIAT study:  
Day 1 of this extended access study will coincide with the End-of-Study visit for patients from LARIAT 
(402-C-1302, NCT02036970).  
Schema for Study of Bardoxolone Methyl in Patients with Pulmonary Hypertension 
 
 
Number of patients (planned):  
Patient numbers will be determined by those who are treatment-compliant and who have previously 
participated in clinical studies with bardoxolone methyl.  
Main criteria for inclusion: 
1. Treatment-compliant patients who are participating in qualifying ongoing studies (CATALYST, 
EudraCT 2016-000196-24; LARIAT, EudraCT 2016-004793-17) and who have completed 
required End-of-Treatment and/or Follow-up visits in one of these prior clinical studies with 
bardoxolone methyl and who, according to the assessment of the investigator, have a potential 
positive benefit-risk assessment for participating in the trial.  
2. Evidence of a personally signed and dated informed consent document indicating that the patient 
has been informed of all pertinent aspects of the study prior to initiation of any protocol-
mandated procedures. 
Major exclusion criteria: 
1. Participation in other investigational clinical studies involving interventional products being 
tested or used in a way different from the approved form or when used for an unapproved 
indication; 
2. Patients who have an ongoing SAE from a clinical study that is assessed by the investigator as 
related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners of 
childbearing potential and females of childbearing potential) while taking study drug;  


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4. Women who are pregnant or breastfeeding; 
5. 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; 
6. Known hypersensitivity to any component of the study drug. 
Investigational product, dosage, mode of administration, and duration of treatment:  
Bardoxolone methyl will be administered orally (every other day or once daily) at 10 mg for up to 
5 years.  The treatment duration may be extended in a future protocol amendment subject to all applicable 
regulatory and ethics approvals.  Dose de-escalation (down to 5 mg) is permitted during the study, if 
indicated clinically. 
Reference therapy, dosage and mode of administration:  
None. 


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Criteria for evaluation: 
Safety: Results of physical examinations, laboratory results, BNP, NT-ProBNP, vital sign measurements, 
weight, AEs, and SAEs. 
Statistical methods: 
Sample size: The aim of this long-term extended access study is primarily to provide continuing treatment 
to patients with bardoxolone methyl and to assess long-term safety and tolerability, hence no single 
primary variable has been identified.  Patient numbers will be determined by those who have been 
treatment-compliant and who have previously participated in clinical studies with bardoxolone methyl. 
Primary analysis of safety: As the extension is of an open-label design with no comparator group, all 
statistical analyses will be descriptive.  The summary tables will be presented for the overall group of 
patients, and also split by previous treatment groups (i.e., bardoxolone methyl or placebo) in prior 
bardoxolone methyl clinical studies.  


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3. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................9 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
5. 
INTRODUCTION ......................................................................................................16 
5.1. 
Study Rationale ...........................................................................................................18 
5.2. 
Clinical Experience with Bardoxolone Methyl ..........................................................18 
5.2.1. 
Safety and Tolerability ...............................................................................................18 
5.2.2. 
Fluid Overload ............................................................................................................18 
5.2.3. 
Transaminase and Gamma-Glutamyl Transpeptidase Elevations ..............................19 
5.2.4. 
Muscle Spasms ...........................................................................................................19 
5.2.5. 
Weight Loss ................................................................................................................20 
5.2.6. 
Hypomagnesaemia ......................................................................................................20 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................22 
6.1. 
Primary Objectives .....................................................................................................22 
6.2. 
Primary Safety Endpoint: ...........................................................................................22 
7. 
INVESTIGATIONAL PLAN .....................................................................................23 
7.1. 
Overall Study Design ..................................................................................................23 
7.2. 
Number of Patients .....................................................................................................23 
7.3. 
Treatment Assignment ................................................................................................23 
7.3.1. 
Dose Escalation and Dose De-Escalation ...................................................................24 
7.4. 
Criteria for Study Termination ...................................................................................24 
7.5. 
Criteria for Premature Termination or Suspension of Investigational Sites ...............24 
7.6. 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites ..........................................................................24 
7.7. 
Schedule of Assessments ............................................................................................24 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................27 
8.1. 
Patient Inclusion Criteria ............................................................................................27 
8.2. 
Patient Exclusion Criteria ...........................................................................................27 


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8.3. 
Patient Discontinuation and Termination ...................................................................27 
9. 
TREATMENT OF PATIENTS ..................................................................................29 
9.1. 
Select Management Guidelines ..................................................................................29 
9.1.1. 
Management of Fluid Status .......................................................................................29 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................29 
9.1.3. 
Management of Muscle Spasms .................................................................................30 
9.1.4. 
Weight Loss ................................................................................................................30 
9.1.5. 
Hypomagnesaemia ......................................................................................................30 
9.1.6. 
Nausea .........................................................................................................................30 
9.2. 
Description of Study Drug ..........................................................................................31 
9.3. 
Concomitant Medications ...........................................................................................31 
9.3.1. 
Excluded Medications ................................................................................................31 
9.3.2. 
Permitted Medications ................................................................................................31 
9.4. 
Treatment Compliance ................................................................................................32 
9.5. 
Randomization ............................................................................................................32 
9.6. 
Blinding ......................................................................................................................32 
9.7. 
Unscheduled Visits .....................................................................................................32 
9.8. 
Pregnancy ...................................................................................................................32 
9.8.1. 
Women of Childbearing Potential ..............................................................................32 
9.8.2. 
Methods of Birth Control............................................................................................32 
9.8.3. 
Suspected Pregnancy ..................................................................................................33 
9.9. 
Serious Toxicities .......................................................................................................33 
9.10. 
Study Procedures ........................................................................................................34 
9.10.1. 
Informed Consent .......................................................................................................34 
9.10.2. 
Inclusion/Exclusion ....................................................................................................34 
9.10.3. 
Prior and Current Concomitant Medications ..............................................................34 
9.10.4. 
Current PAH Background Medications ......................................................................34 
9.10.5. 
Weight and Body Mass Index .....................................................................................34 
9.10.6. 
Vital Sign Measurements ............................................................................................34 
9.10.7. 
Physical Examination .................................................................................................35 
9.10.8. 
Pregnancy Test ............................................................................................................35 
9.10.9. 
Study Drug Administration.........................................................................................35 
9.10.10. 
Study Drug Dispensation and Collection ...................................................................35 


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9.10.11. 
Telephone Contact ......................................................................................................35 
9.10.12. 
Adverse Event Collection ...........................................................................................35 
9.10.13. 
Clinical Chemistry ......................................................................................................36 
9.10.14. 
N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide .................36 
9.10.15. 
6-Minute Walk Test ....................................................................................................36 
9.10.16. 
WHO/NYHA Functional Class Assessment ..............................................................36 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................37 
10.1. 
Study Drug ..................................................................................................................37 
10.2. 
Study Drug Packaging and Labeling ..........................................................................37 
10.3. 
Study Drug Storage .....................................................................................................37 
10.4. 
Study Drug Administration.........................................................................................37 
10.5. 
Study Drug Accountability .........................................................................................38 
10.6. 
Study Drug Handling and Disposal ............................................................................38 
11. 
SAFETY ASSESSMENTS ........................................................................................39 
11.1. 
Safety Parameters .......................................................................................................39 
11.2. 
Adverse and Serious Adverse Events .........................................................................39 
11.2.1. 
Definition of Adverse Events .....................................................................................39 
11.2.1.1. 
Adverse Event .............................................................................................................39 
11.2.1.2. 
Serious Adverse Event ................................................................................................39 
11.3. 
Eliciting Adverse Event Information ..........................................................................40 
11.4. 
Assessment of Causality .............................................................................................41 
11.5. 
Assessment of Severity ...............................................................................................41 
11.6. 
Recording Adverse Events .........................................................................................41 
11.7. 
Reporting Serious Adverse Events .............................................................................42 
12. 
STATISTICS ..............................................................................................................45 
12.1. 
Sample Size ................................................................................................................45 
12.2. 
Study Variables ...........................................................................................................45 
12.2.1. 
Safety Variables ..........................................................................................................45 
12.3. 
Statistical Analyses .....................................................................................................45 
12.3.1. 
Primary Analysis of Safety .........................................................................................45 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................46 
13.1. 
Study-Specific Committees ........................................................................................46 
13.2. 
Study Monitoring ........................................................................................................46 


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13.3. 
Audits and Inspections ................................................................................................46 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................47 
14.1. 
Quality Assurance .......................................................................................................47 
14.2. 
Financial Disclosure ...................................................................................................47 
14.3. 
Sponsor Obligations....................................................................................................47 
14.4. 
Investigator Documentation ........................................................................................47 
14.5. 
Clinical Study Insurance .............................................................................................48 
14.6. 
Use of Information ......................................................................................................48 
15. 
ETHICS ......................................................................................................................49 
15.1. 
Institutional Review Board or Ethics Committee Review ..........................................49 
15.2. 
Ethical Conduct of the Study ......................................................................................49 
15.3. 
Written Informed Consent ..........................................................................................49 
15.4. 
Confidentiality ............................................................................................................50 
15.5. 
Modification of the Protocol .......................................................................................50 
15.6. 
Protocol Deviations ....................................................................................................51 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................52 
16.1. 
Retention of Records ..................................................................................................52 
16.2. 
Case Report Forms .....................................................................................................52 
17. 
PUBLICATION POLICY ..........................................................................................53 
18. 
REFERENCES ...........................................................................................................54 
19. 
APPENDIX 1: ATS GUIDELINES FOR THE SIX-MINUTE WALK TEST ..........56 
20. 
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF PULMONARY 
HYPERTENSION MODIFIED AFTER THE NEW YORK HEART 
ASSOCIATION FUNCTIONAL CLASSIFICATION ACCORDING TO 
THE WHO 1998 (GALIE, 2009) ...............................................................................64 
21. 
APPENDIX 3:  BORG CR10 SCALE .......................................................................65 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................14 
Table 3: 
Schedule of Assessments ............................................................................................25 
Table 4: 
Bardoxolone Methyl Drug Product Information ........................................................31 
Table 5: 
SAE Reporting Contact Information ..........................................................................43 
 


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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 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
ATS 
American Thoracic Society 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
CFR 
Code of Federal Regulations (US) 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
CRO 
Contract research organization 
CTD-PAH 
Connective tissue disease-associated pulmonary arterial 
hypertension 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
ICH 
International Conference on Harmonization 
IKKβ 
Inhibitor of nuclear factor kappa β kinase beta subunit 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   


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Abbreviation or Specialist Term 
Explanation 
NYHA FC 
New York Heart Association Functional Classification 
PAH 
Pulmonary arterial hypertension 
PH 
Pulmonary hypertension 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 


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




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patients with CTD-PAH had similar sustained increases in 6MWD through Week 32.  On the 
basis of these data, Reata expanded the LARIAT protocol (Version 5.0) to include PH patients 
with ILD, including WHO Group III patients with CTD-associated ILD, idiopathic pulmonary 
fibrosis, non-specific interstitial pneumonia, and WHO Group V patients with sarcoidosis.  Reata 
has also initiated a Phase 3 study in WHO Group I CTD-PAH patients (402-C-1504, 
CATALYST, NCT02657356, EudraCT 2016-000196-24) to study the safety and efficacy of 
bardoxolone methyl in those patients.   
5.1. 
Study Rationale 
The established pharmacologic effects of bardoxolone methyl, including the suppression of 
pathologic NF-κB signaling and inflammation and mitochondrial dysfunction, are directly 
applicable to the treatment of PH.  Despite available therapies, the prognosis for PH remains 
poor, especially for patients with CTD (Chung, 2014) and ILD.  Given the severity of the 
underlying disease, this study seeks to offer patients who previously participated in clinical 
studies extended access to bardoxolone methyl until it is available through commercial channels 
(including reimbursement).  For sites in Germany, the trial duration is limited to 5 years 
following the enrollment of the first patient in Germany.  The trial duration may be extended in a 
future protocol amendment subject to all applicable regulatory and ethics approvals. 
For further information, refer to the Investigator’s Brochure.  
5.2. 
Clinical Experience with Bardoxolone Methyl 
Approximately 1950 individuals have been exposed to bardoxolone methyl at the time of 
initiation of this study.  Sixteen studies have been completed (7 in patients with chronic kidney 
disease (CKD) who also had type 2 diabetes, 4 in non-CKD indications, and 5 in healthy 
subjects) and 2 studies are ongoing in patients with PH.   
5.2.1. 
Safety and Tolerability 
Please refer to the Investigator’s Brochure for a detailed discussion of safety findings with 
bardoxolone methyl for studies in healthy subjects, oncology, CKD, and patients with PH. 
5.2.2. 
Fluid Overload 
Similar to endothelin receptor antagonists 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 a Phase 3 trial (BEACON), which enrolled patients with Stage 4 CKD (eGFR 
of 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 B-type natriuretic peptide (BNP) and prior 
hospitalization for heart failure were identified as risk factors that contributed to increased risk 
for these events.  The increased risk for these events from bardoxolone methyl treatment had not 
been observed in six previous CKD studies, which were conducted mostly in patients with Stage 
3b CKD (eGFR of 30-44 mL/min/1.73 m2), patients with hepatic dysfunction, cancer patients, or 
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Review of admission notes and narrative descriptions for heart failure hospitalizations in 
BEACON indicates that heart failure in bardoxolone methyl-treated patients was often preceded 
by rapid fluid weight gain (several kilograms within the first weeks of treatment initiation) and 
was not associated with acute renal decompensation or acutely reduced left ventricular 
contractility.  Available data from BEACON and other studies suggest that bardoxolone methyl 
treatment can differentially affect hemodynamic status according to the clinical condition of 
patients and likely promotes fluid retention in patients with more advanced renal dysfunction and 
other recognized risk factors associated with heart failure at baseline.   
In a Phase 2 dose-ranging study of the efficacy and safety of bardoxolone methyl in patients with 
PH (LARIAT), risk mitigation procedures were employed to reduce the potential for 
bardoxolone methyl-induced fluid overload; these procedures excluded patients with the 
identified risk factors and ensured close monitoring for fluid retention within the first month of 
treatment.  To date, the risk for acute fluid overload adverse events (AEs) with bardoxolone 
methyl in late-stage CKD patients has not been observed in PAH patients.   
5.2.3. 
Transaminase and Gamma-Glutamyl Transpeptidase Elevations  
In clinical studies of bardoxolone methyl, almost all patients had increases of transaminase 
enzymes above baseline upon initiation of treatment, which followed a consistent pattern.  These 
increases were not associated with elevations in bilirubin or other signs of liver toxicity.  In a 
large Phase 3 study that enrolled 2185 patients with type 2 diabetes and stage 4 CKD 
(BEACON), fewer hepatobiliary SAEs were observed in the bardoxolone methyl arm than in the 
placebo arm.  The elevations begin immediately after initiation of treatment or an increase in 
dose; they peak approximately two to four weeks later.  In most patients, transaminase elevations 
were mild, but approximately 4% to 11% of patients experienced an elevation greater than 3X 
the upper limit of normal (ULN).  The elevations resolved to levels less than the ULN in most all 
patients with elevations, within two weeks after peak values while patients continued taking 
study drug.  Patients who experienced elevations to greater than 3X the ULN sometimes required 
additional time to resolve.  While some patients have had elevations to above 3X the ULN, 
persistent elevations to above 3X the ULN have not been observed, and the elevations did not 
recur once resolved, unless caused by other factors. 
Bardoxolone methyl regulates gamma-glutamyl transpeptidase (GGT), a known Nrf2 target 
gene.  In clinical studies, low level GGT elevations during treatment were common, mild, and 
typically lasted longer than alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevations.  Bilirubin levels in patients experiencing transaminase or GGT elevations due to 
treatment with bardoxolone methyl either remained at baseline levels or decreased.  The ALT, 
AST, and GGT elevations were generally self-limiting in patients who continued treatment with 
study drug.  
5.2.4. 
Muscle Spasms 
Muscle spasm was the most frequently reported AE in clinical studies of bardoxolone methyl in 
patients with CKD who also had type 2 diabetes.  The muscle spasms most often manifested in 
the first two months of treatment and resolved spontaneously or with empirical treatment.  They 
occurred mostly at night, in the lower extremities, and were generally mild to moderate in 
severity.  Muscle spasms have also been reported in bardoxolone methyl-treated PAH patients 


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but at lower incidences than that observed in prior CKD studies.  Moreover, the incidence of 
muscle spasms is similar to that observed in placebo-treated PAH patients.  Muscle spasms may 
result from improved insulin sensitivity and glucose uptake in skeletal muscle cells.  Increases in 
glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp procedure, were 
observed in response to bardoxolone methyl in a defined subset of patients enrolled in a Phase 2a 
study.  To date, in those cases where serum creatinine kinase (CK) levels have been measured, 
no association has been observed between muscle spasms and elevated CK levels in patients 
treated with bardoxolone methyl.  Clinical signs and laboratory findings associated with the 
reports of muscle spasms have not been consistent with muscle toxicity.  Bardoxolone methyl 
subjects showed no increase in prominent laboratory findings associated with muscle toxicity, 
such as increased levels of serum markers, including creatinine, lactate dehydrogenase, blood 
urea nitrogen, uric acid, phosphorus, and potassium, which were monitored weekly during the 
first two months of a prior study (BEAM) when muscle spasms were most frequently reported.  
Increases in the whole-body glucose disposal rate have been observed in mice treated with 
bardoxolone methyl, as well.  Increased glucose uptake was observed in isolated calf muscles of 
the mice, but not in white adipose tissue (Saha, 2010).   
5.2.5. 
Weight Loss 
Decreases in weight and reports of anorexia/decreased appetite have been observed following 
treatment with bardoxolone methyl in patients with CKD who also had type 2 diabetes.  In 
studies of these patients, 17% of bardoxolone methyl patients reported AEs of weight decrease or 
decreased appetite (irrespective of relationship to treatment).  Weight reduction was more 
pronounced in patients treated with bardoxolone methyl than in those given placebo. 
Weight loss of approximately one kilogram per month was observed, with patients of higher 
body-mass index at baseline losing more weight (in absolute terms) than those of normal or 
moderately-elevated body-mass index.   
Bardoxolone methyl-treated PAH patients have also had decreases in weight, with mean weight 
decreases of approximately 3 kg versus placebo at Week 16.  Weight loss in PAH patients has 
not coincided with reports of decreased appetite or anorexia AEs. 
5.2.6. 
Hypomagnesaemia 
Hypomagnesaemia has not been reported in PAH patients to date, but was reported as an AE for 
15.5% of patients with CKD who also had type 2 diabetes who received bardoxolone methyl.  
The AE of hypomagnesaemia (of any reported relationship to study drug) was more frequently 
reported in bardoxolone methyl-treated patients than in patients given placebo.  The investigators 
considered almost all reported events to be mild.  Additionally, patients treated with bardoxolone 
methyl had a greater decrease from baseline in serum magnesium levels than patients given 
placebo; the decrease was evident within 4 weeks and attenuated after 8 weeks of starting 
therapy.  In bardoxolone methyl clinical studies performed to date, a post-hoc analysis identified 
no correlation between hypomagnesaemia and either gastrointestinal AEs or cardiac AEs, 
including cardiac dysrhythmias and prolonged QTc.  The 24-hour urine collections from the 
BEACON ambulatory blood pressure monitoring sub-study showed no increase in urinary 
magnesium levels, indicating that renal loss of magnesium did not account for the reductions in 
serum magnesium observed with bardoxolone methyl treatment in CKD patients.  Notably, a 


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thorough QT study that tested doses of bardoxolone methyl up to 80 mg, bardoxolone methyl 
showed no increase in the QT interval.  


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objectives 
To provide continuing treatment with bardoxolone methyl as part of this extended access 
program while collecting ongoing safety and tolerability data of bardoxolone methyl.  
6.2. 
Primary Safety Endpoint: 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse 
events (SAEs), and change from baseline in the following assessments: physical examinations, 
vital sign measurements, BNP, N-terminal pro-brain natriuretic peptide (NT-proBNP), and 
weight. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This extended access study will assess the long-term safety and tolerability of bardoxolone 
methyl in qualified patients with PH who previously participated in controlled clinical studies 
with bardoxolone methyl. 
Qualified patients will start dosing at 10 mg of bardoxolone methyl every other day, then begin 
once daily dosing at Week 4 (unless contraindicated clinically) and continue the drug for up to 
5 years or until patient withdrawal, whichever is sooner.  The treatment duration may be 
extended in a future protocol amendment subject to all applicable regulatory and ethics 
approvals.  Dose de-escalation (down to 5 mg) is permitted during the study if indicated 
clinically.  Refer to Section 7.3.1 for additional details on dose de-escalation.  
All patients in the study will follow the same visit and assessment schedule.  Patients will be 
scheduled to be assessed in person during treatment at Day 1, Week 2, Week 4, Week 6, Week 8, 
Week 24, and every 24 weeks thereafter.  Patients will also be assessed by telephone contact on 
Days 3, 10, 21, 31, and 38.  Day 1 for this extended access study should occur on the same day 
as the last visit in the controlled clinical study.  Patient status should be carefully monitored by 
the investigator during the first 8 weeks of study treatment.  Assessments required for both the 
last visit in the controlled study and Day 1 for this study should only be completed once. 
Patients from the CATALYST study: 
Day 1 of this extended access study will coincide with the Week 28 follow-up visit for patients 
from CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended 
access program is not yet open for enrollment at the time of a patient’s Week 28 visit, the Day 1 
visit (i.e., enrollment) must occur within 30 days of site activation.  Exceptions allowing 
CATALYST patients who have completed 24 weeks of treatment to schedule their follow-up 
assessments prior to Week 28 and still be considered eligible for this open-label study should be 
discussed with the Chief Medical Officer at Reata, or designee, and will be considered on a case-
by-case basis.   
Patients from the LARIAT study: 
Day 1 of this extended access study will coincide with the End-of-Treatment visit for patients 
from LARIAT (402-C-1302, NCT02036970).   
7.2. 
Number of Patients 
Patient numbers will be determined by those who have been treatment-compliant and who have 
previously participated in clinical studies with bardoxolone methyl. 
7.3. 
Treatment Assignment 
All patients will receive bardoxolone methyl in this study. 


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7.3.1. 
Dose Escalation and Dose De-Escalation  
Patients will start dosing at 10 mg of bardoxolone methyl every other day, then begin once daily 
dosing at Week 4 unless contraindicated clinically.  The investigator should discuss any reasons 
for not dose-escalating to once daily dosing at Week 4 with the medical monitor. 
Dose de-escalation is permitted during the study and the investigator may choose to decrease the 
patient’s dose to 5 mg if clinically indicated.  Reasons for dose de-escalation should be discussed 
with the medical monitor prior to changing dose.  Once a patient’s dose has been decreased to 
5 mg, they cannot dose-escalate back to 10 mg of bardoxolone methyl. 
Unscheduled visits due to dose de-escalation should include assessments detailed in Section 9.7.  
7.4. 
Criteria for Study Termination 
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 
drugs will be discontinued and the investigator will be responsible for securing any alternative 
therapy to be administered, as appropriate. 
7.5. 
Criteria for Premature Termination or Suspension of Investigational 
Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement with Sponsor or the site is unable to ensure adequate performance of the study. 
7.6. 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Sites 
In the event that the Sponsor, an institutional review board (IRB)/ethics committee (EC), or 
regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor. 
7.7. 
Schedule of Assessments 
Table 3 lists the overall schedule of assessments for the study. 
 


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Table 3: 
Schedule of Assessments  
Study Week 
(Day) 
Assessment 
Day 1a 
Week 1  
(Phone) 
Day 3±2 
Week 1  
Day 7±3 
Week 2  
(Phone) 
Day 10±2 
Week 2 
Day 14±3 
Week 3 
(Phone) 
Day 21±2 
Week 4 
Day 28±3 
Week 4 
(Phone) 
Day 31±2 
Week 5  
(Phone) 
 Day 38±2 
Week 6 
Day 42±3 
Week 8 
Day 56±3 
Week 
24±3,  
Every 24 
Weeks  
End of  
Study 
 Visitb 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current PAH background 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight at home 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight in clinic  
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Vital sign measurements 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Physical examination 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
Pregnancy testd 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
 
Dispense study drug 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Collect study drug 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Telephone contact 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
Adverse event collection 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistriesf 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
BNP and/or NT-Pro BNP 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
6-min walk test 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
Dyspnea and fatigueg 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
WHO functional class 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
a On Day 1, all procedures should be performed before study drug administration for patients who are treatment-compliant and have previously participated in 
clinical studies with bardoxolone methyl. 
b After the Week 24 visit, patients will continue to be assessed in person every 24 weeks.  The End of  Study visit should occur within 30 days after the patient 
receives their final dose of study medication under this protocol.  Patients who will be discontinued from the study prior to the completion of the study must 
also complete all End-of-Study assessments. 
c Day 1 assessments should be performed as part of End-of-Treatment or Follow-up visit procedures from a prior study with bardoxolone methyl.  
d A serum pregnancy test will be performed 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 health authorities or IRBs/ECs. 


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e AE assessments on Day 1 should be performed following study drug administration. 
f Clinical chemistries will be analyzed locally. 
g Dyspnea and fatigue must be assessed prior to beginning and immediately following completion of the 6MWT using the Borg scale. 
 
Abbreviations: PAH, pulmonary arterial hypertension; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro B-type natriuretic peptide; WHO, World 
Health Organization; AE, adverse event; 6MWT, 6-minute walk test.


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Main criteria for inclusion:  
1. Treatment-compliant patients who are participating in qualifying ongoing studies 
(CATALYST, EudraCT 2016-000196-24; LARIAT, EudraCT 2016-004793-17) and who 
have completed required End-of-Treatment and/or Follow-up visits in one of these prior 
clinical studies with bardoxolone methyl and who, according to the assessment of the 
investigator, have a potential positive benefit-risk assessment for participating in the trial.   
2. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study prior to initiation of any 
protocol-mandated procedures. 
8.2. 
Patient Exclusion Criteria 
All patients with any of the following conditions or characteristics must be excluded from the 
study: 
1. Participation in other investigational clinical studies involving interventional products 
being tested or used in a way different from the approved form or when used for an 
unapproved indication; 
2. Patients who have an ongoing serious adverse event (SAE) from a clinical study that is 
assessed by the investigator as related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners 
of childbearing potential and females of childbearing potential) while taking study drug;  
4. Women who are pregnant or breastfeeding; 
5. 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; 
6. Known hypersensitivity to any component of the study drug. 
8.3. 
Patient Discontinuation and Termination 
Patients have the right to discontinue study drug or withdraw from the study at any time for any 
reason, without prejudice to their medical care.  Furthermore, the investigator may discontinue a 
patient from study drug.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study.  The reason for a patient’s 
discontinuation from study drug or study termination will be recorded in the electronic case 
report form (eCRF).  
Discontinuation refers to a patient’s stopping administration of study drug and all study 
assessments and visits.  Reasons for study drug discontinuation may include the following: 


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• Occurrence of an AE or change in medical status that will lead the investigator to be 
concerned about the patient’s welfare; 
• Administrative reasons (e.g., inability to continue); 
• Sponsor termination of the study; 
• Voluntary withdrawal; 
• Females who become pregnant during the study; 
• Premature termination or suspension of an investigational site; 
• Loss to follow-up; 
• Death; 
• Withdrawal of consent. 
Patients must discontinue study drug if any of the following occur. 
• ALT or AST > 8X ULN; 
• ALT or AST > 5X ULN for more than 2 weeks; 
• ALT or AST > 3X ULN and (total bilirubin > 2X ULN or International Normalized 
Ratio [INR] > 1.5); 
• ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
Patients who discontinue from the study will be asked to complete the End-of-Study procedures 
noted in Table 3. 


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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.  Laboratory data, as well as BNP and/or NT-proBNP, will also be 
used to monitor fluid status.   
Additionally, patients will be monitored for rapid weight gain suggestive of fluid overload.  
Patients will be given a Sponsor-provided scale to use at home to monitor their weights daily 
during the first 8 weeks of the treatment period.  Patients who experience a 
5-pound (2.3 kilogram) or greater increase in weight since their Day 1 weight during the first 
8 weeks of the treatment period 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 advise patients to watch for signs and symptoms of fluid overload.  Patients 
should be informed to notify their physicians immediately if they experience swollen feet, chest 
pain, shortness of breath with mild exertion or while lying down, or other relevant symptoms.  
The investigator should immediately assess symptoms of fluid overload and determine 
appropriate medical management, as necessary, including whether stopping drug administration 
will be 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. 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) 
Transaminases should be monitored following patient’s standard of care.  Nearly all instances of 
elevated transaminases are expected to be asymptomatic.  Transaminase levels (as well as total 
bilirubin [TBL], GGT, alkaline phosphatase, and INR) will be checked within 48 to 72 hours 
during an unscheduled visit if the following occurs: 
• ALT or AST levels > 3X ULN. 
Testing will be repeated every 72 to 96 hours until transaminase levels are below 3X the ULN 
for at least one week or until the patient withdraws consent. 
Study drug administration will be permanently discontinued if any of the following occurs: 
• ALT or AST > 8X ULN; 
• ALT or AST > 5X ULN for more than 2 weeks; 
• ALT or AST > 3X ULN and (TBL > 2X ULN or INR > 1.5); 


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• ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  
The hepatobiliary tree must be visualized (e.g., ultrasound, magnetic resonance imaging) 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 as part of patient’s standard of care may indicate the 
need for replacement.  If vitamin D levels are low, supplementation may be warranted.  Muscle 
relaxants may also help relieve symptoms. 
9.1.4. 
Weight Loss 
Ongoing assessments to ensure that the patient is receiving adequate nutrition and consideration 
of other etiologies of weight loss may be warranted for patients receiving bardoxolone methyl.   
9.1.5. 
Hypomagnesaemia 
In instances where a patient experiences hypomagnesaemia (evaluated as part of patient’s 
standard of care), 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 AEs are typically mild and 
reversible within a few weeks after treatment initiation.  If symptoms will not resolve, dose 
de-escalation, with consultation of the medical monitor, may be necessary.   


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9.2. 
Description of Study Drug 
Bardoxolone methyl (RTA 402) drug product information is shown in Table 4.   
Table 4: 
Bardoxolone Methyl Drug Product Information 
Description 
Bardoxolone methyl capsule (5 mg, 
10 mg) 
Ingredients 
Bardoxolone methyl 
Methacrylic Acid – Ethyl Acrylate 
Copolymer 
Type A  
Silicified Microcrystalline Cellulose  
Hydroxypropyl Methylcellulose  
Lactose Monohydrate 
Sodium Lauryl Sulfate 
Colloidal Silicon Dioxide 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide 
 
Route of Administration 
Oral 
9.3. 
Concomitant Medications 
9.3.1. 
Excluded Medications 
No other investigational drug or device should be taken as part of an interventional study during 
the conduct of this study. 
Patients who take investigational drug or device during the study should not discontinue study 
drug solely on this basis.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study. 
9.3.2. 
Permitted Medications 
Pulmonary arterial hypertension-specific background therapy should be taken as clinically 
indicated and prescribed by the physician for the duration of the study. 
Refer to Section 9.10.15 for guidelines on oxygen use during 6MWTs.  Initiation of 
supplemental long-term oxygen therapy (oxygen application for more than 30 consecutive days) 
or persistent modification of a pre-existing supplemental long-term oxygen therapy (i.e., need for 
a persistent increase of the amount of delivered oxygen for more than 30 days) due to worsening 
PAH is permitted.  
Diuretics may be prescribed as clinically indicated throughout the study.  Any changes to the 
doses of oxygen or diuretics throughout the course of the study must be recorded in the 
electronic case report form (eCRF).   


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9.4. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to patients enrolled in the study in accordance with the protocol.  The study drug must not be 
used for reasons other than that described in the protocol.  
9.5. 
Randomization 
Not applicable. 
9.6. 
Blinding 
Not applicable.  
9.7. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
• Assessment of weight gain per Section 9.1.1;  
• Management of an AE or SAE; 
• Performance of additional laboratory tests for clinically abnormal laboratory test 
values or to confirm a possible pregnancy; 
• Dose de-escalation; 
• Any time the investigator feels that it is clinically appropriate for patient safety. 
At a minimum, unscheduled visits should include collection of AEs, concomitant medications 
and vital signs.  Additional conversations may be necessary with the medical monitor following 
an unscheduled visit to assess patient safety. 
9.8. 
Pregnancy 
9.8.1. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) are those who are not surgically sterile (no history 
of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have 
fallopian inserts with confirmed blockage, have not had reproductive potential terminated by 
radiation, and are not postmenopausal for at least 1 year. 
9.8.2. 
Methods of Birth Control 
While taking study drug and until 30 days following administration of the final dose of study 
medication, WOCBP must practice one of the following acceptable methods of birth control: 
• Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
90 days prior to start of study drug administration; 
• Use of an intrauterine device; 


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• Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted. 
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); 
• Partner use of an intrauterine device; 
• Partner use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) for 
at least 90 days prior to start of study drug administration; 
• Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted. 
9.8.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).  Male patients must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a patient or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If the serum pregnancy test 
confirms the pregnancy, the patient must permanently discontinue taking study drug.  The 
investigator must immediately report to the medical monitor a pregnancy associated with study 
drug exposure.  The early discontinuation protocol-required procedures outlined for End-of-
Study 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 an SAE: 
• Congenital anomaly/birth defect; 
• Stillbirth; 
• Spontaneous miscarriage. 
9.9. 
Serious Toxicities 
In the case of serious toxicities, the investigator may choose to interrupt treatment with 
bardoxolone methyl.  A single dose reduction (from 10 mg to 5 mg) is permitted if clinically 
indicated to manage tolerability issues.  Once a patient’s dose has been reduced, that dose must 


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be maintained.  Patients who resume therapy after an interruption will follow the originally 
planned study schedule.  
9.10. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 3.  All Day 1 procedures, except AE assessments, should be completed prior to 
administration of first dose of study drug. 
9.10.1. 
Informed Consent 
Written informed consent (see Section 15.3) must be obtained from the patient before any 
study-related procedures are performed, and again if there is a change in the study procedures 
that would affect the patient’s willingness to participate. 
9.10.2. 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Table 3.  Patients must meet all 
of the inclusion and none of the exclusion criteria for entry in the study.   
9.10.3. 
Prior and Current Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking.  
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug names 
should be used where possible.  Concomitant medications will be reviewed as indicated in  
Table 3 and all changes will be recorded. 
9.10.4. 
Current PAH Background Medications 
The name, dose, and frequency must be recorded for all PAH background medications that the 
patient is taking.  PAH background medications are those that have been approved by the US 
Food and Drug Administration (FDA) or the local health authority for the treatment of PAH.  
Trade or generic drug names should be used where possible.  PAH background medications will 
be reviewed as indicated in Table 3 and all changes will be recorded.   
9.10.5. 
Weight and Body Mass Index  
Weight must be measured as indicated in Table 3.  Body mass index (BMI) will be calculated in 
the eCRF each time the weight is recorded.  Patients will use Sponsor-provided scales to measure 
weight at home.  Patients will be instructed to stop administering study drug and contact the 
investigator if their daily weight increases per the criteria outlined in Section 9.1.1.  Patients will 
be provided instructions within the Informed Consent Form to help ensure consistent weight 
collection throughout the study. 
9.10.6. 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), respiration rate, and body temperature.  Blood pressure should be taken after the 
patient has rested in a sitting position for at least 5 minutes.  The same arm (usually the non-


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dominant arm) and the appropriate size cuff should be used for each measurement.  Vital sign 
measurements should be taken as indicated in Table 3.  
9.10.7. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner as indicated in Table 3 and as documented within the table 
footnotes.  The examination must include the following organ or body system assessments: head, 
eyes, ears, nose, throat, musculoskeletal, cardiovascular, lymphatic, respiratory, abdomen, skin, 
extremities, and neurological.  Assessments of any specific signs or symptoms reported by the 
patient must also be performed and documented along with any other findings of note.  Clinically 
significant findings at Day 1 must be recorded as medical history.  Following the examination on 
Day 1, new or changed physical examination findings meeting the criteria for an adverse event 
must be recorded as an adverse event.  If possible, the same individual should perform each 
physical examination on a patient during the study. 
9.10.8. 
Pregnancy Test 
WOCBP (see Section 9.8) will complete a pregnancy test as indicated in Table 3, or at any time 
if pregnancy is suspected.  Negative test results are required on Day 1 before study drug 
administration.  Any patient who becomes pregnant during the study must discontinue taking 
study drug immediately.  See Section 9.8.3 for a description of procedures to be followed in case 
of pregnancy. 
9.10.9. 
Study Drug Administration 
Patients should self-administer one capsule orally, once a day, preferably in the morning, as 
indicated in Table 3.  A vomited dose must not be replaced.  A double dose (e.g., missed dose 
from previous day and dose for current day) must not be taken. 
9.10.10. 
Study Drug Dispensation and Collection 
Study drug will be dispensed to the patient and collected from the patient as indicated in Table 3.  
The patient will be dispensed 1 or more treatment kits at Day 1, Week 4, Week 24, and every 
24 weeks thereafter for the duration of the study.  Dispensed treatment kits from each visit 
should be returned to the site for collection at the subsequent visit. 
9.10.11. 
Telephone Contact 
Patients will be contacted by telephone as indicated in Table 3.  Patients will be asked about their 
body weight and other signs of fluid retention, as well as AEs and any changes to concomitant 
medications.  If fluid retention is suspected, the patient must be brought into the clinic and 
evaluated by the investigator as soon as possible, as detailed in Section 9.1.1. 
9.10.12. 
Adverse Event Collection 
Patients will be observed for general appearance, presence of illness or injury, or signs indicative 
of a concurrent illness as indicated in Table 3.  Patients must be instructed to volunteer any 
information regarding AEs on or after the first dose of study drug or query the patients with an 
open question regarding any AEs they may be experiencing (e.g., “How have you been feeling 


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since your last visit?”).  Any findings are to be documented.  Patients must be asked if they have 
been hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (including prescription drugs, over-the-counter medications, vitamins, 
herbal products, and minerals).  Responses must be documented in the source documents. 
9.10.13. 
Clinical Chemistry 
Samples will be collected for clinical chemistry analyses as indicated in Table 3.  Clinical 
chemistries will be analyzed locally and should include those routinely monitored per patient’s 
standard of care.  
9.10.14. 
N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide  
Samples will be collected for NT-Pro BNP and/or BNP as indicated in Table 3.  As recent 
exercise may affect BNP and NT-Pro BNP levels, patients must be allowed to rest for a 
minimum period of 1 hour following arrival at the clinic and prior to obtaining this blood 
sample.  Similarly, this sample must be taken prior to the 6MWT or at least one hour after 
6MWT.  This sample must be taken with the patient in the same position at all appropriate visits, 
e.g., sitting or semi-recumbent. 
9.10.15. 
6-Minute Walk Test 
A 6-minute walk test (6MWT) will be performed by the patients as indicated in Table 3.  Unless 
otherwise indicated as described below, each test must be performed in strict accordance with the 
American Thoracic Society (ATS) guidelines (ATS Statement 2002) provided in Section 19, 
Appendix 1.  The appropriate language version will be applied for patients with a non-English 
informed consent.  The walking course must be 30 m in length, except at sites granted prior 
Sponsor agreement. 
Patients will rate their dyspnea and overall fatigue using the Borg scale (2004 version, provided 
in Section 21, Appendix 3) prior to beginning and immediately following completion of each 
6MWT as indicated in Table 3.   
The assessor of the 6MWT must not provide the patient with the results of the assessment once 
complete.  A patient should wear the same or similar shoes for all 6MWTs.  Additionally, if a 
patient uses a walking aid for the first test, this same aide should be used during all subsequent 
tests.  The shoes worn and walking aid used for each 6MWT should be noted in source 
documents.   
Patients who require supplemental oxygen with exercise may use their prescribed oxygen level 
during 6MWTs.  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.   
9.10.16. 
WHO/NYHA Functional Class Assessment 
WHO/NYHA functional class will be assessed (Section 20, Appendix 2) as indicated in Table 3.  
To the extent feasible, the same evaluator should assess WHO/NYHA FC for a particular patient 
over the entire course of the study.  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 5 mg and 10 mg, will be used in this study. 
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied in tamper-evident kits containing one 30-cc (5-mg capsules, 
30 count), one 60-cc (5-mg capsules, 90 count), or one 100-cc (10-mg capsules, 90 count) high-
density polyethylene bottle.  Each bottle will utilize foil induction-seal liners and a child-resistant 
closure.  Each bottle of study drug will contain 30 or 90 capsules of 5 mg or 10 mg strength 
bardoxolone methyl.  Each bottle will also contain a desiccant insert that must not be ingested.  
Labeling on each kit bottle will contain at minimum the following information: 
• Medication identification number; 
• Protocol 402-C-1602; 
• Caution Statement: New Drug – Limited by Federal Law to Investigational Use.  
Keep out of sight and reach of children; 
• Control or lot number 
• Store at 20° - 25°C (68° - 77°F), short term excursions allowed to 
15° - 30°C (59° - 86°F); 
• Reata Pharmaceuticals, Inc., Irving, TX. 
A double panel label will be presented on the treatment bottle containing this and other 
information as well.  Additionally, labeling in the relevant local languages for investigational 
medicinal product for use and distribution in the EU shall adhere to current Eudralex, Volume 4 
Annex 13 guidance and requirements.   
10.3. 
Study Drug Storage 
The stability of the drug product has been and is currently being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location with room 
temperature conditions of 20°C to 25°C (68°F to 77°F), with brief excursions allowed to 
15°C to 30°C (59°F to 86°F).   
10.4. 
Study Drug Administration 
Please refer to Section 9.10.9 for details on study drug administration.  Clear instructions will be 
provided to the patient regarding the number and type of capsules to be ingested at each study 
drug administration time point listed in Table 3.  Patients must be instructed to continue taking 
study drug unless: (1) patient has been otherwise instructed by the investigator or (2) the patient 
has been formally discontinued from the study.  


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


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


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Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of the first dose of study drug until the final visit 
indicated in Table 3, as appropriate).  Certain pregnancy outcomes will require submission as an 
SAE (See Section 9.8). 
The investigator is responsible for reporting to Reata or designee all AEs and SAEs that are 
observed or reported by the patient during the study (from the time of administration of the first 
dose of study drug until the final visit indicated in Table 3, as appropriate), regardless of their 
relationship to study drug or their clinical significance.   
The Sponsor, or the Contract Research Organization (CRO) on the behalf of the Sponsor, must 
be notified immediately regarding the occurrence of any SAE that occurs after the patient 
receives the first dose of study drug and throughout the study, regardless of study drug 
administration, including SAEs resulting from protocol-associated procedures, as defined in 
relevant legislation.  The procedures for reporting all SAEs, regardless of causal relationship, are 
as follows: 
• Record the SAE on the AE eCRF and complete the “Serious Adverse Event Report” 
form within the electronic database; 
• In the event the electronic database is not functional, a paper SAE form will be 
available for the reporting of SAEs. 
The Sponsor may request additional information from the investigator to ensure the timely 
completion of accurate safety reports. 
All SAEs reported or observed during the study must be followed to resolution or until the 
investigator deems the event to be chronic or the patient to be stable.  Reata or designee may 
contact the investigator to obtain additional information on any SAE which has not resolved at 
the time the patient completes the study. 
11.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, nondirected 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 that are monitored per patient’s standard 
of care, physical examination findings, or from other documents that are relevant to patient 
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11.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Not Related: This relationship suggests that there is no association between the study drug and 
the reported event. 
Unlikely Related: This relationship suggests that the temporal sequence of the event with study 
drug administration makes a causal relationship improbable and/or other factors also provide 
plausible explanations. 
Possibly Related: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence from the time 
of study drug administration, and/or, follows a known response pattern to the study drug, but 
could have been produced by other factors. 
Probably Related: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
Definitely Related: This relationship suggests that a definite causal relationship exists between 
the drug administration and the AE, and other conditions (e.g., concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
11.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities; 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities; 
Severe: Symptoms causing inability to perform usual social and functional activities.  
11.6. 
Recording Adverse Events 
All conditions present prior to the administration of the first dose of study drug (Day 1) in a 
previous study with bardoxolone methyl should be documented as medical history in a previous 
study with bardoxolone methyl.  After the first dose, documentation of AEs shall continue until 
30 days following administration of the final dose of study medication under this protocol 
(i.e., through the End-of-Treatment visit), regardless of the relationship of the AE to study drug.  
Information to be collected will include type of event, date of onset, date of resolution, 
investigator-specified assessment of severity and relationship to study drug, seriousness, as well 
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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 will require 
documentation of onset and duration. 
All drug-related (possibly, probably, or definitely related, see Section 11.4) AEs and abnormal 
laboratory test results reported or observed during the study must be followed to resolution 
(either return to baseline or within normal limits).  All other AEs will be followed through the 
final visit indicated in Table 3, as appropriate. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Preexisting conditions 
(present before the start of the AE collection period) will be 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 shall 
be recorded as an AE.  Investigators shall ensure that the AE term recorded captures the change 
in the condition (e.g., “worsening of…”).  Any improvement in condition shall be documented 
per Section 9.10.7. 
Each AE shall be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values) or symptoms shall NOT be recorded as additional AEs.  If a 
diagnosis is unknown, sign(s) or symptom(s) shall be recorded as an AE(s).  Changes in 
laboratory test values will only be considered AEs if they are judged to be clinically significant 
(i.e., if some action or intervention is required or if the investigator judges the change to be 
beyond the range of normal physiological fluctuation).  If abnormal laboratory test values will be 
the result of pathology for which there will be an overall diagnosis (e.g., increased creatinine 
levels in renal failure), only the diagnosis shall be reported as an AE. 
Elective procedures (surgeries or therapies) that will be scheduled prior to the start of AE 
collection will not be considered AEs.  These elective procedures shall not be recorded as AEs, 
but shall be documented in the patient’s source documents as elective (e.g., elective periodontal 
surgery).  However, if a pre-planned procedure will be performed early (e.g., as an emergency) 
because of a worsening of the preexisting condition, the worsening of the condition shall be 
captured as an AE. 
11.7. 
Reporting Serious Adverse Events 
Any AE the investigator will consider 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, the investigator will complete the SAE form in the clinical database and send 
to 
 (fax numbers listed in Table 5) within 24 hours of awareness.  If the clinical 
database is down for any reason, the manual SAE forms will be utilized; however sites are 
responsible for ensuring the information on the manual SAE forms is entered into the clinical 
database once available. 


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Table 5: 
SAE Reporting Contact Information 
 
 
 
  
Non-North American sites will use access codes 
specific to their country.  Contact information for 
non-North American sites for SAE reporting will 
be provided by the clinical team directly to the 
sites. 
For questions regarding SAE reporting, contact your study manager, monitor, or 
 
 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. 
Within 24 hours of receipt of new information, the SAE form should be updated within the 
clinical database and submitted along with any supporting documentation (e.g., patient discharge 
summary or autopsy reports).  If the clinical database is down for any reason, the manual SAE 
forms should be used; however, sites are responsible for ensuring the updated information on the 
manual SAE forms is entered into the clinical database once available. 
The Sponsor or designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible but no later than 
7 calendar days after the initial receipt of the information.  Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency.  For other 
SAEs that do not meet the fatal or life-threatening unexpected criteria, but are reported to be 
associated with the use of the study drug, Reata or designee will notify the appropriate regulatory 
agencies in writing within the timeframe established by those regulatory agencies.  Reata or 
designee will provide copies of any reports to regulatory agencies regarding serious and 
unexpected SAEs to the investigators for review and submission to their IRB or EC, as 
appropriate.  
Principal investigators will be responsible for informing their IRB/EC of any SAEs at their site.  
SAE correspondence with regulatory authorities or IRBs/ECs must be submitted to the Sponsor 
or designee for recording in the study file. 
Note that the following AEs which are commonly observed in this patient population will not be 
reported to regulatory authorities as individual expedited reports, except in unusual 
circumstances: 
• Shortness of breath; 
• Lightheadedness/dizziness; 
• Syncope; 


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• Chest pain; 
• Palpitations; 
• Fatigue; 
• Edema/fluid retention; 
• Exertional dyspnea; 
• Hypoxemia. 
These events will be reviewed on a regular basis in aggregate and will be reported in an 
expedited manner if a safety signal is detected.  Regular safety study updates will be reported to 
regulatory authorities according to local guidelines. 


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12. 
STATISTICS 
12.1. 
Sample Size 
The aim of this long-term extended access study is primarily to provide continuing treatment to 
patients with bardoxolone methyl and to assess long-term safety and tolerability, hence no single 
primary variable has been identified.  Patient numbers will be determined by those who have 
been treatment-compliant and who have previously participated in clinical studies with 
bardoxolone methyl. 
12.2. 
Study Variables 
12.2.1. 
Safety Variables 
The safety variables will include results of physical examinations, laboratory test results (BNP 
and NT-Pro BNP), vital sign measurements, weight, AEs, and SAEs. 
12.3. 
Statistical Analyses 
A statistical analysis plan (SAP) detailing the analyses will be developed prior to the database 
lock.  All statistical analyses and data summaries will be performed using SAS® (Version 9.1 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized overall using descriptive statistics.  Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, relevant quartiles, 
standard deviation, coefficient of variation, and geometric mean (where applicable).  Categorical 
data will be summarized using frequency counts and percentages.  
12.3.1. 
Primary Analysis of Safety 
As the extension is of an open-label design with no comparator group, all statistical analyses will 
be descriptive.  Patients will be included in these analyses if they are included in the safety 
analysis and have both baseline and post-baseline data available for the variable being analyzed.  
The summary tables will be presented for the overall group of patients, and also split by previous 
treatment groups in prior bardoxolone methyl clinical studies.   
 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study-Specific Committees  
No steering committee, data safety monitoring committee, adjudication committee, or clinical 
endpoint committee will be used in this study. 
13.2. 
Study Monitoring 
The study site will be monitored remotely by the CRO periodically during the study to ensure 
that all aspects of the protocol will be followed and will include an electronic data collection 
which has a set of automatic data checks with data queries for programmed data collection.  
There will be monitoring of study site by telephone to ensure that the drug supplies have been 
provided and protocol instructions are well understood and applied. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Council for Harmonisation (ICH) 
guideline E6(R2): Good Clinical Practice: Consolidated Guideline and current standard operating 
procedures. 
13.3. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/EC review, and regulatory inspections, by providing direct access to 
all study records.  In the event of an audit, the principal investigator will agree to allow the 
Sponsor, representatives of the Sponsor, the FDA, and other relevant regulatory authorities 
access to all study records. 
The principal investigator shall promptly notify the Sponsor or designee of any audits scheduled 
by any regulatory authorities and shall promptly forward copies of any audit reports received to 
the Sponsor or designee. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Reata may conduct a quality assurance audit of the investigator’s clinical site, including 
CTM/IMP storage facilities.   
14.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for one year following the completion 
of the study. 
No potential investigator who has a vested financial interest in the success of this study may 
participate in this study. 
14.3. 
Sponsor Obligations  
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the Screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or designee is not financially responsible for treatment of 
the patient’s underlying disease. 
14.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R2) 
8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents 
to the Sponsor or designee, which include but are not limited to the following: 
• An original investigator-signed investigator agreement page of the protocol;  
• The IRB/EC approval of the protocol; 
• The IRB- or EC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the patient or legal guardians; 
• A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
• Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
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• Completed financial disclosure forms (Section 14.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 
designee a commitment to update this information promptly if any relevant changes 
occur during the course of the investigation and for 1 year following the completion 
of the study; 
• Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study. 
14.5. 
Clinical Study Insurance 
In accordance with the respective national drug laws, the Sponsor has taken out patient liability 
insurance for all patients who give their consent and enroll in this study.  This insurance covers 
potential fatalities, physical injuries, or damage to health that may occur during the clinical 
study. 
14.6. 
Use of Information  
All information regarding bardoxolone methyl supplied by the Sponsor to the investigator is 
privileged and confidential.  The investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor.  Furthermore, the 
investigator is obligated to provide the Sponsor with complete data obtained during the study.  
The information obtained from the clinical study will be used towards the development of 
bardoxolone methyl and may be disclosed to regulatory authorities, other investigators, corporate 
partners, or consultants as required. 


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15. 
ETHICS 
15.1. 
Institutional Review Board 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.  Continuous monitoring 
of the benefits and risks of bardoxolone methyl is performed by Reata in reviewing data from all 
ongoing and prior trials with bardoxolone methyl and by the safety monitoring committees that 
oversee safety for the ongoing placebo-controlled Phase 2 and Phase 3 trials (CATALYST, 
EudraCT 2016-000196-24; LARIAT, EudraCT 2016-004793-17).   
The principal investigator agrees to conduct the study in accordance with the International 
Conference on Harmonization (ICH) for Guidance for Industry on GCP ICH E6(R2) 
[https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_
_Step_4_2016_1109.pdf] and the principles of the Declaration of Helsinki 
[https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-
research-involving-human-subjects/].  The principal investigator must conduct all aspects of this 
study in accordance with all national, state, and local laws or regulations. 
15.3. 
Written Informed Consent 
Because the study will be conducted under a US Investigational New Drug Application, a signed 
informed consent form, in compliance with Title 21 of the US CFR Part 50, will be obtained 
from each patient before the patient enters the study.  For sites outside of the US, the signed 
consent will be obtained in accord with local regulations, ICH E6 (R2), and principles of the 
Declaration of Helsinki.  An informed consent template may be provided by the Sponsor or 
designee to the investigators.  The consent must be reviewed by the Sponsor or designee before 
IRB/EC submission.  Once reviewed, the consent will be submitted by the principal investigator 


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


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immediately notify the investigators and relevant regulatory agencies, including FDA in accord 
with 21 CFR 312.32. 
15.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviation.  The IRB/EC must 
be notified of all protocol deviations in a timely manner by the principal investigator or designee 
as appropriate.  Protocol deviations will be documented by the responsible monitor during 
monitoring visits, and those observations will be communicated to the investigator. 
If there is an immediate hazard to a patient the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/EC approval.  The Sponsor and IRB/EC must be 
notified of the deviation. 


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


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17. 
PUBLICATION POLICY 
The Sponsor supports communication and publication of study results whatever the findings of 
the study.   
The Sponsor reserves the right to review all planned communications and manuscripts based on 
the results of this study.  This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but to allow the Sponsor to confirm the 
accuracy of the data, to protect proprietary information, and to provide comments based on 
information that may not yet be available to the study investigators.  The Sponsor also 
encourages disclosure of any conflict of interest from all authors or investigators when 
manuscripts are submitted for publication.  Those individuals, who have contributed greatly to 
this study, including lead external advisors and select principal investigators, may serve on any 
potential publications committee for the study. 


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18. 
REFERENCES 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS 
Statement: Guidelines for the six-minute walk test.  Am J Respir Crit Care Med. 
2002;166(1):111-7. 
Batt J, Ahmed SS, Correa J, et al. Skeletal muscle dysfunction in idiopathic pulmonary arterial 
hypertension. Am J Respir Cell Mol Biol. 2014;50(1):74-86. 
Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic 
sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension 
assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 
2014;66(3):489-95. 
Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci U S A. 2005;102(12):4584-9. 
Eba S, Hoshikawa Y, Moriguchi T, et al. The nuclear factor erythroid 2-related factor 2 activator 
oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice. Am J Respir 
Cell Mol Biol. 2013;49(2):324-33. 
Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of 
pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary 
Hypertension of the European Society of Cardiology (ESC) and the European Respiratory 
Society (ERS), endorsed by the International Society of Heart and Lung Transplantation 
(ISHLT). Eur Heart J. 2009;30:2493-537. 
Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial 
hypertension. N Engl J Med. 2013;369(4):330-40. 
Holmström KM, Baird L, Zhang Y, et al. Nrf2 impacts cellular bioenergetics by controlling 
substrate availability for mitochondrial respiration. Biol Open. 2013;0:1-10. 
Lee DF, Kuo HP, Liu M, et al. KEAP1 E3 ligase-mediated downregulation of NF-kB signaling 
by targeting IKKbeta. Mol Cell. 2009;36(1):131-40. 
Ludtmann MH, Angelova PR, Zhang Y, et al. Nrf2 impacts the efficiency of mitochondrial fatty 
acid oxidation. Biochem J. 2014;457(3):415-24. 
Mainguy V, Maltais F, Saey D, et al. Peripheral muscle dysfunction in idiopathic pulmonary 
hypertension. Thorax. 2010;65(2):113-7. 
Malenfant S, Potus F, Fournier F, et al. Skeletal muscle proteomic signature and metabolic 
impairment in pulmonary hypertension. J Mol Med (Berl). 2015;93(5):573-84. 
Osburn WOand, Kensler TW. Nrf2 signaling: An adaptive response pathway for protection 
against environmental toxic insults. Mutat Res. 2008;659(1-2):31-9. 
Price L, Caramori G, Dorfmuller P, et al.  Endothelial cell NF-kB activation is increased in 
human idiopathic PAH. Thorax. 2010;65(4):A88-A89. 


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Pugh ME; Robbins, IM; Rice TW, et al. Unrecognized glucose intolerance is common in 
pulmonary arterial hypertension. J Heart Lung Transplant. 2011;30(8):904-11. 
Rojas-Rivera J, Ortiz A, Egido J. Antioxidants in kidney diseases: The impact of bardoxolone 
methyl. Int J Nephrol. 2012;2012:1-11. 
Saha PK, Reddy VT, Konopleva M, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-
28-oic-acid methyl ester has potent antidiabetic effects in diet-induced diabetic mice and 
Lepr(db/db) mice. J Biol Chem. 2010;285(52):40581-92. 
Sutendra G, Michelakis ED. The metabolic basis of pulmonary arterial hypertension. Cell Metab. 
2014;19(4):558-73. 
Tapson VF, Jing ZC, Xu KF, et al. Oral treprostinil for the treatment of pulmonary arterial 
hypertension in patients receiving background endothelin receptor antagonist and 
phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled 
trial. Chest. 2013;144(3):952-8. 
Wu QQ, Wang Y, Senitko M, et al. Bardoxolone methyl (BARD) ameliorates ischemic AKI and 
increases expression of protective genes Nrf2, PPARγ, and HO-1. Am J Physiol Renal Physiol. 
2011;300(5):F1180-F1192. 
 


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


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


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


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TECHNICAL ASPECTS OF THE 6MWT
Location
The 6MWT should be performed indoors, along a long, flat,
straight, enclosed corridor with a hard surface that is seldom
traveled. If the weather is comfortable, the test may be per-
formed outdoors. The walking course must be 30 m in length.
A 100-ft hallway is, therefore, required. The length of the cor-
ridor should be marked every 3 m. The turnaround points should
be marked with a cone (such as an orange traffic cone). A start-
ing line, which marks the beginning and end of each 60-m lap,
should be marked on the floor using brightly colored tape.
Rationale.  A shorter corridor requires patients to take more
time to reverse directions more often, reducing the 6MWD.
Most studies have used a 30-m corridor, but some have used
20-
0- or 50-m corridors (52–55). A recent multicenter st
found no significant effect of the length of straight courses
ranging from 50 to 164 ft, but patients walked farther on con-
tinuous (oval) tracks (mean 92 ft farther) (54).
The use of a treadmill to determine the 6MWD might save
space and allow constant monitoring during the exercise, but
the use of a treadmill for 6-minute walk testing is not recom-
mended. Patients are unable to pace themselves on a tread-
mill. In one study of patients with severe lung disease, the
mean distance walked on the treadmill during 6 minutes (with
the speed adjusted by the patients) was shorter by a mean of
14% when compared with the standard 6MWD using a 100-ft
hallway (57). The range of differences was wide, with patients
walking between 400–1,300 ft on the treadmill who walked
1,200 ft in the hallway. Treadmill test results, therefore, are
not interchangeable with corridor tests.
REQUIRED EQUIPMENT
1. Countdown timer (or stopwatch)
2. Mechanical lap counter
3. Two small cones to mark the turnaround points
4. A chair that can be easily moved along the walking course
5. Worksheets on a clipboard
6. A source of oxygen
7. Sphygmomanometer
8. Telephone
9. Automated electronic defibrillator
PATIENT PREPARATION
1. Comfortable clothing should be worn.
2. Appropriate shoes for walking should be worn.
3. Patients should use their usual walking aids during the test
(cane, walker, etc.).
4. The patient’s usual medical regimen should be continued.
5. A light meal is acceptable before early morning or early af-
ternoon tests.
6. Patients should not have exercised vigorously within 2 hours
of beginning the test.
MEASUREMENTS
1. Repeat testing should be performed about the same time
of day to minimize intraday variability.
2.
3.
A “warm-up” period before the test should not be performed.
The patient should sit at rest in a chair, located near the
starting position, for at least 10 minutes before the test
starts. During this time, check for contraindications, mea-
sure pulse and blood pressure, and make sure that cloth-
ing and shoes are appropriate. Compete the first portion
of the worksheet (see the APPENDIX).
4. Pulse oximetry is optional. If it is performed, measure and
record baseline heart rate and oxygen saturation (SpO2)
and follow manufacturer’s instructions to maximize the sig-
nal and to minimize motion artifact (56, 57). Make sure the
readings are stable before recording. Note pulse regularity
and whether the oximeter signal quality is acceptable.
The rationale for measuring oxygen saturation is that al-
though the distance is the primary outcome measure, im-
provement during serial evaluations may be manifest either
by an increased distance or by reduced symptoms with the
same distance walked (39). The 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. (57)
5. Have the patient stand and rate their baseline dyspnea
and overall fatigue using the Borg scale (see Table 2 for
the Borg scale and instructions [58]).
6. Set the lap counter to zero and the timer to 6 minutes. As-
semble all necessary equipment (lap counter, timer, clip-
board, Borg Scale, worksheet) and move to the starting
point.
7. Instruct the patient as follows:
“The object of this test is to walk as far as possible for 6
minutes. You will walk back and forth in this hallway. Six
minutes is a long time to walk, so you will be exerting your-
self. You will probably get out of breath or become ex-
hausted. You are permitted to slow down, to stop, and to
rest as necessary. You may lean against the wall while rest-
ing, but resume walking as soon as you are able.
You will be walking back and forth around the cones.
You should pivot briskly around the cones and continue
back the other way without hesitation. Now I’m going to
show you. Please watch the way I turn without hesitation.”
Demonstrate by walking one lap yourself. Walk and
pivot around a cone briskly.
“Are you ready to do that? I am going to use this
counter to keep track of the number of laps you complete. I
will click it each time you turn around at this starting line.
Remember that the object is to walk AS FAR AS POSSI-
BLE for 6 minutes, but don’t run or jog.
Start now, or whenever you are ready.”
TABLE 2. THE BORG SCALE
0
Nothing at all
0.5
Very, very slight (just noticeable)
1
Very slight
2
Slight (light)
3
Moderate
4
Somewhat severe
5
Severe (heavy)
6
7
Very severe
8
9
10
Very, very severe (maximal)
This Borg scale should be printed on heavy paper (11 inches high and perhaps lami-
nated) in 20-point type size. At the beginning of the 6-minute exercise, show the scale
to the patient and ask the patient this: “Please grade your level of shortness of breath
using this scale.” Then ask this: “Please grade your level of fatigue using this scale.”
At the end of the exercise, remind the patient of the breathing number that they
chose before the exercise and ask the patient to grade their breathing level again. Then
ask the patient to grade their level of fatigue, after reminding them of their grade be-
fore the exercise.


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8. Position the patient at the starting line. You should also
stand near the starting line during the test. Do not walk
with the patient. As soon as the patient starts to walk,
start the timer.
9. Do not talk to anyone during the walk. Use an even tone
of voice when using the standard phrases of encourage-
ment. Watch the patient. Do not get distracted and lose
count of the laps. Each time the participant returns to the
starting line, click the lap counter once (or mark the lap
on the worksheet). Let the participant see you do it. Ex-
aggerate the click using body language, like using a stop-
watch at a race.
After the first minute, tell the patient the following (in
even tones): “You are doing well. You have 5 minutes to
go.”
When the timer shows 4 minutes remaining, tell the pa-
tient the following: “Keep up the good work. You have 4
minutes to go.”
When the timer shows 3 minutes remaining, tell the pa-
tient the following: “You are doing well. You are halfway
done.”
When the timer shows 2 minutes remaining, tell the pa-
tient the following: “Keep up the good work. You have only
2 minutes left.”
When the timer shows only 1 minute remaining, tell the
patient: “You are doing well. You have only 1 minute to
go.”
Do not use other words of encouragement (or body lan-
guage to speed up).
If the patient stops walking during the test and needs a
rest, say this: “You can lean against the wall if you would
like; then continue walking whenever you feel able.” Do
not stop the timer. If the patient stops before the 6 minutes
are up and refuses to continue (or you decide that they
should not continue), wheel the chair over for the patient to
sit on, discontinue the walk, and note on the worksheet the
distance, the time stopped, and the reason for stopping pre-
maturely.
When the timer is 15 seconds from completion, say this:
“In a moment I’m going to tell you to stop. When I do, just
stop right where you are and I will come to you.”
When the timer rings (or buzzes), say this: “Stop!” Walk
over to the patient. Consider taking the chair if they look
exhausted. Mark the spot where they stopped by placing a
bean bag or a piece of tape on the floor.
10.
11.
Post-test: Record the postwalk Borg dyspnea and fatigue
levels and ask this: “What, if anything, kept you from walk-
ing farther?”
If using a pulse oximeter, measure SpO2 and pulse rate
from the oximeter and then remove the sensor.
12. Record the number of laps from the counter (or tick marks
on the worksheet).
13. Record the additional distance covered (the number of meters
in the final partial lap) using the markers on the wall as dis-
tance guides. Calculate the total distance walked, rounding to
the nearest meter, and record it on the worksheet.
14. Congratulate the patient on good effort and offer a drink
of water.
QUALITY ASSURANCE
Sources of Variability
There are many sources of 6MWD variability (see Table 3).
The sources of variability caused by the test procedure itself
should be controlled as much as possible. This is done by fol-
lowing the standards found in this document and by using a
quality-assurance program.
Practice Tests
A practice test is not needed in most clinical settings but
should be considered. If a practice test is done, wait for at least
1 hour before the second test and report the highest 6MWD as
the patient’s 6MWD baseline.
Rationale.  The 6MWD is only slightly higher for a second
6MWT performed a day later. The mean reported increase
ranges from 0 to 17% (23, 27, 40, 41, 54, 59). A multicenter
study of 470 highly motivated patients with severe COPD per-
formed two 6MWTs 1 day apart, and on average, the 6MWD
was only 66 ft (5.8%) higher on the second day (54).
Performance (without an intervention) usually reaches a
plateau after two tests done within a week (8, 60). The training
effect may be due to improved coordination, finding optimal
stride length, and overcoming anxiety. The possibility of a
practice or training effect from tests repeated after more than
a month has not been studied or reported; however, it is likely
that the effect of training wears off (does not persist) after a
few weeks.
Technician Training and Experience
Technicians who perform 6MWTs should be trained using the
standard protocol and then supervised for several tests before
performing them alone. They should also have completed car-
diopulmonary resuscitation training.
Rationale.  One multicenter study of older people found
that after correction for many other factors, two of the techni-
cians had mean 6MWDs that were approximately 7% lower
than the other two sites (31).
Encouragement
Only the standardized phrases for encouragement (as speci-
fied previously here) must be used during the test.
Rationale.  Encouragement significantly increases the dis-
tance walked (42). Reproducibility for tests with and without
encouragement is similar. Some studies have used encourage-
ment every 30 seconds, every minute, or every 2 minutes. We
have chosen every minute and standard phrases. Some studies
(53)
53) have instructed patients to walk as fast as possible.
though larger mean 6MWDs may be obtained thereby, we rec-
ommend that such phrases not be used, as they emphasize ini-
tial speed at the expense of earlier fatigue and possible
excessive cardiac stress in some patients with heart disease.
TABLE 3. 6MWD SOURCES OF VARIABILITY
Factors reducing the 6MWD
Shorter height
Older age
Higher body weight
Female sex
Impaired cognition
A shorter corridor (more turns)
Pulmonary disease (COPD, asthma, cystic fibrosis, interstitial lung disease)
Cardiovascular disease (angina, MI, CHF, stroke, TIA, PVD, AAI)
Musculoskeletal disorders (arthritis, ankle, knee, or hip injuries, muscle wasting, etc.)
Factors increasing the 6MWD
Taller height (longer legs)
Male sex
High motivation
A patient who has previously performed the test
Medication for a disabling disease taken just before the test
Oxygen supplementation in patients with exercise-induced hypoxemia
Definition of abbreviations: COPD  chronic obstructive pulmonary disease; 6MWD  
6-minute walking distance.


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Supplemental Oxygen
If oxygen supplementation is needed during the walks and se-
rial tests are planned (after an intervention other than oxygen
therapy), then during all walks by that patient oxygen should
be delivered in the same way with the same flow. If the flow
must be increased during subsequent visits due to worsening
gas exchange, this should be noted on the worksheet and con-
sidered during interpretation of the change noted in 6MWD.
The type of oxygen delivery device should also be noted on
the report: for instance, the patient carried liquid oxygen or
pushed or pulled an oxygen tank, the delivery was pulsed or
continuous, or a technician walked behind the patient with the
oxygen source (not recommended). Measurements of pulse
and SpO2 should be made after waiting at least 10 minutes af-
ter any change in oxygen delivery.
Rationale.  For patients with COPD or interstitial lung dis-
ease, oxygen supplementation increases the 6MWD (17, 59,
61, 63). Carrying a portable gas container (but not using it for
supplemental oxygen) reduced the mean 6MWD by 14% in
one study of patients with severe respiratory disability, but us-
ing the container to deliver supplemental oxygen during the
exercise increased the mean 6MWD by 20–35% (59).
Medications
The type of medication, dose, and number of hours taken be-
fore the test should be noted.
Rationale.  Significant improvement in the distance walked,
or the dyspnea scale, after administration of bronchodilators
has been demonstrated in patients with COPD (62, 63), as well
as cardiovascular medications in patients with heart failure (19).
INTERPRETATION
Most 6MWTs will be done before and after intervention, and
the primary question to be answered after both tests have
been completed is whether the patient has experienced a clini-
cally significant improvement. With a good quality-assurance
program, with patients tested by the same technician, and af-
ter one or two practice tests, short-term reproducibility of the
6MWD is excellent (37). It is not known whether it is best for
clinical purposes to express change in 6MWD as (1) an abso-
lute value, (2) a percentage change, or (3) a change in the per-
centage of predicted value. Until further research is available,
we recommend that change in 6MWD be expressed as an ab-
solute value (e.g., the patient walked 50 m farther).
A statistically significant mean increase in 6MWD in a
group of study participants is often much less than a clinically
significant increase in an individual patient. In one study of
112 patients (half of them women) with stable, severe COPD,
the smallest difference in 6MWD that was associated with a
noticeable clinical difference in the patients’ perception of ex-
ercise performance was a mean of 54 m (95% confidence in-
terval, 37–71 m) (64). This study suggests that for individual
patients with COPD, an improvement of more than 70 m in
the 6MWD after an intervention is necessary to be 95% confi-
dent that the improvement was significant. In an observational
study of 45 older patients with heart failure, the smallest dif-
ference in 6MWD that was associated with a noticeable differ-
ence in their global rating of worsening was a mean of 43 m
(20). The 6MWD was more responsive to deterioration than
to improvement in heart failure symptoms.
Reported Mean Changes in 6MWD After Interventions
Supplemental oxygen (4 L/min) during exercise in patients with
COPD or interstitial lung disease increased mean 6MWD by
approximately 95 m (36%) in one study (59). Patients taking
an inhaled corticosteroid experienced a mean 33 m (8%) in-
crease in 6MWD in an international COPD study (16). Pa-
tients with COPD in a study of the effects of exercise and dia-
phragmatic strength training experienced a mean increase in
6MWD of 50 m (20%) (65). Lung volume reduction surgery in
patients with very severe COPD has been reported to increase
6MWD by a mean of 55 m (20%) (13).
Cardiac rehabilitation in patients referred with various heart
diseases increased 6MWD by a mean of 170 m (15%) in a recent
study (66). In 25 older patients with heart failure, an angiotensin-
converting enzyme inhibitor medication (50 mg captopril per
day) improved 6MWD a mean of 64 m (39%) compared with a
mean increase of only 8% in those receiving a placebo (19).
Interpreting Single Measurements of Functional Status
Optimal reference equations from healthy population-based
samples using standardized 6MWT methods are not yet avail-
able. In one study, the median 6MWD was approximately 580
m for 117 healthy men and 500 m for 173 healthy women (50).
A mean 6MWD of 630 m was reported by another study of 51
healthy older adults (55). Differences in the population sam-
pled, type and frequency of encouragement, corridor length,
and number of practice tests may account for reported differ-
ences in mean 6MWD in healthy persons. Age, height, weight,
and sex independently affect the 6MWD in healthy adults;
therefore, these factors should be taken into consideration
when interpreting the results of single measurements made to
determine functional status. We encourage investigators to pub-
lish reference equations for healthy persons using the previ-
ously mentioned standardized procedures.
A low 6MWD is nonspecific and nondiagnostic. When the
6MWD is reduced, a thorough search for the cause of the im-
pairment is warranted. The following tests may then be help-
ful: pulmonary function, cardiac function, ankle–arm index,
muscle strength, nutritional status, orthopedic function, and
cognitive function.
Conclusions
The 6MWT is a useful measure of functional capacity targeted
at people with at least moderately severe impairment. The test
has been widely used for preoperative and postoperative eval-
uation and for measuring the response to therapeutic inter-
ventions for pulmonary and cardiac disease. These guidelines
provide a standardized approach to performing the 6MWT.
The committee hopes that these guidelines will encourage fur-
ther research into the 6MWT and allow direct comparisons
among different studies.
This statement was developed by the ATS Committee on Proficiency Stan-
dards for Clinical Pulmonary Function Laboratories.
Members of the committee are:
ROBERT O. CRAPO, M.D., Chair*
RICHARD CASABURI, PH.D, M.D.
ALLAN L. COATES, M.D.
PAUL L. ENRIGHT, M.D.*
NEIL R. MACINTYRE, M.D.
ROY T. MCKAY, PH.D.
DOUGLAS JOHNSON, M.D.
JACK S. WANGER, M.S.
R. JORGE ZEBALLOS, M.D.*
Ad Hoc Committee members are:
VERA BITTNER, M.D.
CARL MOTTRAM, R.R.T.
*Writing Committee Members
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APPENDIX
The following elements should be present on the 6MWT worksheet and report:
Lap counter:
__ __ __ __ __
__ __ __ __ __
__ __ __ __ __
Patient name: ____________________
Patient ID# ___________
Walk # ______
Tech ID: _________ Date: __________
Gender: M F
Age: ____
Race: ____
Height: ___ft ____in, ____ meters
Weight: ______ lbs, _____kg
Blood pressure: _____ / _____
Medications taken before the test (dose and time): __________________
Supplemental oxygen during the test: No
Yes, flow ______ L/min, type _____
End of Test
___:___
Baseline
Time
___:___
Heart Rate
_____
_____
Dyspnea
____
____
Fatigue
SpO2
____ %
____ (Borg scale)
____ (Borg scale)
____%
Stopped or paused before 6 minutes? No
Yes, reason: _______________
Other symptoms at end of exercise: angina
dizziness
hip, leg, or calf pain
Number of laps: ____ (60 meters)  final partial lap: _____ meters 
Total distance walked in 6 minutes: ______ meters
Predicted distance: _____ meters
Percent predicted: _____%
Tech comments:
Interpretation (including comparison with a preintervention 6MWD):


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20.
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF
PULMONARY HYPERTENSION MODIFIED AFTER THE NEW 
YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ACCORDING TO THE WHO 1998
(GALIE, 2009)
World Health Organization functional assessment classification 
Class 
I:  
Patients with pulmonary hypertension (PH) but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, 
or near syncope. 
Class 
II:  
Patients with PH resulting in slight limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near 
syncope. 
Class 
III:  
Patients with PH resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class 
IV:  
Patients with PH with inability to carry out any physical activity without symptoms. 
These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even be 
present at rest. Discomfort is increased by any physical activity. 


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21. 
APPENDIX 3:  BORG CR10 SCALE 
 
 
 

Prot_002.pdf: 
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1 
 
 
 
 
 
 
BARDOXOLONE METHYL (RTA 402) 
 
402-C-1602 
 
EUDRACT NUMBER: 2016-004365-16 
 
AN EXTENDED ACCESS PROGRAM TO ASSESS 
LONG-TERM SAFETY OF BARDOXOLONE METHYL 
IN PATIENTS WITH PULMONARY HYPERTENSION 
Version 3.1 – 16 July 2018 
United Kingdom 
 
Protocol History 
Version 1.0 – 27 October 2016 
Version 2.0 – 05 January 2017 
Version 2.1 – 09 May 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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3 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for bardoxolone methyl.  I have read the 
402-C-1602 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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4 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Medical and Scientific 
Leader 
 
 
 
 
 
 
 
 
Clinical Study 
Manager 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
SAE Reporting 
 
 
 
 
 
 
 
 
 
 
Non-North American sites will use access codes specific to their country.  
Numbers for non-North American sites for SAE reporting will be provided 
by the clinical team directly to the sites for reporting and submitting SAE 
information to 
.  
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Product: 
Bardoxolone methyl 
Title of Study:  
An Extended Access Program to Assess Long-Term Safety of Bardoxolone Methyl in Patients with 
Pulmonary Hypertension  
Study center(s): Approximately 150 study centers  
Studied period: Until commercial availability of 
bardoxolone methyl 
Estimated date first patient enrolled: February 2017 
Estimated date last patient completed: Patient will 
remain in the study until bardoxolone methyl is 
available through commercial channels or until patient 
withdrawal, whichever is sooner  
The end of the study is defined as the last visit of the 
last patient. 
Phase of development:  
3a 
Primary Objectives:   
To provide continuing open-label treatment with bardoxolone methyl as part of this extended access 
program while collecting ongoing safety and tolerability data of bardoxolone methyl.   
Primary Safety Endpoint: 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse events 
(SAEs), and change from baseline in the following assessments: physical examinations, vital sign 
measurements, B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), 
and weight. 
Methodology:  
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in 
qualified patients with pulmonary hypertension (PH) who previously participated in controlled clinical 
studies with bardoxolone methyl.  
Qualified patients will start dosing at 10 mg of bardoxolone methyl every other day, then begin once daily 
dosing at Week 4 (unless contraindicated clinically) and continue until the drug is available through 
commercial channels (including reimbursement) or until patient withdrawal, whichever is sooner.  Dose 
de-escalation (down to 5 mg) is permitted during the study, if indicated clinically.    
All patients in the study will follow the same visit and assessment schedule.  Patients will be scheduled to 
be assessed in person during treatment at Day 1, Week 2, Week 4, Week 6, Week 8, Week 24, and every 
24 weeks thereafter.  Patients will also be assessed by telephone contact on Days 3, 10, 21, 31, and 38.  
Day 1 for this extended access study should occur on the same day as the last visit in the controlled 
clinical study.  Patient status should be carefully monitored by the investigator during the first 8 weeks of 
study treatment.  Assessments required for both the last visit in the controlled study and Day 1 for this 
study should only be completed once. 


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Patients from the CATALYST study: 
Day 1 of this extended access study will coincide with the Week 28 follow-up visit for patients from 
CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended access program 
is not yet open for enrollment at the time of a patient’s Week 28 visit, the Day 1 visit (i.e., enrollment) 
must occur within 30 days of site activation.  Exceptions allowing CATALYST patients who have 
completed 24 weeks of treatment to schedule their follow-up assessments prior to Week 28 and still be 
considered eligible for this open-label study should be discussed with the Chief Medical Officer at Reata, 
or designee, and will be considered on a case-by-case basis.  
Patients from the LARIAT study:  
Day 1 of this extended access study will coincide with the End-of-Study visit for patients from LARIAT 
(402-C-1302, NCT02036970).  
Schema for Study of Bardoxolone Methyl in Patients with Pulmonary Hypertension 
 
 
Number of patients (planned):  
Patient numbers will be determined by those who are treatment-compliant and who have previously 
participated in clinical studies with bardoxolone methyl.  
Main criteria for inclusion: 
Treatment-compliant patients who are participating in qualifying ongoing studies and have completed 
required End-of-Treatment and/or Follow-up visits in a prior clinical study with bardoxolone methyl.   
Major exclusion criteria: 
1. Participation in other investigational clinical studies involving interventional products being 
tested or used in a way different from the approved form or when used for an unapproved 
indication; 
2. Patients who have an ongoing SAE from a clinical study that is assessed by the investigator as 
related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners of 
childbearing potential and females of childbearing potential) while taking study drug;  
4. Women who are pregnant or breastfeeding; 
5. 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; 
6. Known hypersensitivity to any component of the study drug. 


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Investigational product, dosage, mode of administration, and duration of treatment:  
Bardoxolone methyl will be administered orally (every other day or once daily) at 10 mg until it becomes 
commercially available.  Dose de-escalation (down to 5 mg) is permitted during the study, if indicated 
clinically. 
Reference therapy, dosage and mode of administration:  
None. 
Criteria for evaluation: 
Safety: Results of physical examinations, laboratory results, BNP, NT-ProBNP, vital sign measurements, 
weight, AEs, and SAEs. 
Statistical methods: 
Sample size: The aim of this long-term extended access study is primarily to provide continuing treatment 
to patients with bardoxolone methyl and to assess long-term safety and tolerability, hence no single 
primary variable has been identified.  Patient numbers will be determined by those who have been 
treatment-compliant and who have previously participated in clinical studies with bardoxolone methyl. 
Primary analysis of safety: As the extension is of an open-label design with no comparator group, all 
statistical analyses will be descriptive.  The summary tables will be presented for the overall group of 
patients, and also split by previous treatment groups (i.e., bardoxolone methyl or placebo) in prior 
bardoxolone methyl clinical studies.  


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3. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................8 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Study Rationale ...........................................................................................................17 
5.2. 
Clinical Experience with Bardoxolone Methyl ..........................................................17 
5.2.1. 
Safety and Tolerability ...............................................................................................17 
5.2.2. 
Fluid Overload ............................................................................................................17 
5.2.3. 
Transaminase and Gamma-Glutamyl Transpeptidase Elevations ..............................18 
5.2.4. 
Muscle Spasms ...........................................................................................................19 
5.2.5. 
Weight Loss ................................................................................................................19 
5.2.6. 
Hypomagnesaemia ......................................................................................................19 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................21 
6.1. 
Primary Objectives .....................................................................................................21 
6.2. 
Primary Safety Endpoint: ...........................................................................................21 
7. 
INVESTIGATIONAL PLAN .....................................................................................22 
7.1. 
Overall Study Design ..................................................................................................22 
7.2. 
Number of Patients .....................................................................................................22 
7.3. 
Treatment Assignment ................................................................................................22 
7.3.1. 
Dose Escalation and Dose De-Escalation ...................................................................23 
7.4. 
Criteria for Study Termination ...................................................................................23 
7.5. 
Criteria for Premature Termination or Suspension of Investigational Sites ...............23 
7.6. 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites ..........................................................................23 
7.7. 
Schedule of Assessments ............................................................................................23 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................26 
8.1. 
Patient Inclusion Criteria ............................................................................................26 
8.2. 
Patient Exclusion Criteria ...........................................................................................26 


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8.3. 
Patient Discontinuation and Termination ...................................................................26 
9. 
TREATMENT OF PATIENTS ..................................................................................28 
9.1. 
Select Management Guidelines ..................................................................................28 
9.1.1. 
Management of Fluid Status .......................................................................................28 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................28 
9.1.3. 
Management of Muscle Spasms .................................................................................29 
9.1.4. 
Weight Loss ................................................................................................................29 
9.1.5. 
Hypomagnesaemia ......................................................................................................29 
9.1.6. 
Nausea .........................................................................................................................29 
9.2. 
Description of Study Drug ..........................................................................................30 
9.3. 
Concomitant Medications ...........................................................................................30 
9.3.1. 
Excluded Medications ................................................................................................30 
9.3.2. 
Permitted Medications ................................................................................................30 
9.4. 
Treatment Compliance ................................................................................................31 
9.5. 
Randomization ............................................................................................................31 
9.6. 
Blinding ......................................................................................................................31 
9.7. 
Unscheduled Visits .....................................................................................................31 
9.8. 
Pregnancy ...................................................................................................................31 
9.8.1. 
Women of Childbearing Potential ..............................................................................31 
9.8.2. 
Methods of Birth Control............................................................................................31 
9.8.3. 
Suspected Pregnancy ..................................................................................................32 
9.9. 
Serious Toxicities .......................................................................................................33 
9.10. 
Study Procedures ........................................................................................................33 
9.10.1. 
Informed Consent .......................................................................................................33 
9.10.2. 
Inclusion/Exclusion ....................................................................................................33 
9.10.3. 
Prior and Current Concomitant Medications ..............................................................33 
9.10.4. 
Current PAH Background Medications ......................................................................33 
9.10.5. 
Weight and Body Mass Index .....................................................................................33 
9.10.6. 
Vital Sign Measurements ............................................................................................34 
9.10.7. 
Physical Examination .................................................................................................34 
9.10.8. 
Pregnancy Test ............................................................................................................34 
9.10.9. 
Study Drug Administration.........................................................................................34 
9.10.10. 
Study Drug Dispensation and Collection ...................................................................34 


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9.10.11. 
Telephone Contact ......................................................................................................34 
9.10.12. 
Adverse Event Collection ...........................................................................................35 
9.10.13. 
Clinical Chemistry ......................................................................................................35 
9.10.14. 
N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide .................35 
9.10.15. 
6-Minute Walk Test ....................................................................................................35 
9.10.16. 
WHO/NYHA Functional Class Assessment ..............................................................36 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................37 
10.1. 
Study Drug ..................................................................................................................37 
10.2. 
Study Drug Packaging and Labeling ..........................................................................37 
10.3. 
Study Drug Storage .....................................................................................................37 
10.4. 
Study Drug Administration.........................................................................................37 
10.5. 
Study Drug Accountability .........................................................................................38 
10.6. 
Study Drug Handling and Disposal ............................................................................38 
11. 
SAFETY ASSESSMENTS ........................................................................................39 
11.1. 
Safety Parameters .......................................................................................................39 
11.2. 
Adverse and Serious Adverse Events .........................................................................39 
11.2.1. 
Definition of Adverse Events .....................................................................................39 
11.2.1.1. 
Adverse Event .............................................................................................................39 
11.2.1.2. 
Serious Adverse Event ................................................................................................39 
11.3. 
Eliciting Adverse Event Information ..........................................................................40 
11.4. 
Assessment of Causality .............................................................................................41 
11.5. 
Assessment of Severity ...............................................................................................41 
11.6. 
Recording Adverse Events .........................................................................................41 
11.7. 
Reporting Serious Adverse Events .............................................................................42 
12. 
STATISTICS ..............................................................................................................45 
12.1. 
Sample Size ................................................................................................................45 
12.2. 
Study Variables ...........................................................................................................45 
12.2.1. 
Safety Variables ..........................................................................................................45 
12.3. 
Statistical Analyses .....................................................................................................45 
12.3.1. 
Primary Analysis of Safety .........................................................................................45 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................46 
13.1. 
Study-Specific Committees ........................................................................................46 
13.2. 
Study Monitoring ........................................................................................................46 


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13.3. 
Audits and Inspections ................................................................................................46 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................47 
14.1. 
Quality Assurance .......................................................................................................47 
14.2. 
Financial Disclosure ...................................................................................................47 
14.3. 
Sponsor Obligations....................................................................................................47 
14.4. 
Investigator Documentation ........................................................................................47 
14.5. 
Clinical Study Insurance .............................................................................................48 
14.6. 
Use of Information ......................................................................................................48 
15. 
ETHICS ......................................................................................................................49 
15.1. 
Institutional Review Board or Ethics Committee Review ..........................................49 
15.2. 
Ethical Conduct of the Study ......................................................................................49 
15.3. 
Written Informed Consent ..........................................................................................49 
15.4. 
Confidentiality ............................................................................................................50 
15.5. 
Modification of the Protocol .......................................................................................50 
15.6. 
Protocol Deviations ....................................................................................................51 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................52 
16.1. 
Retention of Records ..................................................................................................52 
16.2. 
Case Report Forms .....................................................................................................52 
17. 
PUBLICATION POLICY ..........................................................................................53 
18. 
REFERENCES ...........................................................................................................54 
19. 
APPENDIX 1: ATS GUIDELINES FOR THE SIX-MINUTE WALK TEST ..........56 
20. 
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF PULMONARY 
HYPERTENSION MODIFIED AFTER THE NEW YORK HEART 
ASSOCIATION FUNCTIONAL CLASSIFICATION ACCORDING TO 
THE WHO 1998 (GALIE, 2009) ...............................................................................64 
21. 
APPENDIX 3:  BORG CR10 SCALE .......................................................................65 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................13 
Table 3: 
Schedule of Assessments ............................................................................................24 
Table 4: 
Bardoxolone Methyl Drug Product Information ........................................................30 
Table 5: 
SAE Reporting Contact Information ..........................................................................43 
 


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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 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
ATS 
American Thoracic Society 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
CFR 
Code of Federal Regulations (US) 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
CRO 
Contract research organization 
CTD-PAH 
Connective tissue disease-associated pulmonary arterial 
hypertension 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
ICH 
International Conference on Harmonization 
IKKβ 
Inhibitor of nuclear factor kappa β kinase beta subunit 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   


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Abbreviation or Specialist Term 
Explanation 
NYHA FC 
New York Heart Association Functional Classification 
PAH 
Pulmonary arterial hypertension 
PH 
Pulmonary hypertension 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 


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




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patients with CTD-PAH had similar sustained increases in 6MWD through Week 32.  On the 
basis of these data, Reata expanded the LARIAT protocol (Version 5.0) to include PH patients 
with ILD, including WHO Group III patients with CTD-associated ILD, idiopathic pulmonary 
fibrosis, non-specific interstitial pneumonia, and WHO Group V patients with sarcoidosis.  Reata 
has also initiated a Phase 3 study in WHO Group I CTD-PAH patients (402-C-1504, 
CATALYST, NCT02657356, EudraCT 2016-000196-24) to study the safety and efficacy of 
bardoxolone methyl in those patients.   
5.1. 
Study Rationale 
The established pharmacologic effects of bardoxolone methyl, including the suppression of 
pathologic NF-κB signaling and inflammation and mitochondrial dysfunction, are directly 
applicable to the treatment of PH.  Despite available therapies, the prognosis for PH remains 
poor, especially for patients with CTD (Chung, 2014) and ILD.  Given the severity of the 
underlying disease, this study seeks to offer patients who previously participated in clinical 
studies extended access to bardoxolone methyl until it is available through commercial channels 
(including reimbursement). 
The bardoxolone methyl dose of 10 mg (with an option to decrease to 5 mg, if indicated 
clinically) was selected based on preliminary data from a Phase 2 trial (402-C-1302), which 
suggest this may be an optimum dose for PAH patients.  In the Phase 2 trial, bardoxolone methyl 
doses of 2.5 mg, 5 mg, and 10 mg produced increases in 6MWD in PAH patients during a 16-
week treatment period.  A 20-mg dose was also effective; however, increased rates of AEs, 
particularly nausea, were observed in PAH patients receiving 20 mg of bardoxolone methyl.  No 
specific safety concerns have been observed in PAH patients to date, including patients that have 
received bardoxolone methyl for over 1 year as part of the open-label extension portion of the 
Phase 2 trial. 
For further information regarding the scientific rationale and available safety and efficacy data 
for bardoxolone methyl, refer to the Investigator’s Brochure.  
5.2. 
Clinical Experience with Bardoxolone Methyl 
Approximately 1950 individuals have been exposed to bardoxolone methyl at the time of 
initiation of this study.  Sixteen studies have been completed (7 in patients with chronic kidney 
disease (CKD) who also had type 2 diabetes, 4 in non-CKD indications, and 5 in healthy 
subjects) and 2 studies are ongoing in patients with PH.   
5.2.1. 
Safety and Tolerability 
Please refer to the Investigator’s Brochure for a detailed discussion of safety findings with 
bardoxolone methyl for studies in healthy subjects, oncology, CKD, and patients with PH. 
5.2.2. 
Fluid Overload 
Similar to endothelin receptor antagonists 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 a Phase 3 trial (BEACON), which enrolled patients with Stage 4 CKD (eGFR 
of 15-29 mL/min/1.73 m2) and type 2 diabetes.  The overall increased risk for fluid overload and 


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heart failure events with bardoxolone methyl appeared to be limited to the first three to four 
weeks after initiation of treatment.  Elevated B-type natriuretic peptide (BNP) and prior 
hospitalization for heart failure were identified as risk factors that contributed to increased risk 
for these events.  The increased risk for these events from bardoxolone methyl treatment had not 
been observed in six previous CKD studies, which were conducted mostly in patients with Stage 
3b CKD (eGFR of 30-44 mL/min/1.73 m2), patients with hepatic dysfunction, cancer patients, or 
healthy volunteers.  
Review of admission notes and narrative descriptions for heart failure hospitalizations in 
BEACON indicates that heart failure in bardoxolone methyl-treated patients was often preceded 
by rapid fluid weight gain (several kilograms within the first weeks of treatment initiation) and 
was not associated with acute renal decompensation or acutely reduced left ventricular 
contractility.  Available data from BEACON and other studies suggest that bardoxolone methyl 
treatment can differentially affect hemodynamic status according to the clinical condition of 
patients and likely promotes fluid retention in patients with more advanced renal dysfunction and 
other recognized risk factors associated with heart failure at baseline.   
In a Phase 2 dose-ranging study of the efficacy and safety of bardoxolone methyl in patients with 
PH (LARIAT), risk mitigation procedures were employed to reduce the potential for 
bardoxolone methyl-induced fluid overload; these procedures excluded patients with the 
identified risk factors and ensured close monitoring for fluid retention within the first month of 
treatment.  To date, the risk for acute fluid overload adverse events (AEs) with bardoxolone 
methyl in late-stage CKD patients has not been observed in PAH patients.   
5.2.3. 
Transaminase and Gamma-Glutamyl Transpeptidase Elevations  
In clinical studies of bardoxolone methyl, almost all patients had increases of transaminase 
enzymes above baseline upon initiation of treatment, which followed a consistent pattern.  These 
increases were not associated with elevations in bilirubin or other signs of liver toxicity.  In a 
large Phase 3 study that enrolled 2185 patients with type 2 diabetes and stage 4 CKD 
(BEACON), fewer hepatobiliary SAEs were observed in the bardoxolone methyl arm than in the 
placebo arm.  The elevations begin immediately after initiation of treatment or an increase in 
dose; they peak approximately two to four weeks later.  In most patients, transaminase elevations 
were mild, but approximately 4% to 11% of patients experienced an elevation greater than 3X 
the upper limit of normal (ULN).  The elevations resolved to levels less than the ULN in most all 
patients with elevations, within two weeks after peak values while patients continued taking 
study drug.  Patients who experienced elevations to greater than 3X the ULN sometimes required 
additional time to resolve.  While some patients have had elevations to above 3X the ULN, 
persistent elevations to above 3X the ULN have not been observed, and the elevations did not 
recur once resolved, unless caused by other factors. 
Bardoxolone methyl regulates gamma-glutamyl transpeptidase (GGT), a known Nrf2 target 
gene.  In clinical studies, low level GGT elevations during treatment were common, mild, and 
typically lasted longer than alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevations.  Bilirubin levels in patients experiencing transaminase or GGT elevations due to 
treatment with bardoxolone methyl either remained at baseline levels or decreased.  The ALT, 
AST, and GGT elevations were generally self-limiting in patients who continued treatment with 
study drug.  


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5.2.4. 
Muscle Spasms 
Muscle spasm was the most frequently reported AE in clinical studies of bardoxolone methyl in 
patients with CKD who also had type 2 diabetes.  The muscle spasms most often manifested in 
the first two months of treatment and resolved spontaneously or with empirical treatment.  They 
occurred mostly at night, in the lower extremities, and were generally mild to moderate in 
severity.  Muscle spasms have also been reported in bardoxolone methyl-treated PAH patients 
but at lower incidences than that observed in prior CKD studies.  Moreover, the incidence of 
muscle spasms is similar to that observed in placebo-treated PAH patients.  Muscle spasms may 
result from improved insulin sensitivity and glucose uptake in skeletal muscle cells.  Increases in 
glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp procedure, were 
observed in response to bardoxolone methyl in a defined subset of patients enrolled in a Phase 2a 
study.  To date, in those cases where serum creatinine kinase (CK) levels have been measured, 
no association has been observed between muscle spasms and elevated CK levels in patients 
treated with bardoxolone methyl.  Clinical signs and laboratory findings associated with the 
reports of muscle spasms have not been consistent with muscle toxicity.  Bardoxolone methyl 
subjects showed no increase in prominent laboratory findings associated with muscle toxicity, 
such as increased levels of serum markers, including creatinine, lactate dehydrogenase, blood 
urea nitrogen, uric acid, phosphorus, and potassium, which were monitored weekly during the 
first two months of a prior study (BEAM) when muscle spasms were most frequently reported.  
Increases in the whole-body glucose disposal rate have been observed in mice treated with 
bardoxolone methyl, as well.  Increased glucose uptake was observed in isolated calf muscles of 
the mice, but not in white adipose tissue (Saha, 2010).   
5.2.5. 
Weight Loss 
Decreases in weight and reports of anorexia/decreased appetite have been observed following 
treatment with bardoxolone methyl in patients with CKD who also had type 2 diabetes.  In 
studies of these patients, 17% of bardoxolone methyl patients reported AEs of weight decrease or 
decreased appetite (irrespective of relationship to treatment).  Weight reduction was more 
pronounced in patients treated with bardoxolone methyl than in those given placebo. 
Weight loss of approximately one kilogram per month was observed, with patients of higher 
body-mass index at baseline losing more weight (in absolute terms) than those of normal or 
moderately-elevated body-mass index.   
Bardoxolone methyl-treated PAH patients have also had decreases in weight, with mean weight 
decreases of approximately 3 kg versus placebo at Week 16.  Weight loss in PAH patients has 
not coincided with reports of decreased appetite or anorexia AEs. 
5.2.6. 
Hypomagnesaemia 
Hypomagnesaemia has not been reported in PAH patients to date, but was reported as an AE for 
15.5% of patients with CKD who also had type 2 diabetes who received bardoxolone methyl.  
The AE of hypomagnesaemia (of any reported relationship to study drug) was more frequently 
reported in bardoxolone methyl-treated patients than in patients given placebo.  The investigators 
considered almost all reported events to be mild.  Additionally, patients treated with bardoxolone 
methyl had a greater decrease from baseline in serum magnesium levels than patients given 
placebo; the decrease was evident within 4 weeks and attenuated after 8 weeks of starting 


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therapy.  In bardoxolone methyl clinical studies performed to date, a post-hoc analysis identified 
no correlation between hypomagnesaemia and either gastrointestinal AEs or cardiac AEs, 
including cardiac dysrhythmias and prolonged QTc.  The 24-hour urine collections from the 
BEACON ambulatory blood pressure monitoring sub-study showed no increase in urinary 
magnesium levels, indicating that renal loss of magnesium did not account for the reductions in 
serum magnesium observed with bardoxolone methyl treatment in CKD patients.  Notably, a 
thorough QT study that tested doses of bardoxolone methyl up to 80 mg, bardoxolone methyl 
showed no increase in the QT interval.  


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objectives 
To provide continuing treatment with bardoxolone methyl as part of this extended access 
program while collecting ongoing safety and tolerability data of bardoxolone methyl.  
6.2. 
Primary Safety Endpoint: 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse 
events (SAEs), and change from baseline in the following assessments: physical examinations, 
vital sign measurements, BNP, N-terminal pro-brain natriuretic peptide (NT-proBNP), and 
weight. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This extended access study will assess the long-term safety and tolerability of bardoxolone 
methyl in qualified patients with PH who previously participated in controlled clinical studies 
with bardoxolone methyl. 
Qualified patients will start dosing at 10 mg of bardoxolone methyl every other day, then begin 
once daily dosing at Week 4 (unless contraindicated clinically) and continue until the drug is 
available through commercial channels (including reimbursement) or until patient withdrawal, 
whichever is sooner.  Dose de-escalation (down to 5 mg) is permitted during the study if 
indicated clinically.  Refer to Section 7.3.1 for additional details on dose de-escalation.  
All patients in the study will follow the same visit and assessment schedule.  Patients will be 
scheduled to be assessed in person during treatment at Day 1, Week 2, Week 4, Week 6, Week 8, 
Week 24, and every 24 weeks thereafter.  Patients will also be assessed by telephone contact on 
Days 3, 10, 21, 31, and 38.  Day 1 for this extended access study should occur on the same day 
as the last visit in the controlled clinical study.  Patient status should be carefully monitored by 
the investigator during the first 8 weeks of study treatment.  Assessments required for both the 
last visit in the controlled study and Day 1 for this study should only be completed once. 
Patients from the CATALYST study: 
Day 1 of this extended access study will coincide with the Week 28 follow-up visit for patients 
from CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended 
access program is not yet open for enrollment at the time of a patient’s Week 28 visit, the Day 1 
visit (i.e., enrollment) must occur within 30 days of site activation.  Exceptions allowing 
CATALYST patients who have completed 24 weeks of treatment to schedule their follow-up 
assessments prior to Week 28 and still be considered eligible for this open-label study should be 
discussed with the Chief Medical Officer at Reata, or designee, and will be considered on a case-
by-case basis.   
Patients from the LARIAT study: 
Day 1 of this extended access study will coincide with the End-of-Treatment visit for patients 
from LARIAT (402-C-1302, NCT02036970).   
7.2. 
Number of Patients 
Patient numbers will be determined by those who have been treatment-compliant and who have 
previously participated in clinical studies with bardoxolone methyl. 
7.3. 
Treatment Assignment 
All patients will receive bardoxolone methyl in this study. 


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7.3.1. 
Dose Escalation and Dose De-Escalation  
Patients will start dosing at 10 mg of bardoxolone methyl every other day, then begin once daily 
dosing at Week 4 unless contraindicated clinically.  The investigator should discuss any reasons 
for not dose-escalating to once daily dosing at Week 4 with the medical monitor. 
Dose de-escalation is permitted during the study and the investigator may choose to decrease the 
patient’s dose to 5 mg if clinically indicated.  Reasons for dose de-escalation should be discussed 
with the medical monitor prior to changing dose.  Once a patient’s dose has been decreased to 
5 mg, they cannot dose-escalate back to 10 mg of bardoxolone methyl. 
Unscheduled visits due to dose de-escalation should include assessments detailed in Section 9.7.  
7.4. 
Criteria for Study Termination 
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 
drugs will be discontinued and the investigator will be responsible for securing any alternative 
therapy to be administered, as appropriate. 
7.5. 
Criteria for Premature Termination or Suspension of Investigational 
Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement with Sponsor or the site is unable to ensure adequate performance of the study. 
7.6. 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Sites 
In the event that the Sponsor, an institutional review board (IRB)/ethics committee (EC), or 
regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor. 
7.7. 
Schedule of Assessments 
Table 3 lists the overall schedule of assessments for the study. 
 


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Table 3: 
Schedule of Assessments  
Study Week 
(Day) 
Assessment 
Day 1a 
Week 1  
(Phone) 
Day 3±2 
Week 1  
Day 7±3 
Week 2  
(Phone) 
Day 10±2 
Week 2 
Day 14±3 
Week 3 
(Phone) 
Day 21±2 
Week 4 
Day 28±3 
Week 4 
(Phone) 
Day 31±2 
Week 5  
(Phone) 
 Day 38±2 
Week 6 
Day 42±3 
Week 8 
Day 56±3 
Week 
24±3,  
Every 24 
Weeks  
End of  
Study 
 Visitb 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current PAH background 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight at home 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight in clinic  
Xc 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Vital sign measurements 
Xc 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Physical examination 
Xc 
 
X 
X 
 
X 
 
 
X 
X 
X 
X 
Pregnancy testd 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
 
Dispense study drug 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Collect study drug 
 
 
 
 
X 
 
 
 
 
X 
X 
Telephone contact 
X 
 
X 
 
X 
X 
X 
 
 
 
 
Adverse event collection 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistriesf 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
BNP and/or NT-Pro BNP 
Xc 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
6-min walk test 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
Dyspnea and fatigueg 
Xc 
 
 
 
 
 
 
 
 
 
 
X 
X 
WHO functional class 
Xc 
 
 
 
 
 
 
 
 
X 
X 
a On Day 1, all procedures should be performed before study drug administration for patients who are treatment-compliant and have previously participated in 
clinical studies with bardoxolone methyl. 
b After the Week 24 visit, patients will continue to be assessed in person every 24 weeks until bardoxolone methyl becomes commercially available.  The 
End-of- Study visit should occur within 30 days after bardoxolone methyl becomes available through commercial channels.  Patients who will be discontinued 
from the study prior to commercial availability of bardoxolone methyl must also complete all End-of-Study assessments.  
c Day 1 assessments should be performed as part of End-of-Treatment or Follow-up visit procedures from a prior study with bardoxolone methyl.  
d A serum pregnancy test will be performed 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 health authorities or IRBs/ECs.   
e AE assessments on Day 1 should be performed following study drug administration. 
f Clinical chemistries will be analyzed locally. 


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g Dyspnea and fatigue must be assessed prior to beginning and immediately following completion of the 6MWT using the Borg scale. 
 
Abbreviations: PAH, pulmonary arterial hypertension; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro B-type natriuretic peptide; WHO, World 
Health Organization; AE, adverse event; 6MWT, 6-minute walk test.


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Main criteria for inclusion:  
Treatment-compliant patients who are participating in qualifying ongoing studies and have 
completed required End-of-Treatment and/or Follow-up visits in a prior clinical study with 
bardoxolone methyl.   
8.2. 
Patient Exclusion Criteria 
All patients with any of the following conditions or characteristics must be excluded from the 
study: 
1. Participation in other investigational clinical studies involving interventional products 
being tested or used in a way different from the approved form or when used for an 
unapproved indication; 
2. Patients who have an ongoing serious adverse event (SAE) from a clinical study that is 
assessed by the investigator as related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners 
of childbearing potential and females of childbearing potential) while taking study drug;  
4. Women who are pregnant or breastfeeding; 
5. 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; 
6. Known hypersensitivity to any component of the study drug. 
8.3. 
Patient Discontinuation and Termination 
Patients have the right to discontinue study drug or withdraw from the study at any time for any 
reason, without prejudice to their medical care.  Furthermore, the investigator may discontinue a 
patient from study drug.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study.  The reason for a patient’s 
discontinuation from study drug or study termination will be recorded in the electronic case 
report form (eCRF).  
Discontinuation refers to a patient’s stopping administration of study drug and all study 
assessments and visits.  Reasons for study drug discontinuation may include the following: 
 Occurrence of an AE or change in medical status that will lead the investigator to be 
concerned about the patient’s welfare; 
 Administrative reasons (e.g., inability to continue); 
 Sponsor termination of the study; 
 Voluntary withdrawal; 


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 Females who become pregnant during the study; 
 Premature termination or suspension of an investigational site; 
 Loss to follow-up; 
 Death; 
 Withdrawal of consent. 
Patients must discontinue study drug if any of the following occur. 
 ALT or AST > 8X ULN; 
 ALT or AST > 5X ULN for more than 2 weeks; 
 ALT or AST > 3X ULN and (total bilirubin > 2X ULN or International Normalized 
Ratio [INR] > 1.5); 
 ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
Patients who discontinue from the study will be asked to complete the End-of-Study procedures 
noted in Table 3. 


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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.  Laboratory data, as well as BNP and/or NT-proBNP, will also be 
used to monitor fluid status.  Additionally, patients will be monitored for rapid weight gain 
suggestive of fluid overload.  Patients will be given a Sponsor-provided scale to use at home to 
monitor their weights daily during the first 8 weeks of the treatment period.  Patients who 
experience a 5-pound (2.3 kilogram) or greater increase in weight since their Day 1 weight 
during the first 8 weeks of the treatment period 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 advise patients to watch for signs and symptoms of fluid overload.  Patients 
should be informed to notify their physicians immediately if they experience swollen feet, chest 
pain, shortness of breath with mild exertion or while lying down, or other relevant symptoms.  
The investigator should immediately assess symptoms of fluid overload and determine 
appropriate medical management, as necessary, including whether stopping drug administration 
will be 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. 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) 
Transaminases should be monitored following patient’s standard of care.  Nearly all instances of 
elevated transaminases are expected to be asymptomatic.  Transaminase levels (as well as total 
bilirubin [TBL], GGT, alkaline phosphatase, and INR) will be checked within 48 to 72 hours 
during an unscheduled visit if the following occurs: 
 ALT or AST levels > 3X ULN. 
Testing will be repeated every 72 to 96 hours until transaminase levels are below 3X the ULN 
for at least one week or until the patient withdraws consent. 
Study drug administration will be permanently discontinued if any of the following occurs: 
 ALT or AST > 8X ULN; 
 ALT or AST > 5X ULN for more than 2 weeks; 
 ALT or AST > 3X ULN and (TBL > 2X ULN or INR > 1.5); 
 ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  


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The hepatobiliary tree must be visualized (e.g., ultrasound, magnetic resonance imaging) 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 as part of patient’s standard of care may indicate the 
need for replacement.  If vitamin D levels are low, supplementation may be warranted.  Muscle 
relaxants may also help relieve symptoms. 
9.1.4. 
Weight Loss 
Ongoing assessments to ensure that the patient is receiving adequate nutrition and consideration 
of other etiologies of weight loss may be warranted for patients receiving bardoxolone methyl.   
9.1.5. 
Hypomagnesaemia 
In instances where a patient experiences hypomagnesaemia (evaluated as part of patient’s 
standard of care), 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 AEs are typically mild and 
reversible within a few weeks after treatment initiation.  If symptoms will not resolve, dose 
de-escalation, with consultation of the medical monitor, may be necessary.   




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9.4. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to patients enrolled in the study in accordance with the protocol.  The study drug must not be 
used for reasons other than that described in the protocol.  
9.5. 
Randomization 
Not applicable. 
9.6. 
Blinding 
Not applicable.  
9.7. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
 Assessment of weight gain per Section 9.1.1;  
 Management of an AE or SAE; 
 Performance of additional laboratory tests for clinically abnormal laboratory test 
values or to confirm a possible pregnancy; 
 Dose de-escalation; 
 Any time the investigator feels that it is clinically appropriate for patient safety. 
At a minimum, unscheduled visits should include collection of AEs, concomitant medications 
and vital signs.  Additional conversations may be necessary with the medical monitor following 
an unscheduled visit to assess patient safety. 
9.8. 
Pregnancy 
9.8.1. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) are those who are not surgically sterile (no history 
of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have 
fallopian inserts with confirmed blockage, have not had reproductive potential terminated by 
radiation, and are not postmenopausal for at least 1 year. 
9.8.2. 
Methods of Birth Control 
While taking study drug and until 30 days following administration of the final dose of study 
medication, WOCBP must practice one of the following acceptable methods of birth control: 
 Use double barrier contraception method defined as male use of a condom and female 
use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, or 
diaphragm [always use with spermicidal jelly/cream]); 
 Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
90 days prior to start of study drug administration; 


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 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. 
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, 
or diaphragm [always use with spermicidal jelly/cream]); 
 Partner use of an intrauterine device; 
 Partner use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) for 
at least 90 days prior to start of study drug administration; 
 Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted. 
9.8.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).  Male patients must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a patient or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If the serum pregnancy test 
confirms the pregnancy, the patient must permanently discontinue taking study drug.  The 
investigator must immediately report to the medical monitor a pregnancy associated with study 
drug exposure.  The early discontinuation protocol-required procedures outlined for End-of-
Study 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 an SAE: 
 Congenital anomaly/birth defect; 
 Stillbirth; 
 Spontaneous miscarriage. 


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9.9. 
Serious Toxicities 
In the case of serious toxicities, the investigator may choose to interrupt treatment with 
bardoxolone methyl.  A single dose reduction (from 10 mg to 5 mg) is permitted if clinically 
indicated to manage tolerability issues.  Once a patient’s dose has been reduced, that dose must 
be maintained.  Patients who resume therapy after an interruption will follow the originally 
planned study schedule.  
9.10. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 3.  All Day 1 procedures, except AE assessments, should be completed prior to 
administration of first dose of study drug. 
9.10.1. 
Informed Consent 
Written informed consent (see Section 15.3) must be obtained from the patient before any 
study-related procedures are performed, and again if there is a change in the study procedures 
that would affect the patient’s willingness to participate. 
9.10.2. 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Table 3.  Patients must meet all 
of the inclusion and none of the exclusion criteria for entry in the study.   
9.10.3. 
Prior and Current Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking.  
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug names 
should be used where possible.  Concomitant medications will be reviewed as indicated in  
Table 3 and all changes will be recorded. 
9.10.4. 
Current PAH Background Medications 
The name, dose, and frequency must be recorded for all PAH background medications that the 
patient is taking.  PAH background medications are those that have been approved by the US 
Food and Drug Administration (FDA) or the local health authority for the treatment of PAH.  
Trade or generic drug names should be used where possible.  PAH background medications will 
be reviewed as indicated in Table 3 and all changes will be recorded.   
9.10.5. 
Weight and Body Mass Index  
Weight must be measured as indicated in Table 3.  Body mass index (BMI) will be calculated in 
the eCRF each time the weight is recorded.  Patients will use Sponsor-provided scales to measure 
weight at home.  Patients will be instructed to stop administering study drug and contact the 
investigator if their daily weight increases per the criteria outlined in Section 9.1.1.  Patients will 
be provided instructions within the Informed Consent Form to help ensure consistent weight 
collection throughout the study. 


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9.10.6. 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), respiration rate, and body temperature.  Blood pressure should be taken after the 
patient has rested in a sitting position for at least 5 minutes.  The same arm (usually the non-
dominant arm) and the appropriate size cuff should be used for each measurement.  Vital sign 
measurements should be taken as indicated in Table 3.  
9.10.7. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner as indicated in Table 3 and as documented within the table 
footnotes.  The examination must include the following organ or body system assessments: head, 
eyes, ears, nose, throat, musculoskeletal, cardiovascular, lymphatic, respiratory, abdomen, skin, 
extremities, and neurological.  Assessments of any specific signs or symptoms reported by the 
patient must also be performed and documented along with any other findings of note.  Clinically 
significant findings at Day 1 must be recorded as medical history.  Following the examination on 
Day 1, new or changed physical examination findings meeting the criteria for an adverse event 
must be recorded as an adverse event.  If possible, the same individual should perform each 
physical examination on a patient during the study. 
9.10.8. 
Pregnancy Test 
WOCBP (see Section 9.8) will complete a pregnancy test as indicated in Table 3, or at any time 
if pregnancy is suspected.  Negative test results are required on Day 1 before study drug 
administration.  Any patient who becomes pregnant during the study must discontinue taking 
study drug immediately.  See Section 9.8.3 for a description of procedures to be followed in case 
of pregnancy. 
9.10.9. 
Study Drug Administration 
Patients should self-administer one capsule orally, once a day, preferably in the morning, as 
indicated in Table 3.  A vomited dose must not be replaced.  A double dose (e.g., missed dose 
from previous day and dose for current day) must not be taken. 
9.10.10. 
Study Drug Dispensation and Collection 
Study drug will be dispensed to the patient and collected from the patient as indicated in Table 3.  
The patient will be dispensed 1 or more treatment kits at Day 1, Week 4, Week 24, and every 
24 weeks thereafter for the duration of the study.  Dispensed treatment kits from each visit 
should be returned to the site for collection at the subsequent visit. 
9.10.11. 
Telephone Contact 
Patients will be contacted by telephone as indicated in Table 3.  Patients will be asked about their 
body weight and other signs of fluid retention, as well as AEs and any changes to concomitant 
medications.  If fluid retention is suspected, the patient must be brought into the clinic and 
evaluated by the investigator as soon as possible, as detailed in Section 9.1.1. 


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9.10.12. 
Adverse Event Collection 
Patients will be observed for general appearance, presence of illness or injury, or signs indicative 
of a concurrent illness as indicated in Table 3.  Patients must be instructed to volunteer any 
information regarding AEs on or after the first dose of study drug or query the patients with an 
open question regarding any AEs they may be experiencing (e.g., “How have you been feeling 
since your last visit?”).  Any findings are to be documented.  Patients must be asked if they have 
been hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (including prescription drugs, over-the-counter medications, vitamins, 
herbal products, and minerals).  Responses must be documented in the source documents. 
9.10.13. 
Clinical Chemistry 
Samples will be collected for clinical chemistry analyses as indicated in Table 3.  Clinical 
chemistries will be analyzed locally and should include those routinely monitored per patient’s 
standard of care. 
9.10.14. 
N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide  
Samples will be collected for NT-Pro BNP and/or BNP as indicated in Table 3.  As recent 
exercise may affect BNP and NT-Pro BNP levels, patients must be allowed to rest for a 
minimum period of 1 hour following arrival at the clinic and prior to obtaining this blood 
sample.  Similarly, this sample must be taken prior to the 6MWT or at least one hour after 
6MWT.  This sample must be taken with the patient in the same position at all appropriate visits, 
e.g., sitting or semi-recumbent. 
9.10.15. 
6-Minute Walk Test 
A 6-minute walk test (6MWT) will be performed by the patients as indicated in Table 3.  Unless 
otherwise indicated as described below, each test must be performed in strict accordance with the 
American Thoracic Society (ATS) guidelines (ATS Statement 2002) provided in Section 19, 
Appendix 1.  The appropriate language version will be applied for patients with a non-English 
informed consent.  The walking course must be 30 m in length, except at sites granted prior 
Sponsor agreement. 
Patients will rate their dyspnea and overall fatigue using the Borg scale (2004 version, provided 
in Section 21, Appendix 3) prior to beginning and immediately following completion of each 
6MWT as indicated in Table 3.   
The assessor of the 6MWT must not provide the patient with the results of the assessment once 
complete.  A patient should wear the same or similar shoes for all 6MWTs.  Additionally, if a 
patient uses a walking aid for the first test, this same aide should be used during all subsequent 
tests.  The shoes worn and walking aid used for each 6MWT should be noted in source 
documents.   
Patients who require supplemental oxygen with exercise may use their prescribed oxygen level 
during 6MWTs.  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.   


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9.10.16. 
WHO/NYHA Functional Class Assessment 
WHO/NYHA functional class will be assessed (Section 20, Appendix 2) as indicated in Table 3.  
To the extent feasible, the same evaluator should assess WHO/NYHA FC for a particular patient 
over the entire course of the study.  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 5 mg and 10 mg, will be used in this study. 
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied in tamper-evident kits containing one 30-cc (5-mg capsules, 
30 count), one 60-cc (5-mg capsules, 90 count), or one 100-cc (10-mg capsules, 90 count) high-
density polyethylene bottle.  Each bottle will utilize foil induction-seal liners and a child-resistant 
closure.  Each bottle of study drug will contain 30 or 90 capsules of 5 mg or 10 mg strength 
bardoxolone methyl.  Each bottle will also contain a desiccant insert that must not be ingested.  
Labeling on each kit bottle will contain at minimum the following information: 
 Medication identification number; 
 Protocol 402-C-1602; 
 Caution Statement: New Drug – Limited by Federal Law to Investigational Use.  
Keep out of sight and reach of children; 
 Control or lot number 
 Store at 20° - 25°C (68° - 77°F), short term excursions allowed to 
15° - 30°C (59° - 86°F); 
 Reata Pharmaceuticals, Inc., Irving, TX. 
A double panel label will be presented on the treatment bottle containing this and other 
information as well.  Additionally, labeling in the relevant local languages for investigational 
medicinal product for use and distribution in the EU shall adhere to current Eudralex, Volume 4 
Annex 13 guidance and requirements.   
10.3. 
Study Drug Storage 
The stability of the drug product has been and is currently being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location with room 
temperature conditions of 20°C to 25°C (68°F to 77°F), with brief excursions allowed to 
15°C to 30°C (59°F to 86°F).   
10.4. 
Study Drug Administration 
Please refer to Section 9.10.9 for details on study drug administration.  Clear instructions will be 
provided to the patient regarding the number and type of capsules to be ingested at each study 
drug administration time point listed in Table 3.  Patients must be instructed to continue taking 
study drug unless: (1) patient has been otherwise instructed by the investigator or (2) the patient 
has been formally discontinued from the study.  


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


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


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Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of the first dose of study drug until the final visit 
indicated in Table 3, as appropriate).  Certain pregnancy outcomes will require submission as an 
SAE (See Section 9.8). 
The investigator is responsible for reporting to Reata or designee all AEs and SAEs that are 
observed or reported by the patient during the study (from the time of administration of the first 
dose of study drug until the final visit indicated in Table 3, as appropriate), regardless of their 
relationship to study drug or their clinical significance.   
The Sponsor, or the Contract Research Organization (CRO) on the behalf of the Sponsor, must 
be notified immediately regarding the occurrence of any SAE that occurs after the patient 
receives the first dose of study drug and throughout the study, regardless of study drug 
administration, including SAEs resulting from protocol-associated procedures, as defined in 
relevant legislation.  The procedures for reporting all SAEs, regardless of causal relationship, are 
as follows: 
 Record the SAE on the AE eCRF and complete the “Serious Adverse Event Report” 
form within the electronic database; 
 In the event the electronic database is not functional, a paper SAE form will be 
available for the reporting of SAEs. 
The Sponsor may request additional information from the investigator to ensure the timely 
completion of accurate safety reports. 
All SAEs reported or observed during the study must be followed to resolution or until the 
investigator deems the event to be chronic or the patient to be stable.  Reata or designee may 
contact the investigator to obtain additional information on any SAE which has not resolved at 
the time the patient completes the study. 
11.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, nondirected 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 that are monitored per patient’s standard 
of care, physical examination findings, or from other documents that are relevant to patient 
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11.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Not Related: This relationship suggests that there is no association between the study drug and 
the reported event. 
Unlikely Related: This relationship suggests that the temporal sequence of the event with study 
drug administration makes a causal relationship improbable and/or other factors also provide 
plausible explanations. 
Possibly Related: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence from the time 
of study drug administration, and/or, follows a known response pattern to the study drug, but 
could have been produced by other factors. 
Probably Related: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
Definitely Related: This relationship suggests that a definite causal relationship exists between 
the drug administration and the AE, and other conditions (e.g., concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
11.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities; 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities; 
Severe: Symptoms causing inability to perform usual social and functional activities.  
11.6. 
Recording Adverse Events 
All conditions present prior to the administration of the first dose of study drug (Day 1) in a 
previous study with bardoxolone methyl should be documented as medical history in a previous 
study with bardoxolone methyl.  After the first dose, documentation of AEs shall continue until 
30 days following administration of the final dose of study medication under this protocol or 
through 30 days after commercial availability of bardoxolone methyl (i.e., through the End-of-
Treatment visit), regardless of the relationship of the AE to study drug.  Information to be 
collected will include type of event, date of onset, date of resolution, investigator-specified 
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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 will require 
documentation of onset and duration. 
All drug-related (possibly, probably, or definitely related, see Section 11.4) AEs and abnormal 
laboratory test results reported or observed during the study must be followed to resolution 
(either return to baseline or within normal limits).  All other AEs will be followed through the 
final visit indicated in Table 3, as appropriate. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Preexisting conditions 
(present before the start of the AE collection period) will be 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 shall 
be recorded as an AE.  Investigators shall ensure that the AE term recorded captures the change 
in the condition (e.g., “worsening of…”).  Any improvement in condition shall be documented 
per Section 9.10.7. 
Each AE shall be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values) or symptoms shall NOT be recorded as additional AEs.  If a 
diagnosis is unknown, sign(s) or symptom(s) shall be recorded as an AE(s).  Changes in 
laboratory test values will only be considered AEs if they are judged to be clinically significant 
(i.e., if some action or intervention is required or if the investigator judges the change to be 
beyond the range of normal physiological fluctuation).  If abnormal laboratory test values will be 
the result of pathology for which there will be an overall diagnosis (e.g., increased creatinine 
levels in renal failure), only the diagnosis shall be reported as an AE. 
Elective procedures (surgeries or therapies) that will be scheduled prior to the start of AE 
collection will not be considered AEs.  These elective procedures shall not be recorded as AEs, 
but shall be documented in the patient’s source documents as elective (e.g., elective periodontal 
surgery).  However, if a pre-planned procedure will be performed early (e.g., as an emergency) 
because of a worsening of the preexisting condition, the worsening of the condition shall be 
captured as an AE. 
11.7. 
Reporting Serious Adverse Events 
Any AE the investigator will consider 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, the investigator will complete the SAE form in the clinical database and send 
to 
(fax numbers listed in Table 5) within 24 hours of awareness.  If the clinical 
database is down for any reason, the manual SAE forms will be utilized; however sites are 
responsible for ensuring the information on the manual SAE forms is entered into the clinical 
database once available. 


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Table 5: 
SAE Reporting Contact Information 
 
 
 
  
Non-North American sites will use access codes 
specific to their country.  Contact information for 
non-North American sites for SAE reporting will 
be provided by the clinical team directly to the 
sites. 
For questions regarding SAE reporting, contact your study manager, monitor, or 
 
. 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. 
Within 24 hours of receipt of new information, the SAE form should be updated within the 
clinical database and submitted along with any supporting documentation (e.g., patient discharge 
summary or autopsy reports).  If the clinical database is down for any reason, the manual SAE 
forms should be used; however, sites are responsible for ensuring the updated information on the 
manual SAE forms is entered into the clinical database once available. 
The Sponsor or designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible but no later than 
7 calendar days after the initial receipt of the information.  Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency.  For other 
SAEs that do not meet the fatal or life-threatening unexpected criteria, but are reported to be 
associated with the use of the study drug, Reata or designee will notify the appropriate regulatory 
agencies in writing within the timeframe established by those regulatory agencies.  Reata or 
designee will provide copies of any reports to regulatory agencies regarding serious and 
unexpected SAEs to the investigators for review and submission to their IRB or EC, as 
appropriate.  
Principal investigators will be responsible for informing their IRB/EC of any SAEs at their site.  
SAE correspondence with regulatory authorities or IRBs/ECs must be submitted to the Sponsor 
or designee for recording in the study file. 
Note that the following AEs which are commonly observed in this patient population will not be 
reported to regulatory authorities as individual expedited reports, except in unusual 
circumstances: 
 Shortness of breath; 
 Lightheadedness/dizziness; 
 Syncope; 


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 Chest pain; 
 Palpitations; 
 Fatigue; 
 Exertional dyspnea; 
 Hypoxemia. 
These events will be reviewed on a regular basis in aggregate and will be reported in an 
expedited manner if a safety signal is detected.  Regular safety study updates will be reported to 
regulatory authorities according to local guidelines. 


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12. 
STATISTICS 
12.1. 
Sample Size 
The aim of this long-term extended access study is primarily to provide continuing treatment to 
patients with bardoxolone methyl and to assess long-term safety and tolerability, hence no single 
primary variable has been identified.  Patient numbers will be determined by those who have 
been treatment-compliant and who have previously participated in clinical studies with 
bardoxolone methyl. 
12.2. 
Study Variables 
12.2.1. 
Safety Variables 
The safety variables will include results of physical examinations, laboratory test results (BNP 
and NT-Pro BNP), vital sign measurements, weight, AEs, and SAEs. 
12.3. 
Statistical Analyses 
A statistical analysis plan (SAP) detailing the analyses will be developed prior to the database 
lock.  All statistical analyses and data summaries will be performed using SAS® (Version 9.1 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized overall using descriptive statistics.  Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, relevant quartiles, 
standard deviation, coefficient of variation, and geometric mean (where applicable).  Categorical 
data will be summarized using frequency counts and percentages.  
12.3.1. 
Primary Analysis of Safety 
As the extension is of an open-label design with no comparator group, all statistical analyses will 
be descriptive.  Patients will be included in these analyses if they are included in the safety 
analysis and have both baseline and post-baseline data available for the variable being analyzed.  
The summary tables will be presented for the overall group of patients, and also split by previous 
treatment groups in prior bardoxolone methyl clinical studies.   
 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study-Specific Committees  
No steering committee, data safety monitoring committee, adjudication committee, or clinical 
endpoint committee will be used in this study. 
13.2. 
Study Monitoring 
The study site will be monitored remotely by the CRO periodically during the study to ensure 
that all aspects of the protocol will be followed and will include an electronic data collection 
which has a set of automatic data checks with data queries for programmed data collection.  
There will be monitoring of study site by telephone to ensure that the drug supplies have been 
provided and protocol instructions are well understood and applied. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Council for Harmonisation (ICH) 
guideline E6(R1): Good Clinical Practice: Consolidated Guideline and current standard operating 
procedures. 
13.3. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/EC review, and regulatory inspections, by providing direct access to 
all study records.  In the event of an audit, the principal investigator will agree to allow the 
Sponsor, representatives of the Sponsor, the FDA, and other relevant regulatory authorities 
access to all study records. 
The principal investigator shall promptly notify the Sponsor or designee of any audits scheduled 
by any regulatory authorities and shall promptly forward copies of any audit reports received to 
the Sponsor or designee. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Reata may conduct a quality assurance audit of the investigator’s clinical site, including 
CTM/IMP storage facilities.   
14.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for one year following the completion 
of the study. 
No potential investigator who has a vested financial interest in the success of this study may 
participate in this study. 
14.3. 
Sponsor Obligations  
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the Screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or designee is not financially responsible for treatment of 
the patient’s underlying disease. 
14.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R1) 
8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents 
to the Sponsor or designee, which include but are not limited to the following: 
 An original investigator-signed investigator agreement page of the protocol;  
 The IRB/EC approval of the protocol; 
 The IRB- or EC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the patient or legal guardians; 
 A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
 Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
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 Completed financial disclosure forms (Section 14.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 
designee a commitment to update this information promptly if any relevant changes 
occur during the course of the investigation and for 1 year following the completion 
of the study; 
 Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study. 
14.5. 
Clinical Study Insurance 
In accordance with the respective national drug laws, the Sponsor has taken out patient liability 
insurance for all patients who give their consent and enroll in this study.  This insurance covers 
potential fatalities, physical injuries, or damage to health that may occur during the clinical 
study. 
14.6. 
Use of Information  
All information regarding bardoxolone methyl supplied by the Sponsor to the investigator is 
privileged and confidential.  The investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor.  Furthermore, the 
investigator is obligated to provide the Sponsor with complete data obtained during the study.  
The information obtained from the clinical study will be used towards the development of 
bardoxolone methyl and may be disclosed to regulatory authorities, other investigators, corporate 
partners, or consultants as required. 


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15. 
ETHICS 
15.1. 
Institutional Review Board 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 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 US Investigational New Drug Application, a signed 
informed consent form, in compliance with Title 21 of the US CFR Part 50, will be obtained 
from each patient before the patient enters the study.  For sites outside of the US, the signed 
consent will be obtained in accord with local regulations, ICH E6 (R1), and principles of the 
Declaration of Helsinki.  An informed consent template may be provided by the Sponsor or 
designee to the investigators.  The consent must be reviewed by the Sponsor or designee before 
IRB/EC submission.  Once reviewed, the consent will be submitted by the principal investigator 
to his or her IRB/EC for review and approval before the start of the study.  If the informed 
consent form is revised during the course of the study, all participants affected by the revision 
must sign the revised IRB/EC-approved consent form. 


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Before enrollment, each prospective patient will be given a full explanation of the study and be 
allowed to read the approved informed consent form.  Once the principal investigator or designee 
is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing the informed consent form.  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.  Informed consent must be 
obtained before conducting any study-specific procedures (i.e., all of the procedures described in 
the protocol).  The process of obtaining informed consent must be documented in the patient 
source documents. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/EC, and a copy of the approved version and the notice 
of approval must be provided to the Sponsor’s designated monitor after IRB/EC approval. 
The principal investigator or designee will provide a copy of the informed consent form (signed 
copy to be provided per applicable law) to the patient and/or legal guardian.  The original form 
will be maintained in the patient’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/EC. 
The principal investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to them for the purpose of the study.  Prior 
written agreement from the Sponsor or designee must be obtained for the disclosure of any said 
confidential information to other parties. 
15.5. 
Modification of the Protocol 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments.  The FDA or other applicable regulatory agencies must be notified of protocol 
amendments.  The changes will become effective only after approval of the Sponsor, the 
investigator, the IRB/EC, and where necessary, the applicable regulatory agency.  In cases when 
the protocol is modified to enhance patient safety, changes may be implemented and the 
amendment must be immediately submitted to the IRB/EC. 
The investigator is responsible for informing the IRB/EC of all problems involving risks to 
patients according to national legislation.  In case of urgent safety measures, the Sponsor will 
immediately notify the investigators and relevant regulatory agencies, including FDA in accord 
with 21 CFR 312.32. 


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15.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviation.  The IRB/EC must 
be notified of all protocol deviations in a timely manner by the principal investigator or designee 
as appropriate.  Protocol deviations will be documented by the responsible monitor during 
monitoring visits, and those observations will be communicated to the investigator.  Protocol 
deviations will be reviewed and any that are a serious breach of GCP and the protocol will be 
reported to the Regulatory Authority, as required.  Protocol waivers are not allowed for sites in 
the United Kingdom. 
If there is an immediate hazard to a patient the principal investigator may deviate from the 
protocol without prior Sponsor and IRB/EC approval.  The Sponsor and IRB/EC must be 
notified of the deviation. 


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


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17. 
PUBLICATION POLICY 
The Sponsor supports communication and publication of study results whatever the findings of 
the study.   
The Sponsor reserves the right to review all planned communications and manuscripts based on 
the results of this study.  This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but to allow the Sponsor to confirm the 
accuracy of the data, to protect proprietary information, and to provide comments based on 
information that may not yet be available to the study investigators.  The Sponsor also 
encourages disclosure of any conflict of interest from all authors or investigators when 
manuscripts are submitted for publication.  Those individuals, who have contributed greatly to 
this study, including lead external advisors and select principal investigators, may serve on any 
potential publications committee for the study. 


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18. 
REFERENCES 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS 
Statement: Guidelines for the six-minute walk test.  Am J Respir Crit Care Med. 
2002;166(1):111-7. 
Batt J, Ahmed SS, Correa J, et al. Skeletal muscle dysfunction in idiopathic pulmonary arterial 
hypertension. Am J Respir Cell Mol Biol. 2014;50(1):74-86. 
Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic 
sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension 
assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 
2014;66(3):489-95. 
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the phase 2 response: correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci U S A. 2005;102(12):4584-9. 
Eba S, Hoshikawa Y, Moriguchi T, et al. The nuclear factor erythroid 2-related factor 2 activator 
oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice. Am J Respir 
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2011;300(5):F1180-F1192. 
 


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


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

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

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

 
 chronic obstructive pulmonary disease; 6MWD 
 

 
 
6-minute walking distance.
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Supplemental Oxygen
 
If oxygen supplementation is needed during the walks and se-
rial tests are planned (after an intervention other than oxygen
therapy), then during all walks by that patient oxygen should
be delivered in the same way with the same flow. If the flow
must be increased during subsequent visits due to worsening
gas exchange, this should be noted on the worksheet and con-
sidered during interpretation of the change noted in 6MWD.
The type of oxygen delivery device should also be noted on
the report: for instance, the patient carried liquid oxygen or
pushed or pulled an oxygen tank, the delivery was pulsed or
continuous, or a technician walked behind the patient with the
oxygen source (not recommended). Measurements of pulse
and SpO
 
2
 
 should be made after waiting at least 10 minutes af-
ter any change in oxygen delivery.
 
Rationale.  
 
For patients with COPD or interstitial lung dis-
ease, oxygen supplementation increases the 6MWD (17, 59,
61, 63). Carrying a portable gas container (but not using it for
supplemental oxygen) reduced the mean 6MWD by 14% in
one study of patients with severe respiratory disability, but us-
ing the container to deliver supplemental oxygen during the
exercise increased the mean 6MWD by 20–35% (59).
 
Medications
 
The type of medication, dose, and number of hours taken be-
fore the test should be noted.
 
Rationale.  
 
Significant improvement in the distance walked,
or the dyspnea scale, after administration of bronchodilators
has been demonstrated in patients with COPD (62, 63), as well
as cardiovascular medications in patients with heart failure (19).
 
INTERPRETATION
 
Most 6MWTs will be done before and after intervention, and
the primary question to be answered after both tests have
been completed is whether the patient has experienced a clini-
cally significant improvement. With a good quality-assurance
program, with patients tested by the same technician, and af-
ter one or two practice tests, short-term reproducibility of the
6MWD is excellent (37). It is not known whether it is best for
clinical purposes to express change in 6MWD as (
 
1
 
) an abso-
lute value, (
 
2
 
) a percentage change, or (
 
3
 
) a change in the per-
centage of predicted value. Until further research is available,
we recommend that change in 6MWD be expressed as an ab-
solute value (e.g., the patient walked 50 m farther).
A statistically significant mean increase in 6MWD in a
group of study participants is often much less than a clinically
significant increase in an individual patient. In one study of
112 patients (half of them women) with stable, severe COPD,
the smallest difference in 6MWD that was associated with a
noticeable clinical difference in the patients’ perception of ex-
ercise performance was a mean of 54 m (95% confidence in-
terval, 37–71 m) (64). This study suggests that for individual
patients with COPD, an improvement of more than 70 m in
the 6MWD after an intervention is necessary to be 95% confi-
dent that the improvement was significant. In an observational
study of 45 older patients with heart failure, the smallest dif-
ference in 6MWD that was associated with a noticeable differ-
ence in their global rating of worsening was a mean of 43 m
(20). The 6MWD was more responsive to deterioration than
to improvement in heart failure symptoms.
 
Reported Mean Changes in 6MWD After Interventions
 
Supplemental oxygen (4 L/min) during exercise in patients with
COPD or interstitial lung disease increased mean 6MWD by
approximately 95 m (36%) in one study (59). Patients taking
 
an inhaled corticosteroid experienced a mean 33 m (8%) in-
crease in 6MWD in an international COPD study (16). Pa-
tients with COPD in a study of the effects of exercise and dia-
phragmatic strength training experienced a mean increase in
6MWD of 50 m (20%) (65). Lung volume reduction surgery in
patients with very severe COPD has been reported to increase
6MWD by a mean of 55 m (20%) (13).
Cardiac rehabilitation in patients referred with various heart
diseases increased 6MWD by a mean of 170 m (15%) in a recent
study (66). In 25 older patients with heart failure, an angiotensin-
converting enzyme inhibitor medication (50 mg captopril per
day) improved 6MWD a mean of 64 m (39%) compared with a
mean increase of only 8% in those receiving a placebo (19).
 
Interpreting Single Measurements of Functional Status
 
Optimal reference equations from healthy population-based
samples using standardized 6MWT methods are not yet avail-
able. In one study, the median 6MWD was approximately 580
m for 117 healthy men and 500 m for 173 healthy women (50).
A mean 6MWD of 630 m was reported by another study of 51
healthy older adults (55). Differences in the population sam-
pled, type and frequency of encouragement, corridor length,
and number of practice tests may account for reported differ-
ences in mean 6MWD in healthy persons. Age, height, weight,
and sex independently affect the 6MWD in healthy adults;
therefore, these factors should be taken into consideration
when interpreting the results of single measurements made to
determine functional status. We encourage investigators to pub-
lish reference equations for healthy persons using the previ-
ously mentioned standardized procedures.
A low 6MWD is nonspecific and nondiagnostic. When the
6MWD is reduced, a thorough search for the cause of the im-
pairment is warranted. The following tests may then be help-
ful: pulmonary function, cardiac function, ankle–arm index,
muscle strength, nutritional status, orthopedic function, and
cognitive function.
 
Conclusions
 
The 6MWT is a useful measure of functional capacity targeted
at people with at least moderately severe impairment. The test
has been widely used for preoperative and postoperative eval-
uation and for measuring the response to therapeutic inter-
ventions for pulmonary and cardiac disease. These guidelines
provide a standardized approach to performing the 6MWT.
The committee hopes that these guidelines will encourage fur-
ther research into the 6MWT and allow direct comparisons
among different studies.
 
This statement was developed by the ATS Committee on Proficiency Stan-
dards for Clinical Pulmonary Function Laboratories.
Members of the committee are:
R
 
OBERT
 
 O. C
 
RAPO
 
, M.D., 
 
Chair
 
*
R
 
ICHARD
 
 C
 
ASABURI
 
, P
 
H
 
.D, M.D.
A
 
LLAN
 
 L. C
 
OATES
 
, M.D.
P
 
AUL
 
 L. E
 
NRIGHT
 
, M.D.*
N
 
EIL
 
 R. M
 
AC
 
I
 
NTYRE
 
, M.D.
R
 
OY
 
 T. M
 
C
 
K
 
AY
 
, P
 
H
 
.D.
D
 
OUGLAS
 
 J
 
OHNSON
 
, M.D.
J
 
ACK
 
 S. W
 
ANGER
 
, M.S.
R. J
 
ORGE
 
 Z
 
EBALLOS
 
, M.D.*
Ad Hoc Committee members are:
V
 
ERA
 
 B
 
ITTNER
 
, M.D.
C
 
ARL
 
 M
 
OTTRAM
 
, R.R.T.
*Writing Committee Members
 
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APPENDIX
The following elements should be present on the 6MWT worksheet and report:
Lap counter:
__ __ __ __ __
__ __ __ __ __
__ __ __ __ __
Patient name: ____________________
Patient ID# ___________
Walk # ______
Tech ID: _________ Date: __________
Gender: M F
Age: ____
Race: ____
Height: ___ft ____in, ____ meters
Weight: ______ lbs, _____kg
Blood pressure: _____ / _____
Medications taken before the test (dose and time): __________________
Supplemental oxygen during the test: No
Yes, flow ______ L/min, type _____
Baseline
End of Test
Time
___:___
___:___
Heart Rate
_____
_____
Dyspnea
____
____ (Borg scale)
Fatigue
____
____ (Borg scale)
SpO2
____ %
____%
Stopped or paused before 6 minutes? No
Yes, reason: _______________
Other symptoms at end of exercise: angina
dizziness
hip, leg, or calf pain
Number of laps: ____ (60 meters)  final partial lap: _____ meters 
Total distance walked in 6 minutes: ______ meters
Predicted distance: _____ meters
Percent predicted: _____%
Tech comments:
Interpretation (including comparison with a preintervention 6MWD):
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20. 
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF 
PULMONARY HYPERTENSION MODIFIED AFTER THE NEW 
YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ACCORDING TO THE WHO 1998 
(GALIE, 2009) 
World Health Organization functional assessment classification  
Class 
I:  
Patients with pulmonary hypertension (PH) but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, 
or near syncope. 
Class 
II:  
Patients with PH resulting in slight limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near 
syncope. 
Class 
III:  
Patients with PH resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class 
IV:  
Patients with PH with inability to carry out any physical activity without symptoms. 
These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even be 
present at rest. Discomfort is increased by any physical activity. 


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21. 
APPENDIX 3:  BORG CR10 SCALE 
 
 
 

Prot_001.pdf: 
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1 
 
 
 
 
 
 
BARDOXOLONE METHYL (RTA 402) 
 
402-C-1602 
 
EUDRACT NUMBER: 2016-004365-16 
 
AN EXTENDED ACCESS PROGRAM TO ASSESS 
LONG-TERM SAFETY OF BARDOXOLONE METHYL 
IN PATIENTS WITH PULMONARY HYPERTENSION 
Version 3.1 – 25 July 2018 
JAPAN 
 
Protocol History 
Version 1.0 – 27 October 2016 
Version 2.0/2.1 – 05 January 2017 
Version 2.2 – 01 March 2017 
 
The information contained herein is confidential and the proprietary property of 
Reata Pharmaceuticals, Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of Reata Pharmaceuticals, 
Inc. is expressly prohibited. 




Protocol 402-C-1602 
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3 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for bardoxolone methyl.  I have read the 
402-C-1602 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 
 
 
 
 
 
 
 
 
 
 
Non-North American sites will use access codes specific to their country.  
Numbers for non-North American sites for SAE reporting will be provided 
by the clinical team directly to the sites for reporting and submitting SAE 
information to 
.  
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals, Inc. 
Name of Investigational Product: 
Bardoxolone methyl 
Title of Study:  
An Extended Access Program to Assess Long-Term Safety of Bardoxolone Methyl in Patients with 
Pulmonary Hypertension  
Study center(s): Approximately 150 study centers  
Studied period: Until commercial availability of 
bardoxolone methyl 
Estimated date first patient enrolled: February 2017 
Estimated date last patient completed: Patient will 
remain in the study until bardoxolone methyl is 
available through commercial channels or until 
patient withdrawal, whichever is sooner  
Phase of development:  
3a 
Primary Objectives:   
To provide continuing open-label treatment with bardoxolone methyl as part of this extended access 
program while collecting ongoing safety and tolerability data of bardoxolone methyl.   
Primary Safety Endpoint: 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse events 
(SAEs), and change from baseline in the following assessments: physical examinations, vital sign 
measurements, B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-
proBNP), and weight. 
Methodology:  
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in 
qualified patients with pulmonary hypertension (PH) who previously participated in controlled clinical 
studies with bardoxolone methyl.  
Qualified patients will receive bardoxolone methyl once daily until the drug is available through 
commercial channels (including reimbursement) or until patient withdrawal, whichever is sooner.  
Patients will start at 5 mg and will dose-escalate to 10 mg at Week 4 unless contraindicated clinically. 
Dose de-escalation (down to 5 mg) is permitted during the study, if indicated clinically.    
All patients in the study will follow the same visit and assessment schedule.  Patients will be scheduled 
to be assessed in person during treatment at Day 1, Weeks 1, 2, 4, 12, 24, 36,48, and every 12 weeks 
thereafter.  Patients will also be assessed by telephone contact on Days 3, 10, and 21.  Day 1 for this 
study should occur on the same day as the last visit in the controlled clinical study.  Assessments 
required for both the last visit in the controlled study and Day 1 for this study should only be 
completed once. 
Patients from the CATALYST study: 
Day 1 of this extended access study will coincide with the Week 28 follow-up visit for patients from 
CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended access 
program is not yet open for enrollment at the time of a patient’s Week 28 visit, the Day 1 visit 


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6 
(i.e., enrollment) must occur within 30 days of site activation.  Exceptions allowing CATALYST 
patients who have completed 24 weeks of treatment to schedule their follow-up assessments prior to 
Week 28 and still be considered eligible for this open-label study should be discussed with the Chief 
Medical Officer at Reata, or designee, and will be considered on a case-by-case basis.   
Patients from the LARIAT study:  
Day 1 of this extended access study will coincide with the End-of-Study visit for patients from 
LARIAT (402-C-1302, NCT02036970).  
 
 
 
Number of patients (planned):  
Patient numbers will be determined by those who are treatment-compliant and who have previously 
participated in clinical studies with bardoxolone methyl.  
Main criteria for inclusion: 
Treatment-compliant patients who are participating in qualifying ongoing studies and have completed 
required End-of-Treatment and/or Follow-up visits in a prior clinical study with bardoxolone methyl.   
Major exclusion criteria: 
1. Participation in other investigational clinical studies involving interventional products being 
tested or used in a way different from the approved form or when used for an unapproved 
indication; 
2. Patients who have an ongoing SAE from a clinical study that is assessed by the investigator as 
related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners of 
childbearing potential and females of childbearing potential) while taking study drug;  
4. Women who are pregnant or breastfeeding; 
5. 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; 
6. Known hypersensitivity to any component of the study drug. 
Investigational product, dosage, mode of administration, and duration of treatment:  
Bardoxolone methyl will be administered orally once daily at 5 mg or 10 mg until it becomes 
commercially available.   
Reference therapy, dosage and mode of administration:  
None. 


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Criteria for evaluation: 
Safety: Results of physical examinations, laboratory results, BNP, NT-ProBNP, vital sign 
measurements, weight, AEs, and SAEs. 
Statistical methods: 
Sample size: The aim of this long-term extended access study is primarily to provide continuing 
treatment to patients with bardoxolone methyl and to assess long-term safety and tolerability, hence no 
single primary variable has been identified.  Patient numbers will be determined by those who have 
been treatment-compliant and who have previously participated in clinical studies with bardoxolone 
methyl. 
Primary analysis of safety: As the extension is of an open-label design with no comparator group, all 
statistical analyses will be descriptive.  The summary tables will be presented for the overall group of 
patients, and also split by previous treatment groups (i.e., bardoxolone methyl or placebo) in prior 
bardoxolone methyl clinical studies.  


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3. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LIST OF TABLES ....................................................8 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
5. 
INTRODUCTION ......................................................................................................15 
5.1. 
Study Rationale ...........................................................................................................17 
5.2. 
Clinical Experience with Bardoxolone Methyl ..........................................................17 
5.2.1. 
Safety and Tolerability ...............................................................................................17 
5.2.2. 
Fluid Overload ............................................................................................................17 
5.2.3. 
Transaminase and Gamma-Glutamyl Transpeptidase Elevations ..............................18 
5.2.4. 
Muscle Spasms ...........................................................................................................18 
5.2.5. 
Weight Loss ................................................................................................................19 
5.2.6. 
Hypomagnesaemia ......................................................................................................19 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................20 
6.1. 
Primary Objectives .....................................................................................................20 
6.2. 
Primary Safety Endpoint: ...........................................................................................20 
7. 
INVESTIGATIONAL PLAN .....................................................................................21 
7.1. 
Overall Study Design ..................................................................................................21 
7.2. 
Number of Patients .....................................................................................................21 
7.3. 
Treatment Assignment ................................................................................................21 
7.3.1. 
Dose Escalation and Dose De-Escalation ...................................................................21 
7.4. 
Criteria for Study Termination ...................................................................................22 
7.5. 
Criteria for Premature Termination or Suspension of Investigational Sites ...............22 
7.6. 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Sites ..........................................................................22 
7.7. 
Schedule of Assessments ............................................................................................22 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................24 
8.1. 
Patient Inclusion Criteria ............................................................................................24 
8.2. 
Patient Exclusion Criteria ...........................................................................................24 
8.3. 
Patient Discontinuation and Termination ...................................................................24 
9. 
TREATMENT OF PATIENTS ..................................................................................26 


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9.1. 
Select Management Guidelines ..................................................................................26 
9.1.1. 
Management of Fluid Status .......................................................................................26 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................26 
9.1.3. 
Management of Muscle Spasms .................................................................................27 
9.1.4. 
Weight Loss ................................................................................................................27 
9.1.5. 
Hypomagnesaemia ......................................................................................................27 
9.1.6. 
Nausea .........................................................................................................................27 
9.2. 
Description of Study Drug ..........................................................................................28 
9.3. 
Concomitant Medications ...........................................................................................28 
9.3.1. 
Excluded Medications ................................................................................................28 
9.3.2. 
Permitted Medications ................................................................................................28 
9.4. 
Treatment Compliance ................................................................................................29 
9.5. 
Randomization ............................................................................................................29 
9.6. 
Blinding ......................................................................................................................29 
9.7. 
Unscheduled Visits .....................................................................................................29 
9.8. 
Pregnancy ...................................................................................................................29 
9.8.1. 
Women of Childbearing Potential ..............................................................................29 
9.8.2. 
Methods of Birth Control............................................................................................29 
9.8.3. 
Suspected Pregnancy ..................................................................................................30 
9.9. 
Serious Toxicities .......................................................................................................31 
9.10. 
Study Procedures ........................................................................................................31 
9.10.1. 
Informed Consent .......................................................................................................31 
9.10.2. 
Inclusion/Exclusion ....................................................................................................31 
9.10.3. 
Prior and Current Concomitant Medications ..............................................................31 
9.10.4. 
Current PAH Background Medications ......................................................................31 
9.10.5. 
Weight and Body Mass Index .....................................................................................31 
9.10.6. 
Vital Sign Measurements ............................................................................................32 
9.10.7. 
Physical Examination .................................................................................................32 
9.10.8. 
Pregnancy Test ............................................................................................................32 
9.10.9. 
Study Drug Administration.........................................................................................32 
9.10.10. 
Study Drug Dispensation and Collection ...................................................................32 
9.10.11. 
Telephone Contact ......................................................................................................32 
9.10.12. 
Adverse Event Collection ...........................................................................................33 


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9.10.13. 
Clinical Chemistry ......................................................................................................33 
9.10.14. 
N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide .................33 
9.10.15. 
6-Minute Walk Test ....................................................................................................33 
9.10.16. 
WHO/NYHA Functional Class Assessment ..............................................................34 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................35 
10.1. 
Study Drug ..................................................................................................................35 
10.2. 
Study Drug Packaging and Labeling ..........................................................................35 
10.3. 
Study Drug Storage .....................................................................................................35 
10.4. 
Study Drug Administration.........................................................................................35 
10.5. 
Study Drug Accountability .........................................................................................36 
10.6. 
Study Drug Handling and Disposal ............................................................................36 
11. 
SAFETY ASSESSMENTS ........................................................................................37 
11.1. 
Safety Parameters .......................................................................................................37 
11.2. 
Adverse and Serious Adverse Events .........................................................................37 
11.2.1. 
Definition of Adverse Events .....................................................................................37 
11.2.1.1. 
Adverse Event .............................................................................................................37 
11.2.1.2. 
Serious Adverse Event ................................................................................................37 
11.3. 
Eliciting Adverse Event Information ..........................................................................38 
11.4. 
Assessment of Causality .............................................................................................39 
11.5. 
Assessment of Severity ...............................................................................................39 
11.6. 
Recording Adverse Events .........................................................................................39 
11.7. 
Reporting Serious Adverse Events .............................................................................40 
12. 
STATISTICS ..............................................................................................................43 
12.1. 
Sample Size ................................................................................................................43 
12.2. 
Study Variables ...........................................................................................................43 
12.2.1. 
Safety Variables ..........................................................................................................43 
12.3. 
Statistical Analyses .....................................................................................................43 
12.3.1. 
Primary Analysis of Safety .........................................................................................43 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................44 
13.1. 
Study-Specific Committees ........................................................................................44 
13.2. 
Study Monitoring ........................................................................................................44 
13.3. 
Audits and Inspections ................................................................................................44 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................45 


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14.1. 
Quality Assurance .......................................................................................................45 
14.2. 
Financial Disclosure ...................................................................................................45 
14.3. 
Sponsor Obligations....................................................................................................45 
14.4. 
Investigator Documentation ........................................................................................45 
14.5. 
Clinical Study Insurance .............................................................................................46 
14.6. 
Use of Information ......................................................................................................46 
15. 
ETHICS ......................................................................................................................47 
15.1. 
Institutional Review Board or Ethics Committee Review ..........................................47 
15.2. 
Ethical Conduct of the Study ......................................................................................47 
15.3. 
Written Informed Consent ..........................................................................................47 
15.4. 
Confidentiality ............................................................................................................48 
15.5. 
Modification of the Protocol .......................................................................................48 
15.6. 
Protocol Deviations ....................................................................................................48 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................50 
16.1. 
Retention of Records ..................................................................................................50 
16.2. 
Case Report Forms .....................................................................................................50 
17. 
PUBLICATION POLICY ..........................................................................................51 
18. 
REFERENCES ...........................................................................................................52 
19. 
APPENDIX 1: ATS GUIDELINES FOR THE SIX-MINUTE WALK TEST ..........54 
20. 
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF PULMONARY 
HYPERTENSION MODIFIED AFTER THE NEW YORK HEART 
ASSOCIATION FUNCTIONAL CLASSIFICATION ACCORDING TO 
THE WHO 1998 (GALIE, 2009) ...............................................................................62 
21. 
APPENDIX 3:  BORG CR10 SCALE .......................................................................63 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................13 
Table 3: 
Schedule of Assessments ............................................................................................23 
Table 4: 
Bardoxolone Methyl Drug Product Information ........................................................28 
Table 5: 
SAE Reporting Contact Information ..........................................................................41 
 


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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 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
ATS 
American Thoracic Society 
BMI 
Body mass index 
BNP 
B-type natriuretic peptide 
CFR 
Code of Federal Regulations (US) 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
CRO 
Contract research organization 
CTD-PAH 
Connective tissue disease-associated pulmonary arterial 
hypertension 
EC 
Ethics Committee 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
ICH 
International Conference on Harmonization 
IKKβ 
Inhibitor of nuclear factor kappa β kinase beta subunit 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
NT-Pro BNP 
N-Terminal Pro-Brain Natriuretic Peptide   
NYHA FC 
New York Heart Association Functional Classification 


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Abbreviation or Specialist Term 
Explanation 
PAH 
Pulmonary arterial hypertension 
PH 
Pulmonary hypertension 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
US 
United States 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 


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




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patients with CTD-PAH had similar sustained increases in 6MWD through Week 32.  On the 
basis of these data, Reata expanded the LARIAT protocol (Version 5.0) to include PH patients 
with ILD, including WHO Group III patients with CTD-associated ILD, idiopathic pulmonary 
fibrosis, non-specific interstitial pneumonia, and WHO Group V patients with sarcoidosis.  Reata 
has also initiated a Phase 3 study in WHO Group I CTD-PAH patients (402-C-1504, 
CATALYST, NCT02657356, EudraCT 2016-000196-24) to study the safety and efficacy of 
bardoxolone methyl in those patients.   
5.1. 
Study Rationale 
The established pharmacologic effects of bardoxolone methyl, including the suppression of 
pathologic NF-κB signaling and inflammation and mitochondrial dysfunction, are directly 
applicable to the treatment of PH.  Despite available therapies, the prognosis for PH remains 
poor, especially for patients with CTD (Chung, 2014) and ILD.  Given the severity of the 
underlying disease, this study seeks to offer patients who previously participated in clinical 
studies extended access to bardoxolone methyl until it is available through commercial channels 
(including reimbursement). 
For further information, refer to the Investigator’s Brochure.  
5.2. 
Clinical Experience with Bardoxolone Methyl 
Approximately 1950 individuals have been exposed to bardoxolone methyl at the time of 
initiation of this study.  Sixteen studies have been completed (7 in patients with chronic kidney 
disease (CKD) who also had type 2 diabetes, 4 in non-CKD indications, and 5 in healthy 
subjects) and 2 studies are ongoing in patients with PH.   
5.2.1. 
Safety and Tolerability 
Please refer to the Investigator’s Brochure for a detailed discussion of safety findings with 
bardoxolone methyl for studies in healthy subjects, oncology, CKD, and patients with PH. 
5.2.2. 
Fluid Overload 
Similar to endothelin receptor antagonists 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 a Phase 3 trial (BEACON), which enrolled patients with Stage 4 CKD (eGFR 
of 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 B-type natriuretic peptide (BNP) and prior 
hospitalization for heart failure were identified as risk factors that contributed to increased risk 
for these events.  The increased risk for these events from bardoxolone methyl treatment had not 
been observed in six previous CKD studies, which were conducted mostly in patients with Stage 
3b CKD (eGFR of 30-44 mL/min/1.73 m2), patients with hepatic dysfunction, cancer patients, or 
healthy volunteers.  
Review of admission notes and narrative descriptions for heart failure hospitalizations in 
BEACON indicates that heart failure in bardoxolone methyl-treated patients was often preceded 
by rapid fluid weight gain (several kilograms within the first weeks of treatment initiation) and 


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was not associated with acute renal decompensation or acutely reduced left ventricular 
contractility.  Available data from BEACON and other studies suggest that bardoxolone methyl 
treatment can differentially affect hemodynamic status according to the clinical condition of 
patients and likely promotes fluid retention in patients with more advanced renal dysfunction and 
other recognized risk factors associated with heart failure at baseline.   
In a Phase 2 dose-ranging study of the efficacy and safety of bardoxolone methyl in patients with 
PH (LARIAT), risk mitigation procedures were employed to reduce the potential for 
bardoxolone methyl-induced fluid overload; these procedures excluded patients with the 
identified risk factors and ensured close monitoring for fluid retention within the first month of 
treatment.  To date, the risk for acute fluid overload adverse events (AEs) with bardoxolone 
methyl in late-stage CKD patients has not been observed in PAH patients.   
5.2.3. 
Transaminase and Gamma-Glutamyl Transpeptidase Elevations  
In clinical studies of bardoxolone methyl, almost all patients had increases of transaminase 
enzymes above baseline upon initiation of treatment, which followed a consistent pattern.  These 
increases were not associated with elevations in bilirubin or other signs of liver toxicity.  In a 
large Phase 3 study that enrolled 2185 patients with type 2 diabetes and stage 4 CKD 
(BEACON), fewer hepatobiliary SAEs were observed in the bardoxolone methyl arm than in the 
placebo arm.  The elevations begin immediately after initiation of treatment or an increase in 
dose; they peak approximately two to four weeks later.  In most patients, transaminase elevations 
were mild, but approximately 4% to 11% of patients experienced an elevation greater than 3X 
the upper limit of normal (ULN).  The elevations resolved to levels less than the ULN in most all 
patients with elevations, within two weeks after peak values while patients continued taking 
study drug.  Patients who experienced elevations to greater than 3X the ULN sometimes required 
additional time to resolve.  While some patients have had elevations to above 3X the ULN, 
persistent elevations to above 3X the ULN have not been observed, and the elevations did not 
recur once resolved, unless caused by other factors. 
Bardoxolone methyl regulates gamma-glutamyl transpeptidase (GGT), a known Nrf2 target 
gene.  In clinical studies, low level GGT elevations during treatment were common, mild, and 
typically lasted longer than alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevations.  Bilirubin levels in patients experiencing transaminase or GGT elevations due to 
treatment with bardoxolone methyl either remained at baseline levels or decreased.  The ALT, 
AST, and GGT elevations were generally self-limiting in patients who continued treatment with 
study drug.  
5.2.4. 
Muscle Spasms 
Muscle spasm was the most frequently reported AE in clinical studies of bardoxolone methyl in 
patients with CKD who also had type 2 diabetes.  The muscle spasms most often manifested in 
the first two months of treatment and resolved spontaneously or with empirical treatment.  They 
occurred mostly at night, in the lower extremities, and were generally mild to moderate in 
severity.  Muscle spasms have also been reported in bardoxolone methyl-treated PAH patients 
but at lower incidences than that observed in prior CKD studies.  Moreover, the incidence of 
muscle spasms is similar to that observed in placebo-treated PAH patients.  Muscle spasms may 
result from improved insulin sensitivity and glucose uptake in skeletal muscle cells.  Increases in 


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glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp procedure, were 
observed in response to bardoxolone methyl in a defined subset of patients enrolled in a Phase 2a 
study.  To date, in those cases where serum creatinine kinase (CK) levels have been measured, 
no association has been observed between muscle spasms and elevated CK levels in patients 
treated with bardoxolone methyl.  Clinical signs and laboratory findings associated with the 
reports of muscle spasms have not been consistent with muscle toxicity.  Bardoxolone methyl 
subjects showed no increase in prominent laboratory findings associated with muscle toxicity, 
such as increased levels of serum markers, including creatinine, lactate dehydrogenase, blood 
urea nitrogen, uric acid, phosphorus, and potassium, which were monitored weekly during the 
first two months of a prior study (BEAM) when muscle spasms were most frequently reported.  
Increases in the whole-body glucose disposal rate have been observed in mice treated with 
bardoxolone methyl, as well.  Increased glucose uptake was observed in isolated calf muscles of 
the mice, but not in white adipose tissue (Saha, 2010).   
5.2.5. 
Weight Loss 
Decreases in weight and reports of anorexia/decreased appetite have been observed following 
treatment with bardoxolone methyl in patients with CKD who also had type 2 diabetes.  In 
studies of these patients, 17% of bardoxolone methyl patients reported AEs of weight decrease or 
decreased appetite (irrespective of relationship to treatment).  Weight reduction was more 
pronounced in patients treated with bardoxolone methyl than in those given placebo. 
Weight loss of approximately one kilogram per month was observed, with patients of higher 
body-mass index at baseline losing more weight (in absolute terms) than those of normal or 
moderately-elevated body-mass index.   
Bardoxolone methyl-treated PAH patients have also had decreases in weight, with mean weight 
decreases of approximately 3 kg versus placebo at Week 16.  Weight loss in PAH patients has 
not coincided with reports of decreased appetite or anorexia AEs. 
5.2.6. 
Hypomagnesaemia 
Hypomagnesaemia has not been reported in PAH patients to date, but was reported as an AE for 
15.5% of patients with CKD who also had type 2 diabetes who received bardoxolone methyl.  
The AE of hypomagnesaemia (of any reported relationship to study drug) was more frequently 
reported in bardoxolone methyl-treated patients than in patients given placebo.  The investigators 
considered almost all reported events to be mild.  Additionally, patients treated with bardoxolone 
methyl had a greater decrease from baseline in serum magnesium levels than patients given 
placebo; the decrease was evident within 4 weeks and attenuated after 8 weeks of starting 
therapy.  In bardoxolone methyl clinical studies performed to date, a post-hoc analysis identified 
no correlation between hypomagnesaemia and either gastrointestinal AEs or cardiac AEs, 
including cardiac dysrhythmias and prolonged QTc.  The 24-hour urine collections from the 
BEACON ambulatory blood pressure monitoring sub-study showed no increase in urinary 
magnesium levels, indicating that renal loss of magnesium did not account for the reductions in 
serum magnesium observed with bardoxolone methyl treatment in CKD patients.  Notably, a 
thorough QT study that tested doses of bardoxolone methyl up to 80 mg, bardoxolone methyl 
showed no increase in the QT interval.  


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Primary Objectives 
To provide continuing treatment with bardoxolone methyl as part of this extended access 
program while collecting ongoing safety and tolerability data of bardoxolone methyl.  
6.2. 
Primary Safety Endpoint: 
Frequency, intensity, and relationship to study drug of adverse events (AEs) and serious adverse 
events (SAEs), and change from baseline in the following assessments: physical examinations, 
vital sign measurements, BNP, N-terminal pro-brain natriuretic peptide (NT-proBNP), and 
weight. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This extended access study will assess the long-term safety and tolerability of bardoxolone 
methyl in qualified patients with PH who previously participated in controlled clinical studies 
with bardoxolone methyl. 
Qualified patients will receive  bardoxolone methyl once daily until the drug is available through 
commercial channels (including reimbursement) or until patient withdrawal, whichever is 
sooner.  Patients will start at 5 mg and will dose-escalate to 10 mg at Week 4 unless 
contraindicated clinically. Dose de-escalation (down to 5 mg) is permitted during the study if 
indicated clinically.  Refer to Section 7.3.1 for additional details on dose de-escalation.  
All patients in the study will follow the same visit and assessment schedule.  Patients will be 
scheduled to be assessed in person during treatment at Day 1, Weeks 1, 2, 4, 12, 24, 36, 48, and 
every 12 weeks thereafter.  Patients will also be assessed by telephone contact on Days 3, 10, and 
21.  Day 1 for this extended access study should occur on the same day as the last visit in the 
controlled clinical study.  Assessments required for both the last visit in the controlled study and 
Day 1 for this study should only be completed once. 
Patients from the CATALYST study: 
Day 1 of this extended access study will coincide with the Week 28 follow-up visit for patients 
from CATALYST (402-C-1504, NCT02657356, EudraCT 2016-000196-24).  If this extended 
access program is not yet open for enrollment at the time of a patient’s Week 28 visit, the Day 1 
visit (i.e., enrollment) must occur within 30 days of site activation.  Exceptions allowing 
CATALYST patients who have completed 24 weeks of treatment to schedule their follow-up 
assessments prior to Week 28 and still be considered eligible for this open-label study should be 
discussed with the Chief Medical Officer at Reata, or designee, and will be considered on a case-
by-case basis.   
Patients from the LARIAT study:  
Day 1 of this extended access study will coincide with  the End-of-Treatment visit for patients 
from LARIAT (402-C-1302, NCT02036970).   
7.2. 
Number of Patients 
Patient numbers will be determined by those who have been treatment-compliant and who have 
previously participated in clinical studies with bardoxolone methyl. 
7.3. 
Treatment Assignment 
All patients will receive bardoxolone methyl in this study. 
7.3.1. 
Dose Escalation and Dose De-Escalation  
Patients will start at a bardoxolone methyl dose of 5 mg and will dose-escalate to 10 mg at 
Week 4, unless contraindicated clinically.  The Week 4 visit is the only study visit when dose 
escalation is permitted.   


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Dose de-escalation is permitted during the study and the investigator may choose to decrease the 
patient’s dose to 5 mg, the minimum dose, if clinically indicated.  Reasons for dose de-escalation 
should be discussed with the medical monitor prior to changing dose.  Once a patient’s dose has 
been decreased to 5 mg, they cannot dose-escalate back to 10 mg of bardoxolone methyl. 
Unscheduled visits due to dose de-escalation should include assessments detailed in Section 9.7.  
7.4. 
Criteria for Study Termination 
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 
drugs will be discontinued and the investigator will be responsible for securing any alternative 
therapy to be administered, as appropriate. 
7.5. 
Criteria for Premature Termination or Suspension of Investigational 
Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of Good Clinical Practice (GCP), protocol, or contractual 
agreement with Sponsor or the site is unable to ensure adequate performance of the study. 
7.6. 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Sites 
In the event that the Sponsor, an institutional review board (IRB)/ethics committee (EC), or 
regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor. 
7.7. 
Schedule of Assessments 
Table 3 lists the overall schedule of assessments for the study. 
 


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Table 3: 
Schedule of Assessments  
Study Week  
(Day) 
Assessment 
Day 
1a 
Week 1 
(Phone) 
Day 
3±2 
Week 1  
Day 
7±3 
Week 2  
(Phone) 
Day 
10±2 
Week 2 
Day 
14±3 
Week 3 
(Phone) 
Day  
21±2 
Week 4 
Day 
28±3 
Week 
12 
Day  
84±3 
Week 
24 
Day  
168±3 
Week 
36 Day  
252±3 
Week 
48 Day  
336±3 
Week 
60±3, 
Every 
24 
Weeks 
Week 
72±3,  
Every 
24 
Weeks  
End of  
Study 
 Visitb 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current PAH background 
medications 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight at home 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Weight in clinic  
Xc 
 
 
 
 
 
X 
 
X 
 
X 
X  
X 
X 
Vital sign measurements 
Xc 
 
 
 
 
 
X 
 
X 
 
X 
X  
X 
X 
Physical examination 
Xc 
 
 
 
 
 
X 
 
X 
 
X 
X  
X 
X 
Pregnancy testd 
Xc 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Dispense study drug 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Collect study drug 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Telephone contact 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
Adverse event collection 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
Clinical chemistryf 
Xc 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
BNP and NT-Pro BNP 
Xc 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
6-min walk test 
Xc 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
Dyspnea and fatigueg 
Xc 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
WHO functional class 
Xc 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
a On Day 1, all procedures should be performed before study drug administration for patients who are treatment-compliant and have previously participated in clinical studies with bardoxolone methyl. 
b After the Week 60 visit, patients will continue to be assessed in person every 12 weeks until bardoxolone methyl becomes commercially available.  The End-of- Study visit should occur within 30 
days after bardoxolone methyl becomes available through commercial channels.  Patients who will be discontinued from the study prior to commercial availability of bardoxolone methyl must also 
complete all End-of-Study assessments.  
c Day 1 assessments should be performed as part of End-of-Treatment or Follow-up visit procedures from a prior study with bardoxolone methyl.  
d A serum pregnancy test will be performed 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 health authorities or IRBs/ECs.   
e AE assessments on Day 1 should be performed following study drug administration. 
f Clinical chemistries will be analyzed locally. 
g Dyspnea and fatigue must be assessed prior to beginning and immediately following completion of the 6MWT using the Borg scale. 
Abbreviations: PAH, pulmonary arterial hypertension; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro B-type natriuretic peptide; WHO, World Health Organization; 
AE, adverse event; 6MWT, 6-minute walk test.


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
Main criteria for inclusion:  
Treatment-compliant patients who are participating in qualifying ongoing studies and have 
completed required End-of-Treatment and/or Follow-up visits in a prior clinical study with 
bardoxolone methyl.   
8.2. 
Patient Exclusion Criteria 
All patients with any of the following conditions or characteristics must be excluded from the 
study: 
1. Participation in other investigational clinical studies involving interventional products 
being tested or used in a way different from the approved form or when used for an 
unapproved indication; 
2. Patients who have an ongoing serious adverse event (SAE) from a clinical study that is 
assessed by the investigator as related to bardoxolone methyl; 
3. Unwilling to practice acceptable methods of birth control (both males who have partners 
of childbearing potential and females of childbearing potential) while taking study drug;  
4. Women who are pregnant or breastfeeding; 
5. 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; 
6. Known hypersensitivity to any component of the study drug. 
8.3. 
Patient Discontinuation and Termination 
Patients have the right to discontinue study drug or withdraw from the study at any time for any 
reason, without prejudice to their medical care.  Furthermore, the investigator may discontinue a 
patient from study drug.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study.  The reason for a patient’s 
discontinuation from study drug or study termination will be recorded in the electronic case 
report form (eCRF).  
Discontinuation refers to a patient’s stopping administration of study drug and all study 
assessments and visits.  Reasons for study drug discontinuation may include the following: 
 Occurrence of an AE or change in medical status that will lead the investigator to be 
concerned about the patient’s welfare; 
 Administrative reasons (e.g., inability to continue); 
 Sponsor termination of the study; 
 Voluntary withdrawal; 


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 Females who become pregnant during the study; 
 Premature termination or suspension of an investigational site; 
 Loss to follow-up; 
 Death; 
 Withdrawal of consent. 
Patients must discontinue study drug if any of the following occur. 
 ALT or AST > 8X ULN; 
 ALT or AST > 5X ULN for more than 2 weeks; 
 ALT or AST > 3X ULN and (total bilirubin > 2X ULN or International Normalized 
Ratio [INR] > 1.5); 
 ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
Patients who discontinue from the study will be asked to complete the End-of-Study procedures 
noted in Table 3. 


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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.  BNP and NT-proBNP collected at Week 4 will also be used to 
monitor fluid status.   
Additionally, patients will be monitored for rapid weight gain suggestive of fluid overload.  
Patients will be given a Sponsor-provided scale to use at home to monitor their weights daily 
during the first 8 weeks of the treatment period and weekly thereafter through Week 24.  Patients 
who experience a 5-pound (2.3 kilogram) or greater increase in weight since their Day 1 weight 
during the first 4 weeks of the treatment period 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 advise patients to watch for signs and symptoms of fluid overload.  Patients 
should be informed to notify their physicians immediately if they experience swollen feet, chest 
pain, shortness of breath with mild exertion or while lying down, or other relevant symptoms.  
The investigator should immediately assess symptoms of fluid overload and determine 
appropriate medical management, as necessary, including whether stopping drug administration 
will be 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. 
9.1.2. 
Management of Elevated Transaminase Levels (ALT and/or AST) 
Transaminases should be monitored following patient’s standard of care.  Nearly all instances of 
elevated transaminases are expected to be asymptomatic.  Transaminase levels (as well as total 
bilirubin [TBL], GGT, alkaline phosphatase, and INR) will be checked within 48 to 72 hours 
during an unscheduled visit if the following occurs: 
 ALT or AST levels > 3X ULN. 
Testing will be repeated every 72 to 96 hours until transaminase levels are below 3X the ULN 
for at least one week or until the patient withdraws consent. 
Study drug administration will be permanently discontinued if any of the following occurs: 
 ALT or AST > 8X ULN; 
 ALT or AST > 5X ULN for more than 2 weeks; 
 ALT or AST > 3X ULN and (TBL > 2X ULN or INR > 1.5); 
 ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  


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The hepatobiliary tree must be visualized (e.g., ultrasound, magnetic resonance imaging) 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 as part of patient’s standard of care may indicate the 
need for replacement.  If vitamin D levels are low, supplementation may be warranted.  Muscle 
relaxants may also help relieve symptoms. 
9.1.4. 
Weight Loss 
Ongoing assessments to ensure that the patient is receiving adequate nutrition and consideration 
of other etiologies of weight loss may be warranted for patients receiving bardoxolone methyl.   
9.1.5. 
Hypomagnesaemia 
In instances where a patient experiences hypomagnesaemia (evaluated as part of patient’s 
standard of care), 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 AEs are typically mild and 
reversible within a few weeks after treatment initiation.  If symptoms will not resolve, dose 
de-escalation, with consultation of the medical monitor, may be necessary.   


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9.2. 
Description of Study Drug 
Bardoxolone methyl (RTA 402) drug product information is shown in Table 4.   
Table 4: 
Bardoxolone Methyl Drug Product Information 
Description 
Bardoxolone methyl capsule (5 mg, 
10 mg) 
Ingredients 
Bardoxolone methyl 
Methacrylic Acid – Ethyl Acrylate 
Copolymer 
Type A  
Silicified Microcrystalline Cellulose  
Hydroxypropyl Methylcellulose  
Lactose Monohydrate 
Sodium Lauryl Sulfate 
Colloidal Silicon Dioxide 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide 
 
Route of Administration 
Oral 
9.3. 
Concomitant Medications 
9.3.1. 
Excluded Medications 
No other investigational drug or device should be taken as part of an interventional study during 
the conduct of this study. 
Patients who take investigational drug or device during the study should not discontinue study 
drug solely on this basis.  Consultation with the medical monitor should occur prior to study drug 
discontinuation or withdrawing a patient from the study. 
9.3.2. 
Permitted Medications 
Pulmonary arterial hypertension-specific background therapy should be taken as clinically 
indicated and prescribed by the physician for the duration of the study. 
Refer to Section 9.10.15 for guidelines on oxygen use during 6MWTs.  Initiation of 
supplemental long-term oxygen therapy (oxygen application for more than 30 consecutive days) 
or persistent modification of a pre-existing supplemental long-term oxygen therapy (i.e., need for 
a persistent increase of the amount of delivered oxygen for more than 30 days) due to worsening 
PAH is permitted.  
Diuretics may be prescribed as clinically indicated throughout the study.  Any changes to the 
doses of oxygen or diuretics throughout the course of the study must be recorded in the 
electronic case report form (eCRF).   


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9.4. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to patients enrolled in the study in accordance with the protocol.  The study drug must not be 
used for reasons other than that described in the protocol.  
9.5. 
Randomization 
Not applicable. 
9.6. 
Blinding 
Not applicable.  
9.7. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
 Assessment of weight gain per Section 9.1.1;  
 Management of an AE or SAE; 
 Performance of additional laboratory tests for clinically abnormal laboratory test 
values or to confirm a possible pregnancy; 
 Dose de-escalation; 
 Any time the investigator feels that it is clinically appropriate for patient safety. 
At a minimum, unscheduled visits should include collection of AEs, concomitant medications 
and vital signs.  Additional conversations may be necessary with the medical monitor following 
an unscheduled visit to assess patient safety. 
9.8. 
Pregnancy 
9.8.1. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) are those who are not surgically sterile (no history 
of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have 
fallopian inserts with confirmed blockage, have not had reproductive potential terminated by 
radiation, and are not postmenopausal for at least 1 year. 
9.8.2. 
Methods of Birth Control 
While taking study drug and until 30 days following administration of the final dose of study 
medication, WOCBP must practice one of the following acceptable methods of birth control: 
 Use double barrier contraception method defined as male use of a condom and female 
use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, or 
diaphragm [always use with spermicidal jelly/cream]); 
 Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
90 days prior to start of study drug administration; 


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 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. 
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, 
or diaphragm [always use with spermicidal jelly/cream]); 
 Partner use of an intrauterine device; 
 Partner use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) for 
at least 90 days prior to start of study drug administration; 
 Abstain from sexual intercourse completely.  Complete abstinence from sexual 
intercourse is only acceptable if it is the preferred and usual lifestyle of the individual.  
Periodic abstinence is not permitted. 
9.8.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).  Male patients must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a patient or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If the serum pregnancy test 
confirms the pregnancy, the patient must permanently discontinue taking study drug.  The 
investigator must immediately report to the medical monitor a pregnancy associated with study 
drug exposure.  The early discontinuation protocol-required procedures outlined for End-of-
Study 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 an SAE: 
 Congenital anomaly/birth defect; 
 Stillbirth; 
 Spontaneous miscarriage. 


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9.9. 
Serious Toxicities 
In the case of serious toxicities, the investigator may choose to interrupt treatment with 
bardoxolone methyl.  A single dose reduction (from 10 mg to 5 mg) is permitted if clinically 
indicated to manage tolerability issues.  Once a patient’s dose has been reduced, that dose should 
be maintained.  Patients who resume therapy after an interruption will follow the originally 
planned study schedule.  
9.10. 
Study Procedures  
The following sections describe each assessment.  The timing of these assessments is noted in 
Table 3.  All Day 1 procedures, except AE assessments, should be completed prior to 
administration of first dose of study drug. 
9.10.1. 
Informed Consent 
Written informed consent (see Section 15.3) must be obtained from the patient before any 
study-related procedures are performed, and again if there is a change in the study procedures 
that would affect the patient’s willingness to participate. 
9.10.2. 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Table 3.  Patients must meet all 
of the inclusion and none of the exclusion criteria for entry in the study.   
9.10.3. 
Prior and Current Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking.  
All allowed and excluded medications should be recorded including all prescription drugs, herbal 
products, vitamins, minerals, and over-the-counter medications.  Trade or generic drug names 
should be used where possible.  Concomitant medications will be reviewed as indicated in  
Table 3 and all changes will be recorded. 
9.10.4. 
Current PAH Background Medications 
The name, dose, and frequency must be recorded for all PAH background medications that the 
patient is taking.  PAH background medications are those that have been approved by the US 
Food and Drug Administration (FDA) or the local health authority for the treatment of PAH.  
Trade or generic drug names should be used where possible.  PAH background medications will 
be reviewed as indicated in Table 3 and all changes will be recorded.   
9.10.5. 
Weight and Body Mass Index  
Weight must be measured as indicated in Table 3.  Body mass index (BMI) will be calculated in 
the eCRF each time the weight is recorded.  Patients will use Sponsor-provided scales to measure 
weight at home.  Patients will be instructed to stop administering study drug and contact the 
investigator if their daily weight increases per the criteria outlined in Section 9.1.1.  Patients will 
be provided instructions within the Informed Consent Form to help ensure consistent weight 
collection throughout the study. 


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9.10.6. 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), respiration rate, and body temperature.  Blood pressure should be taken after the 
patient has rested in a sitting position for at least 5 minutes.  The same arm (usually the non-
dominant arm) and the appropriate size cuff should be used for each measurement.  Vital sign 
measurements should be taken as indicated in Table 3.  
9.10.7. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner as indicated in Table 3 and as documented within the table 
footnotes.  The examination must include the following organ or body system assessments: head, 
eyes, ears, nose, throat, musculoskeletal, cardiovascular, lymphatic, respiratory, abdomen, skin, 
extremities, and neurological.  Assessments of any specific signs or symptoms reported by the 
patient must also be performed and documented along with any other findings of note.  Clinically 
significant findings at Day 1 must be recorded as medical history.  Following the examination on 
Day 1, new or changed physical examination findings meeting the criteria for an adverse event 
must be recorded as an adverse event.  If possible, the same individual should perform each 
physical examination on a patient during the study. 
9.10.8. 
Pregnancy Test 
WOCBP (see Section 9.8) will complete a pregnancy test as indicated in Table 3, or at any time 
if pregnancy is suspected.  Negative test results are required on Day 1 before study drug 
administration.  Any patient who becomes pregnant during the study must discontinue taking 
study drug immediately.  See Section 9.8.3 for a description of procedures to be followed in case 
of pregnancy. 
9.10.9. 
Study Drug Administration 
Patients should self-administer one capsule orally, once a day, preferably in the morning, as 
indicated in Table 3.  A vomited dose must not be replaced.  A double dose (e.g., missed dose 
from previous day and dose for current day) must not be taken. 
9.10.10. 
Study Drug Dispensation and Collection 
Study drug will be dispensed to the patient and collected from the patient as indicated in Table 3.  
The patient will be dispensed 1 or more treatment kits at Day 1, Week 4, Week 24, and every 
24 weeks thereafter for the duration of the study.  Dispensed treatment kits from each visit 
should be returned to the site for collection at the subsequent visit. 
9.10.11. 
Telephone Contact 
Patients will be contacted by telephone as indicated in Table 3.  Patients will be asked about their 
body weight and other signs of fluid retention, as well as AEs and any changes to concomitant 
medications.  If fluid retention is suspected, the patient must be brought into the clinic and 
evaluated by the investigator as soon as possible, as detailed in Section 9.1.1. 


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9.10.12. 
Adverse Event Collection 
Patients will be observed for general appearance, presence of illness or injury, or signs indicative 
of a concurrent illness as indicated in Table 3.  Patients must be instructed to volunteer any 
information regarding AEs on or after the first dose of study drug or query the patients with an 
open question regarding any AEs they may be experiencing (e.g., “How have you been feeling 
since your last visit?”).  Any findings are to be documented.  Patients must be asked if they have 
been hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (including prescription drugs, over-the-counter medications, vitamins, 
herbal products, and minerals).  Responses must be documented in the source documents. 
9.10.13. 
Clinical Chemistry 
Samples will be collected for clinical chemistry analyses as indicated in Table 3.  Clinical 
chemistries will be analyzed locally and should include those routinely monitored per patient’s 
standard of care. 
9.10.14. 
N-Terminal Pro-Brain Natriuretic Peptide and Brain Natriuretic Peptide  
Samples will be collected for NT-Pro BNP and BNP as indicated in Table 3.  As recent exercise 
may affect BNP and NT-Pro BNP levels, patients must be allowed to rest for a minimum period 
of 1 hour following arrival at the clinic and prior to obtaining this blood sample.  Similarly, this 
sample must be taken prior to the 6MWT or at least one hour after 6MWT.  This sample must be 
taken with the patient in the same position at all appropriate visits, e.g., sitting or 
semi-recumbent. 
9.10.15. 
6-Minute Walk Test 
A 6-minute walk test (6MWT) will be performed by the patients as indicated in Table 3.  Unless 
otherwise indicated as described below, each test must be performed in strict accordance with the 
American Thoracic Society (ATS) guidelines (ATS Statement 2002) provided in Section 19, 
Appendix 1.  The appropriate language version will be applied for patients with a non-English 
informed consent.  The walking course must be 30 m in length, except at sites granted prior 
Sponsor agreement. 
Patients will rate their dyspnea and overall fatigue using the Borg scale (2004 version, provided 
in Section 21, Appendix 3) prior to beginning and immediately following completion of each 
6MWT as indicated in Table 3.   
The assessor of the 6MWT must not provide the patient with the results of the assessment once 
complete.  A patient should wear the same or similar shoes for all 6MWTs.  Additionally, if a 
patient uses a walking aid for the first test, this same aide should be used during all subsequent 
tests.  The shoes worn and walking aid used for each 6MWT should be noted in source 
documents.   
Patients who require supplemental oxygen with exercise may use their prescribed oxygen level 
during 6MWTs.  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.   


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9.10.16. 
WHO/NYHA Functional Class Assessment 
WHO/NYHA functional class will be assessed (Section 20, Appendix 2) as indicated in Table 3.  
To the extent feasible, the same evaluator should assess WHO/NYHA FC for a particular patient 
over the entire course of the study.  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
Bardoxolone methyl capsules, 5 mg and 10 mg, will be used in this study. 
10.2. 
Study Drug Packaging and Labeling 
The study drug will be supplied in tamper-evident kits containing one 30-cc (5-mg capsules, 
30 count), one 60-cc (5-mg capsules, 90 count), or one 100-cc (10-mg capsules, 90 count) high-
density polyethylene bottle.  Each bottle will utilize foil induction-seal liners and a child-resistant 
closure.  Each bottle of study drug will contain 30 or 90 capsules of 5 mg or 10 mg strength 
bardoxolone methyl.  Each bottle will also contain a desiccant insert that must not be ingested.  
Labeling on each kit bottle will contain at minimum the following information: 
 Medication identification number; 
 Protocol 402-C-1602; 
 Caution Statement: New Drug – Limited by Federal Law to Investigational Use.  
Keep out of sight and reach of children; 
 Control or lot number 
 Store at 20° - 25°C (68° - 77°F), short term excursions allowed to 
15° - 30°C (59° - 86°F); 
 Reata Pharmaceuticals, Inc., Irving, TX. 
A double panel label will be presented on the treatment bottle containing this and other 
information as well.  Additionally, labeling in the relevant local languages for investigational 
medicinal product for use and distribution in the EU shall adhere to current Eudralex, Volume 4 
Annex 13 guidance and requirements.   
10.3. 
Study Drug Storage 
The stability of the drug product has been and is currently being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location with room 
temperature conditions of 20°C to 25°C (68°F to 77°F), with brief excursions allowed to 
15°C to 30°C (59°F to 86°F).   
10.4. 
Study Drug Administration 
Please refer to Section 9.10.9 for details on study drug administration.  Clear instructions will be 
provided to the patient regarding the number and type of capsules to be ingested at each study 
drug administration time point listed in Table 3.  Patients must be instructed to continue taking 
study drug once daily unless: (1) patient has been otherwise instructed by the investigator or 
(2) the patient has been formally discontinued from the study.  


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


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


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Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of the first dose of study drug until the final visit 
indicated in Table 3, as appropriate).  Certain pregnancy outcomes will require submission as an 
SAE (See Section 9.8). 
The investigator is responsible for reporting to Reata or designee all AEs and SAEs that are 
observed or reported by the patient during the study (from the time of administration of the first 
dose of study drug until the final visit indicated in Table 3, as appropriate), regardless of their 
relationship to study drug or their clinical significance.   
The Sponsor, or the Contract Research Organization (CRO) on the behalf of the Sponsor, must 
be notified immediately regarding the occurrence of any SAE that occurs after the patient 
receives the first dose of study drug and throughout the study, regardless of study drug 
administration, including SAEs resulting from protocol-associated procedures, as defined in 
relevant legislation.  The procedures for reporting all SAEs, regardless of causal relationship, are 
as follows: 
 Record the SAE on the AE eCRF and complete the “Serious Adverse Event Report” 
form within the electronic database; 
 In the event the electronic database is not functional, a paper SAE form will be 
available for the reporting of SAEs. 
The Sponsor may request additional information from the investigator to ensure the timely 
completion of accurate safety reports. 
All SAEs reported or observed during the study must be followed to resolution or until the 
investigator deems the event to be chronic or the patient to be stable.  Reata or designee may 
contact the investigator to obtain additional information on any SAE which has not resolved at 
the time the patient completes the study. 
11.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, nondirected 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 that are monitored per patient’s standard 
of care, physical examination findings, or from other documents that are relevant to patient 
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11.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Not Related: This relationship suggests that there is no association between the study drug and 
the reported event. 
Unlikely Related: This relationship suggests that the temporal sequence of the event with study 
drug administration makes a causal relationship improbable and/or other factors also provide 
plausible explanations. 
Possibly Related: This relationship suggests that treatment with the study drug caused or 
contributed to the AE.  That is, the event follows a reasonable temporal sequence from the time 
of study drug administration, and/or, follows a known response pattern to the study drug, but 
could have been produced by other factors. 
Probably Related: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, or judgment 
based on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
Definitely Related: This relationship suggests that a definite causal relationship exists between 
the drug administration and the AE, and other conditions (e.g., concurrent illness, 
progression/expression of disease state, or concurrent medication reaction) do not appear to 
explain the event. 
11.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
Mild: Symptoms causing no or minimal interference with usual social and functional activities; 
Moderate: Symptoms causing greater than minimal interference with usual social and functional 
activities; 
Severe: Symptoms causing inability to perform usual social and functional activities.  
11.6. 
Recording Adverse Events 
All conditions present prior to the administration of the first dose of study drug (Day 1) in a 
previous study with bardoxolone methyl should be documented as medical history in a previous 
study with bardoxolone methyl.  After the first dose, documentation of AEs shall continue until 
30 days following administration of the final dose of study medication under this protocol or 
through 30 days after commercial availability of bardoxolone methyl (i.e., through the End-of-
Treatment visit), regardless of the relationship of the AE to study drug.  Information to be 
collected will include type of event, date of onset, date of resolution, investigator-specified 
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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 will require 
documentation of onset and duration. 
All drug-related (possibly, probably, or definitely related, see Section 11.4) AEs and abnormal 
laboratory test results reported or observed during the study must be followed to resolution 
(either return to baseline or within normal limits).  All other AEs will be followed through the 
final visit indicated in Table 3, as appropriate. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Preexisting conditions 
(present before the start of the AE collection period) will be 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 shall 
be recorded as an AE.  Investigators shall ensure that the AE term recorded captures the change 
in the condition (e.g., “worsening of…”).  Any improvement in condition shall be documented 
per Section 9.10.7. 
Each AE shall be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values) or symptoms shall NOT be recorded as additional AEs.  If a 
diagnosis is unknown, sign(s) or symptom(s) shall be recorded as an AE(s).  Changes in 
laboratory test values will only be considered AEs if they are judged to be clinically significant 
(i.e., if some action or intervention is required or if the investigator judges the change to be 
beyond the range of normal physiological fluctuation).  If abnormal laboratory test values will be 
the result of pathology for which there will be an overall diagnosis (e.g., increased creatinine 
levels in renal failure), only the diagnosis shall be reported as an AE. 
Elective procedures (surgeries or therapies) that will be scheduled prior to the start of AE 
collection will not be considered AEs.  These elective procedures shall not be recorded as AEs, 
but shall be documented in the patient’s source documents as elective (e.g., elective periodontal 
surgery).  However, if a pre-planned procedure will be performed early (e.g., as an emergency) 
because of a worsening of the preexisting condition, the worsening of the condition shall be 
captured as an AE. 
11.7. 
Reporting Serious Adverse Events 
Any AE the investigator will consider 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, the investigator will complete the SAE form in the clinical database and send 
to 
 (fax numbers listed in Table 5) within 24 hours of awareness.  If the clinical 
database is down for any reason, the manual SAE forms will be utilized; however sites are 
responsible for ensuring the information on the manual SAE forms is entered into the clinical 
database once available. 


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Table 5: 
SAE Reporting Contact Information 
 
 
 
  
Non-North American sites will use access codes 
specific to their country.  Contact information for 
non-North American sites for SAE reporting will 
be provided by the clinical team directly to the 
sites. 
For questions regarding SAE reporting, contact your study manager, monitor, or 
 
. 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. 
Within 24 hours of receipt of new information, the SAE form should be updated within the 
clinical database and submitted along with any supporting documentation (e.g., patient discharge 
summary or autopsy reports).  If the clinical database is down for any reason, the manual SAE 
forms should be used; however, sites are responsible for ensuring the updated information on the 
manual SAE forms is entered into the clinical database once available. 
The Sponsor or designee will notify regulatory agencies of any fatal or life-threatening 
unexpected events associated with the use of the study drug as soon as possible but no later than 
7 calendar days after the initial receipt of the information.  Initial notification will be followed by 
a written report within the timeframe established by the appropriate regulatory agency.  For other 
SAEs that do not meet the fatal or life-threatening unexpected criteria, but are reported to be 
associated with the use of the study drug, Reata or designee will notify the appropriate regulatory 
agencies in writing within the timeframe established by those regulatory agencies.  Reata or 
designee will provide copies of any reports to regulatory agencies regarding serious and 
unexpected SAEs to the investigators for review and submission to their IRB or EC, as 
appropriate.  
Principal investigators will be responsible for informing their IRB/EC of any SAEs at their site.  
SAE correspondence with regulatory authorities or IRBs/ECs must be submitted to the Sponsor 
or designee for recording in the study file. 
Note that the following AEs which are commonly observed in this patient population will not be 
reported to regulatory authorities as individual expedited reports, except in unusual 
circumstances: 
 Shortness of breath; 
 Lightheadedness/dizziness; 
 Syncope; 


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 Chest pain; 
 Palpitations; 
 Fatigue; 
 Edema/fluid retention; 
 Exertional dyspnea; 
 Hypoxemia. 
These events will be reviewed on a regular basis in aggregate and will be reported in an 
expedited manner if a safety signal is detected.  Regular safety study updates will be reported to 
regulatory authorities according to local guidelines. 


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12. 
STATISTICS 
12.1. 
Sample Size 
The aim of this long-term extended access study is primarily to provide continuing treatment to 
patients with bardoxolone methyl and to assess long-term safety and tolerability, hence no single 
primary variable has been identified.  Patient numbers will be determined by those who have 
been treatment-compliant and who have previously participated in clinical studies with 
bardoxolone methyl. 
12.2. 
Study Variables 
12.2.1. 
Safety Variables 
The safety variables will include results of physical examinations, laboratory test results (BNP 
and NT-Pro BNP), vital sign measurements, weight, AEs, and SAEs. 
12.3. 
Statistical Analyses 
A statistical analysis plan (SAP) detailing the analyses will be developed prior to the database 
lock.  All statistical analyses and data summaries will be performed using SAS® (Version 9.1 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized overall using descriptive statistics.  Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, relevant quartiles, 
standard deviation, coefficient of variation, and geometric mean (where applicable).  Categorical 
data will be summarized using frequency counts and percentages.  
12.3.1. 
Primary Analysis of Safety 
As the extension is of an open-label design with no comparator group, all statistical analyses will 
be descriptive.  Patients will be included in these analyses if they are included in the safety 
analysis and have both baseline and post-baseline data available for the variable being analyzed.  
The summary tables will be presented for the overall group of patients, and also split by previous 
treatment groups in prior bardoxolone methyl clinical studies.   
 


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13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study-Specific Committees  
No steering committee, data safety monitoring committee, adjudication committee, or clinical 
endpoint committee will be used in this study. 
13.2. 
Study Monitoring 
The study site will be monitored remotely by the CRO periodically during the study to ensure 
that all aspects of the protocol will be followed and will include an electronic data collection 
which has a set of automatic data checks with data queries for programmed data collection.  
There will be monitoring of study site by telephone to ensure that the drug supplies have been 
provided and protocol instructions are well understood and applied. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Council for Harmonisation (ICH) 
guideline E6(R1): Good Clinical Practice: Consolidated Guideline and current standard operating 
procedures. 
13.3. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB/EC review, and regulatory inspections, by providing direct access to 
all study records.  In the event of an audit, the principal investigator will agree to allow the 
Sponsor, representatives of the Sponsor, the FDA, and other relevant regulatory authorities 
access to all study records. 
The principal investigator shall promptly notify the Sponsor or designee of any audits scheduled 
by any regulatory authorities and shall promptly forward copies of any audit reports received to 
the Sponsor or designee. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1. 
Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Reata may conduct a quality assurance audit of the investigator’s clinical site, including 
CTM/IMP storage facilities.   
14.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for one year following the completion 
of the study. 
No potential investigator who has a vested financial interest in the success of this study may 
participate in this study. 
14.3. 
Sponsor Obligations  
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the Screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or designee is not financially responsible for treatment of 
the patient’s underlying disease. 
14.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R1) 
8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents 
to the Sponsor or designee, which include but are not limited to the following: 
 An original investigator-signed investigator agreement page of the protocol;  
 The IRB/EC approval of the protocol; 
 The IRB- or EC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding this study that 
is to be provided to the patient or legal guardians; 
 A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
 Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
are accurate and current; 
 Completed financial disclosure forms (Section 14.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 


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


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15. 
ETHICS 
15.1. 
Institutional Review Board 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 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 US Investigational New Drug Application, a signed 
informed consent form, in compliance with Title 21 of the US CFR Part 50, will be obtained 
from each patient before the patient enters the study.  For sites outside of the US, 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. 
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 


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is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing the informed consent form.  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/EC-approved informed consent.  Informed consent must be 
obtained before conducting any study-specific procedures (i.e., all of the procedures described in 
the protocol).  The process of obtaining informed consent must be documented in the patient 
source documents. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB/EC, and a copy of the approved version and the notice 
of approval must be provided to the Sponsor’s designated monitor after IRB/EC approval. 
The principal investigator or designee will provide a copy of the informed consent form (signed 
copy to be provided per applicable law) to the patient and/or legal guardian.  The original form 
will be maintained in the patient’s medical records at the site. 
15.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the 
IRB/EC. 
The principal investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record, or other 
unpublished confidential information disclosed to them for the purpose of the study.  Prior 
written agreement from the Sponsor or designee must be obtained for the disclosure of any said 
confidential information to other parties. 
15.5. 
Modification of the Protocol 
Any changes that arise after the approval of the protocol must be documented as protocol 
amendments.  The FDA or other applicable regulatory agencies must be notified of protocol 
amendments.  The changes will become effective only after approval of the Sponsor, the 
investigator, the IRB/EC, and where necessary, the applicable regulatory agency.  In cases when 
the protocol is modified to enhance patient safety, changes may be implemented and the 
amendment must be immediately submitted to the IRB/EC. 
The investigator is responsible for informing the IRB/EC of all problems involving risks to 
patients according to national legislation.  In case of urgent safety measures, the Sponsor will 
immediately notify the investigators and relevant regulatory agencies, including FDA in accord 
with 21 CFR 312.32. 
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 


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


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


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17. 
PUBLICATION POLICY 
The Sponsor supports communication and publication of study results whatever the findings of 
the study.   
The Sponsor reserves the right to review all planned communications and manuscripts based on 
the results of this study.  This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but to allow the Sponsor to confirm the 
accuracy of the data, to protect proprietary information, and to provide comments based on 
information that may not yet be available to the study investigators.  The Sponsor also 
encourages disclosure of any conflict of interest from all authors or investigators when 
manuscripts are submitted for publication.  Those individuals, who have contributed greatly to 
this study, including lead external advisors and select principal investigators, may serve on any 
potential publications committee for the study. 


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18. 
REFERENCES 
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Statement: Guidelines for the six-minute walk test.  Am J Respir Crit Care Med. 
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Batt J, Ahmed SS, Correa J, et al. Skeletal muscle dysfunction in idiopathic pulmonary arterial 
hypertension. Am J Respir Cell Mol Biol. 2014;50(1):74-86. 
Chung L, Domsic RT, Lingala B, et al. Survival and predictors of mortality in systemic 
sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension 
assessment and recognition of outcomes in scleroderma registry. Arthritis Care Res (Hoboken). 
2014;66(3):489-95. 
Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: correlations of protection against oxidant and inflammatory stress.  
Proc Natl Acad Sci U S A. 2005;102(12):4584-9. 
Eba S, Hoshikawa Y, Moriguchi T, et al. The nuclear factor erythroid 2-related factor 2 activator 
oltipraz attenuates chronic hypoxia-induced cardiopulmonary alterations in mice. Am J Respir 
Cell Mol Biol. 2013;49(2):324-33. 
Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of 
pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary 
Hypertension of the European Society of Cardiology (ESC) and the European Respiratory 
Society (ERS), endorsed by the International Society of Heart and Lung Transplantation 
(ISHLT). Eur Heart J. 2009;30:2493-537. 
Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial 
hypertension. N Engl J Med. 2013;369(4):330-40. 
Holmström KM, Baird L, Zhang Y, et al. Nrf2 impacts cellular bioenergetics by controlling 
substrate availability for mitochondrial respiration. Biol Open. 2013;0:1-10. 
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2011;300(5):F1180-F1192. 
 


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


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

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

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

 
 chronic obstructive pulmonary disease; 6MWD 
 

 
 
6-minute walking distance.
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Supplemental Oxygen
 
If oxygen supplementation is needed during the walks and se-
rial tests are planned (after an intervention other than oxygen
therapy), then during all walks by that patient oxygen should
be delivered in the same way with the same flow. If the flow
must be increased during subsequent visits due to worsening
gas exchange, this should be noted on the worksheet and con-
sidered during interpretation of the change noted in 6MWD.
The type of oxygen delivery device should also be noted on
the report: for instance, the patient carried liquid oxygen or
pushed or pulled an oxygen tank, the delivery was pulsed or
continuous, or a technician walked behind the patient with the
oxygen source (not recommended). Measurements of pulse
and SpO
 
2
 
 should be made after waiting at least 10 minutes af-
ter any change in oxygen delivery.
 
Rationale.  
 
For patients with COPD or interstitial lung dis-
ease, oxygen supplementation increases the 6MWD (17, 59,
61, 63). Carrying a portable gas container (but not using it for
supplemental oxygen) reduced the mean 6MWD by 14% in
one study of patients with severe respiratory disability, but us-
ing the container to deliver supplemental oxygen during the
exercise increased the mean 6MWD by 20–35% (59).
 
Medications
 
The type of medication, dose, and number of hours taken be-
fore the test should be noted.
 
Rationale.  
 
Significant improvement in the distance walked,
or the dyspnea scale, after administration of bronchodilators
has been demonstrated in patients with COPD (62, 63), as well
as cardiovascular medications in patients with heart failure (19).
 
INTERPRETATION
 
Most 6MWTs will be done before and after intervention, and
the primary question to be answered after both tests have
been completed is whether the patient has experienced a clini-
cally significant improvement. With a good quality-assurance
program, with patients tested by the same technician, and af-
ter one or two practice tests, short-term reproducibility of the
6MWD is excellent (37). It is not known whether it is best for
clinical purposes to express change in 6MWD as (
 
1
 
) an abso-
lute value, (
 
2
 
) a percentage change, or (
 
3
 
) a change in the per-
centage of predicted value. Until further research is available,
we recommend that change in 6MWD be expressed as an ab-
solute value (e.g., the patient walked 50 m farther).
A statistically significant mean increase in 6MWD in a
group of study participants is often much less than a clinically
significant increase in an individual patient. In one study of
112 patients (half of them women) with stable, severe COPD,
the smallest difference in 6MWD that was associated with a
noticeable clinical difference in the patients’ perception of ex-
ercise performance was a mean of 54 m (95% confidence in-
terval, 37–71 m) (64). This study suggests that for individual
patients with COPD, an improvement of more than 70 m in
the 6MWD after an intervention is necessary to be 95% confi-
dent that the improvement was significant. In an observational
study of 45 older patients with heart failure, the smallest dif-
ference in 6MWD that was associated with a noticeable differ-
ence in their global rating of worsening was a mean of 43 m
(20). The 6MWD was more responsive to deterioration than
to improvement in heart failure symptoms.
 
Reported Mean Changes in 6MWD After Interventions
 
Supplemental oxygen (4 L/min) during exercise in patients with
COPD or interstitial lung disease increased mean 6MWD by
approximately 95 m (36%) in one study (59). Patients taking
 
an inhaled corticosteroid experienced a mean 33 m (8%) in-
crease in 6MWD in an international COPD study (16). Pa-
tients with COPD in a study of the effects of exercise and dia-
phragmatic strength training experienced a mean increase in
6MWD of 50 m (20%) (65). Lung volume reduction surgery in
patients with very severe COPD has been reported to increase
6MWD by a mean of 55 m (20%) (13).
Cardiac rehabilitation in patients referred with various heart
diseases increased 6MWD by a mean of 170 m (15%) in a recent
study (66). In 25 older patients with heart failure, an angiotensin-
converting enzyme inhibitor medication (50 mg captopril per
day) improved 6MWD a mean of 64 m (39%) compared with a
mean increase of only 8% in those receiving a placebo (19).
 
Interpreting Single Measurements of Functional Status
 
Optimal reference equations from healthy population-based
samples using standardized 6MWT methods are not yet avail-
able. In one study, the median 6MWD was approximately 580
m for 117 healthy men and 500 m for 173 healthy women (50).
A mean 6MWD of 630 m was reported by another study of 51
healthy older adults (55). Differences in the population sam-
pled, type and frequency of encouragement, corridor length,
and number of practice tests may account for reported differ-
ences in mean 6MWD in healthy persons. Age, height, weight,
and sex independently affect the 6MWD in healthy adults;
therefore, these factors should be taken into consideration
when interpreting the results of single measurements made to
determine functional status. We encourage investigators to pub-
lish reference equations for healthy persons using the previ-
ously mentioned standardized procedures.
A low 6MWD is nonspecific and nondiagnostic. When the
6MWD is reduced, a thorough search for the cause of the im-
pairment is warranted. The following tests may then be help-
ful: pulmonary function, cardiac function, ankle–arm index,
muscle strength, nutritional status, orthopedic function, and
cognitive function.
 
Conclusions
 
The 6MWT is a useful measure of functional capacity targeted
at people with at least moderately severe impairment. The test
has been widely used for preoperative and postoperative eval-
uation and for measuring the response to therapeutic inter-
ventions for pulmonary and cardiac disease. These guidelines
provide a standardized approach to performing the 6MWT.
The committee hopes that these guidelines will encourage fur-
ther research into the 6MWT and allow direct comparisons
among different studies.
 
This statement was developed by the ATS Committee on Proficiency Stan-
dards for Clinical Pulmonary Function Laboratories.
Members of the committee are:
R
 
OBERT
 
 O. C
 
RAPO
 
, M.D., 
 
Chair
 
*
R
 
ICHARD
 
 C
 
ASABURI
 
, P
 
H
 
.D, M.D.
A
 
LLAN
 
 L. C
 
OATES
 
, M.D.
P
 
AUL
 
 L. E
 
NRIGHT
 
, M.D.*
N
 
EIL
 
 R. M
 
AC
 
I
 
NTYRE
 
, M.D.
R
 
OY
 
 T. M
 
C
 
K
 
AY
 
, P
 
H
 
.D.
D
 
OUGLAS
 
 J
 
OHNSON
 
, M.D.
J
 
ACK
 
 S. W
 
ANGER
 
, M.S.
R. J
 
ORGE
 
 Z
 
EBALLOS
 
, M.D.*
Ad Hoc Committee members are:
V
 
ERA
 
 B
 
ITTNER
 
, M.D.
C
 
ARL
 
 M
 
OTTRAM
 
, R.R.T.
*Writing Committee Members
 
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APPENDIX
The following elements should be present on the 6MWT worksheet and report:
Lap counter:
__ __ __ __ __
__ __ __ __ __
__ __ __ __ __
Patient name: ____________________
Patient ID# ___________
Walk # ______
Tech ID: _________ Date: __________
Gender: M F
Age: ____
Race: ____
Height: ___ft ____in, ____ meters
Weight: ______ lbs, _____kg
Blood pressure: _____ / _____
Medications taken before the test (dose and time): __________________
Supplemental oxygen during the test: No
Yes, flow ______ L/min, type _____
Baseline
End of Test
Time
___:___
___:___
Heart Rate
_____
_____
Dyspnea
____
____ (Borg scale)
Fatigue
____
____ (Borg scale)
SpO2
____ %
____%
Stopped or paused before 6 minutes? No
Yes, reason: _______________
Other symptoms at end of exercise: angina
dizziness
hip, leg, or calf pain
Number of laps: ____ (60 meters)  final partial lap: _____ meters 
Total distance walked in 6 minutes: ______ meters
Predicted distance: _____ meters
Percent predicted: _____%
Tech comments:
Interpretation (including comparison with a preintervention 6MWD):
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20. 
APPENDIX 2: FUNCTIONAL CLASSIFICATION OF 
PULMONARY HYPERTENSION MODIFIED AFTER THE NEW 
YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ACCORDING TO THE WHO 1998 
(GALIE, 2009) 
World Health Organization functional assessment classification  
Class 
I:  
Patients with pulmonary hypertension (PH) but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class 
II:  
Patients with PH resulting in slight limitation of physical activity. They are 
comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class 
III:  
Patients with PH resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest 
pain, or near syncope. 
Class 
IV:  
Patients with PH with inability to carry out any physical activity without symptoms. 
These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even 
be present at rest. Discomfort is increased by any physical activity. 


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21. 
APPENDIX 3:  BORG CR10 SCALE 
 
 
 

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a n d wei g ht. 
Met h o d ol o g y:  
T his e xte n de d access st u d y will assess t he l o n g-ter m safet y a n d t olera bilit y of bar d o x ol o ne met h yl i n 
q ual ifie d patie nts wit h p ul m o nar y h y perte nsi o n ( P H) w h o pre vi o usl y partici pate d i n c o ntr olle d cli nical 
st u dies wit h bar d o x ol o ne met h yl.  
Q ualifie d patie nts will start d osi n g at 1 0 m g of bar d o x ol o ne met h yl e ver y ot her da y, t he n be gi n o nce  dail y 
d osi n g  at Wee k 4 ( u nless c o ntrai n dicate d cli nicall y) a n d c o nti n ue u ntil t he dr u g is a vaila ble t hr o u g h 
c o m mercial c ha n nels (i ncl u di n g rei m b urse me nt) or u ntil patie nt wit h dra wal, w hic he ver is s o o ner.  D ose 
de -escalati o n ( d o w n t o 5 m g) is per mitte d d uri n g t he st u d y , if i n dicate d cli nicall y.    
All patie nts i n t he st u d y will f oll o w t he sa me visit a n d assess me nt sc he d ule.  P atie nts will be sc he d ule d t o 
be assesse d i n pers o n d uri n g treat me nt at Da y 1, Wee k 2, Wee k 4 , Wee k 6, Wee k 8, Wee k 2 4, a n d e ver y 
2 4 wee ks t hereafter.  Patie nts will als o be assesse d b y tele p h o ne c o ntact o n Da y s 3, 1 0 , 2 1, 3 1, a n d 3 8.  
Da y 1 f or t his e xte n de d access st u d y s h o ul d occ ur o n t he sa me da y as t he last visit i n t he c o ntr olle d 
cli nical st u d y.  Patie nt stat us s h o ul d be caref ull y m o nit ore d b y t he i n vest i gat or d uri n g t he first 8  wee ks of 
st u d y treat me nt.  Assess me nts re q uire d f or b ot h t he last visit i n t he c o ntr olle d st u d y a n d Da y 1 f or t his 
st u d y s h o ul d o nl y be c o m plete d o nce. 
Patie nts fr o m t he C A T A L Y S T st u d y: 
Da y 1 of t his e xte n de d access  st u d y will c oinci de wit h  t he Wee k 2 8 f oll o w-u p visit f or patie nts fr o m 


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C A T A L Y S T ( 4 0 2 -C -1 5 0 4 , N C T 0 2 6 5 7 35 6 , E u dra C T 2 0 1 6-0 0 0 1 9 6 -2 4 ).  If t his e xte n de d access pr o gra m 
is n ot yet o pe n f or e nr oll me nt at t he ti me of a patie nt’s Wee k 2 8 visit , t he Da y 1 visit (i.e., e nr oll me nt) 
m ust occ ur wit hi n 3 0 da ys of site acti vati o n.  E xce pti o ns all o wi n g C A T A L Y S T patie nts w h o ha ve 
c o m plete d 2 4 wee ks of treat me nt t o sc he d ule t heir f oll o w-u p assess me nts pri or t o Wee k 2 8 a n d still be 
c o nsi dere d eli gi ble  f or t his o pe n -la bel st u d y s h o ul d be disc usse d wit h t he C hief Me dical Officer at Reata, 
or desi g nee, a n d will be c o nsi dere d o n a case -b y -case basis.  
Patie nts fr o m t he L A RI A T st u d y :  
Da y 1 of t his e xte n de d access st u d y will c oi nci de wit h  t he E n d-of -St u d y visit f or patie nts fr o m L A RI A T 
( 4 0 2-C -1 3 0 2, N C T 0 2 0 3 6 9 7 0) .  
Sc he m a f or St u d y of B ar d o x ol o ne Met h yl i n P atie nts wit h P ul m o n ar y H y perte nsi o n  
6- Mi n ut e W al k T e st
T T el e p h o n e C o nt a ct
D o s e- Titr ati o n
( 1 0 m g B A R D Q O D)
W 2
W 1
W 8
D 1
D 3
T
D 1 0
T
D 2 1
T
W 4
M ai nt e n a n c e
( 1 0 m g B A R D Q D)
D 3 1
T
D 3 8
T
W 6
E n d of 
St u d y
W 2 4,
E v er y 
2 4 W K s
 
 
N u m ber of p atie nts ( pl a n ne d):  
Patie nt n u m bers will be deter mi ne d b y t h ose w h o are treat me nt -c o m plia nt a n d w h o ha ve pre vi o usl y 
partici pate d i n cli nical st u dies wit h bar d o x ol o ne met h yl .  
M ai n criteri a f or i ncl usi o n:  
Treat me nt -c o m plia nt patie nts w h o are partici pati n g i n q ualif yi n g o n g oi n g st u dies  a n d ha ve c o m plete d 
re q uire d E n d-of -Treat me nt  a n d/ or F oll o w -u p visits i n a pri or cli nical st u d y wit h bar d o x ol o ne m et h yl.   
M aj or e xcl usi o n criteri a:  
1.  Partici pati o n i n ot her i n vesti gati o nal cli nical st u dies i n v ol vi n g i nter ve nti o nal pr o d ucts bei n g 
teste d or use d i n a wa y differe nt fr o m t he a p pr o ve d f or m or w he n use d f or a n u na p pr o ve d 
i n dicati o n; 
2.  Patie nts w h o ha ve a n o n g o i n g S A E  fr o m a cli nical st u d y t hat is assesse d b y t he i n vesti gat or as 
relate d t o bar d o x ol o ne met h yl; 
3.  U n willi n g t o practice acce pta ble met h o ds of birt h c o ntr ol ( b ot h males w h o ha ve part ners of 
c hil d beari n g p ote ntial a n d fe males of c hil d beari n g p ote ntial) w h ile ta ki n g st u d y dr u g;  
4.  W o me n w h o are pre g na nt or breastfee di n g;  
5.  Patie nt is, i n t he o pi ni o n of t he i n vesti gat or, u na ble t o c o m pl y wit h t he re q uire me nts of t he st u d y 
pr ot oc ol or is u ns uita ble f or t he st u d y f or a n y reas o n;  
6.  K n o w n  h y perse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g . 
I n vesti g ati o n al pr o d uct, d os a ge, m o de of a d mi nistr ati o n , a n d d ur ati o n of tre at me nt:  
Bar d o x ol o ne met h yl will be a d mi nistere d orall y (e ver y ot her da y or o nce dail y) at 1 0 m g u ntil it bec o mes 
c o m merciall y a vaila ble.  D ose de -escalati o n ( d o w n t o 5 m g) is per mitte d d uri n g t he st u d y , if i n dicate d 
cli nicall y. 


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Ref ere nce t her a p y, d os a ge a n d m o de of a d mi nistr ati o n:  
N o ne.  
Criteri a f or e v al u ati o n:  
Safet y : Res ults of p h ysical e xa mi nati o ns, la b orat or y res ults, B N P, N T -Pr o B N P, vital si g n meas u re me nts, 
wei g ht, A Es , a n d S A Es.  
St atistic al met h o ds:  
Sa m ple size : T he ai m of t his l o n g -ter m e xte nde d access  st u d y is pri maril y t o pr o vi de c o nti n ui n g treat me nt 
t o patie nts wit h bar d o x ol o ne met h yl a n d t o assess  l o n g-ter m safet y a n d t olera bilit y, he nce n o si n gle 
pri mar y varia ble has bee n i de ntifie d.  Patie nt n u m bers will be deter mi ne d b y t h ose w h o ha ve bee n 
treat me nt-c o m plia nt  a n d w h o ha ve pre vi o usl y partici pate d i n cli nical st u dies wit h bar d o x ol o ne met h yl . 
Pri mar y a nal ysis  of safet y : As t he e xte nsi o n is of a n o pe n -la bel desi g n wit h n o c o m parat or gr o u p, all 
statistical a nal yses will be descri pti ve.  T he s u m mar y ta bles will be prese nte d f or t he o verall gr o u p of 
patie nts, a n d als o s plit b y pre vi o us treat me nt gr o u ps (i.e., bar d o x ol o ne met h yl or place b o) i n pri or 
bar d o x ol o ne met h yl cli nical st u dies .  


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3.  
T A B L E O F C O N T E N T S A N D LI S T O F T A B L E S  
T A B L E O F C O N T E N T S 
1.  
T I T L E P A G E ................................................................................................................ 1 
2.  
S Y N O P SI S ................................................................................................................... 5  
3.  
T A B L E O F C O N T E N T S A N D LI S T O F T A B L E S .................................................... 8  
4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S............................. 1 3  
5.  
IN T R O D U C TI O N ...................................................................................................... 1 5  
5. 1.  
S t u d y R ati o nale ........................................................................................................... 1 7 
5. 2.  
C li nical E x perie nce wit h Bar d o x ol o ne Met h yl .......................................................... 1 7 
5. 2. 1.  
S afet y a n d T olera bilit y ............................................................................................... 1 7  
5. 2. 2.  
F l ui d O verl oa d ............................................................................................................ 1 7 
5. 2. 3.  
Tr a nsa mi nase a n d Ga m m a- Gl uta m yl Tra ns p e pti dase Ele vati o ns .............................. 1 8  
5. 2. 4.  
M uscle  S pas ms ........................................................................................................... 1 8 
5. 2. 5.  
W ei g ht L oss ................................................................................................................ 1 9  
5. 2. 6.  
H y p o ma g n esae mia ...................................................................................................... 1 9  
6.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S .............................................................. 2 0  
6. 1.  
P ri mar y O bj ecti ves ..................................................................................................... 2 0 
6. 2.  
P ri mar y Safet y E n d p oi nt: ........................................................................................... 2 0 
7.  
IN V E S TI G A TI O N A L P L A N ..................................................................................... 2 1  
7. 1.  
O ve rall St u d y Desi g n .................................................................................................. 2 1 
7. 2.  
N u m be r of Patie nts ..................................................................................................... 2 1 
7. 3.  
Tr eat me nt Assi g n me nt ................................................................................................ 2 1  
7. 3. 1.  
D ose  Escalati o n a n d D os e De- Es calati o n ................................................................... 2 2 
7. 4.  
C riteria f or St u d y Ter mi nati o n ................................................................................... 2 2 
7. 5.  
Criteria f or Pre m at ure T er mi nati o n or S us pe nsi o n of I n vesti gati o nal Sites ............... 2 2  
7. 6.  
Pr oce d ures f or Pre mat ure Ter mi nati o n or S us pe nsi o n of t he St u d y or t he 
Partici pati o n of I n vesti gati o nal Sites .......................................................................... 2 2  
7. 7.  
S c he d ule of Assess me nts ............................................................................................ 2 2  
8.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S .............................................. 2 5  
8. 1.  
Patie nt I ncl usi o n Criteria ............................................................................................ 2 5  
8. 2.  
Patie nt E x cl usi o n Criteria ........................................................................................... 2 5  


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8. 3.  
Patie nt Disc o nti n uati o n  .............................................................................................. 2 5  
9.  
T R E A T M E N T O F P A TI E N T S .................................................................................. 2 7  
9. 1.  
S elect Ma na ge m e nt G ui deli nes .................................................................................. 2 7  
9. 1. 1.  
Ma na ge me nt of Fl ui d Stat us ....................................................................................... 2 7  
9. 1. 2.  
Ma na ge me nt of El e vate d Tra nsa mi nase Le vels ( A L T a n d/ or A S T) .......................... 2 7  
9. 1. 3.  
Ma na ge me nt of M us cle S pas ms ................................................................................. 2 8  
9. 1. 4.  
W ei g ht L oss ................................................................................................................ 2 8  
9. 1. 5.  
H y p o ma g n esae mia ...................................................................................................... 2 8  
9. 1. 6.  
Na usea ......................................................................................................................... 2 8  
9. 2.  
De scri pti o n of St u d y Dr u g .......................................................................................... 2 9 
9. 3.  
C o nc o mita nt Me dicati o ns ........................................................................................... 2 9  
9. 3. 1.  
E x cl u de d Me dicati o ns ................................................................................................ 2 9  
9. 3. 2.  
P er mitte d Me dicati o ns ................................................................................................ 2 9  
9. 4.  
Tr eat me nt C o m plia nce ................................................................................................ 3 0  
9. 5.  
R a n d o mizati o n ............................................................................................................ 3 0  
9. 6.  
B li n di n g ...................................................................................................................... 3 0 
9. 7.  
U nsc he d ule d Visits ..................................................................................................... 3 0  
9. 8.  
P re g n a nc y ................................................................................................................... 3 0 
9. 8. 1.  
W o me n of C hil d beari n g P ote ntial .............................................................................. 3 0  
9. 8. 2.  
Me t h o ds of Birt h C o ntr ol............................................................................................ 3 0 
9. 8. 3.  
S us pecte d Pre g na n c y .................................................................................................. 3 1  
9. 9.  
S eri o us T o xicities ....................................................................................................... 3 2  
9. 1 0.  
S t u d y Pr oce d ures ........................................................................................................ 3 2 
9. 1 0. 1.  
I nf or me d C o nse nt ....................................................................................................... 3 2 
9. 1 0. 2.  
I n cl usi o n/ E xcl usi o n .................................................................................................... 3 2  
9. 1 0. 3.  
P ri or a n d C urre nt C o nc o mita nt Me dicati o ns .............................................................. 3 2 
9. 1 0. 4.  
C urre nt P A H  Bac k gr o u n d Me dicati o ns ...................................................................... 3 2 
9. 1 0. 5.  
Wei g ht a n d B o d y M ass I n de x ..................................................................................... 3 2  
9. 1 0. 6.  
Vital Si g n Meas ur e me nts ............................................................................................ 3 3  
9. 1 0. 7.  
P h ysical E x a mi nati o n ................................................................................................. 3 3  
9. 1 0. 8.  
Pre g n a nc y T est ............................................................................................................ 3 3  
9. 1 0. 9.  
St u d y Dr u g A d mi nistrati o n......................................................................................... 3 3  
9. 1 0. 1 0.  
St u d y Dr u g Dis pe ns ati o n a n d C ollecti o n ................................................................... 3 3  


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1 0  
9. 1 0. 1 1.  
Tele p h o ne C o ntact ...................................................................................................... 3 3  
9. 1 0. 1 2.  
A d verse E v e nt C ollecti o n ........................................................................................... 3 4  
9. 1 0. 1 3.  
C li nical C he mistr y ...................................................................................................... 3 4 
9. 1 0. 1 4.  
N- Ter mi nal P r o- Brai n N atri uretic Pe pti de a n d Brai n Natri uretic Pe pti de ................. 3 4 
9. 1 0. 1 5.  
6- Mi n ute Wal k Test .................................................................................................... 3 4  
9. 1 0. 1 6.  
W H O/ N Y H A F u n cti o nal Class Assess me nt .............................................................. 3 5  
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T ........................................... 3 6  
1 0. 1.  
S t u d y Dr u g .................................................................................................................. 3 6 
1 0. 2.  
S t u d y Dr u g Pac k a gi n g a n d La b eli n g .......................................................................... 3 6 
1 0. 3.  
S t u d y Dr u g St ora ge ..................................................................................................... 3 6 
1 0. 4.  
S t u d y Dr u g A d mi nistrati o n......................................................................................... 3 6 
1 0. 5.  
S t u d y Dr u g A cc o u nta bilit y ......................................................................................... 3 7 
1 0. 6.  
S t u d y Dr u g H a n dli n g a n d Dis p osal ............................................................................ 3 7 
1 1.  
S A F E T Y A S S E S S M E N T S ........................................................................................ 3 8  
1 1. 1.  
S afet y Para met ers ....................................................................................................... 3 8  
1 1. 2.  
A d ve rse a n d Seri o us A d verse E ve nts ......................................................................... 3 8 
1 1. 2. 1.  
Defi niti o n of A d vers e E v e nts ..................................................................................... 3 8  
1 1. 2. 1. 1.  
A d ve rse E v e nt ............................................................................................................. 3 8 
1 1. 2. 1. 2.  
Seri o us A d verse E v e nt ................................................................................................ 3 8  
1 1. 3.  
Eliciti n g A d vers e E ve nt I nf or mati o n .......................................................................... 3 9  
1 1. 4.  
Asse ss me nt of Ca usalit y ............................................................................................. 4 0 
1 1. 5.  
Asse ss me nt of Se verit y ............................................................................................... 4 0 
1 1. 6.  
R ec or di n g A d verse E ve nts ......................................................................................... 4 0  
1 1. 7.  
Re p orti n g Seri o us A d v erse E ve nts ............................................................................. 4 1  
1 2.  
S T A TI S TI C S .............................................................................................................. 4 4  
1 2. 1.  
S a m ple Siz e ................................................................................................................ 4 4  
1 2. 2.  
St u d y Vari a bles ........................................................................................................... 4 4  
1 2. 2. 1.  
Safet y  Vari a bles .......................................................................................................... 4 4 
1 2. 3.  
S tatistical A nal yses ..................................................................................................... 4 4 
1 2. 3. 1.  
Pri mar y A n al ysis of Safet y ......................................................................................... 4 4  
1 3.  
D I R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S......................................... 4 5 
1 3. 1.  
St u d y- S pecific C o m mittees ........................................................................................ 4 5  
1 3. 2.  
St u d y M o nit ori n g ........................................................................................................ 4 5  


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1 1  
1 3. 3.  
A u dits a n d I ns p ecti o ns ................................................................................................ 4 5  
1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E ......................................... 4 6  
1 4. 1.  
Q ua lit y Ass ura nce ....................................................................................................... 4 6 
1 4. 2.  
F i na ncial Discl os ur e ................................................................................................... 4 6 
1 4. 3.  
S p o ns or O bli gati o ns.................................................................................................... 4 6  
1 4. 4.  
In v esti gat or D oc u me nt ati o n ........................................................................................ 4 6  
1 4. 5.  
C li nical St u d y I ns ura nce ............................................................................................. 4 7 
1 4. 6.  
Use  of I nf or mati o n ...................................................................................................... 4 7 
1 5.  
E T H I C S ...................................................................................................................... 4 8 
1 5. 1.  
Instit uti o nal Re vie w B oar d or Et hics C o m mittee Re vie w .......................................... 4 8  
1 5. 2.  
Et hi cal C o n d uct of t he St u d y ...................................................................................... 4 8  
1 5. 3.  
W ritte n I nf or m e d C o nse nt .......................................................................................... 4 8 
1 5. 4.  
C o nfi de ntialit y ............................................................................................................ 4 9  
1 5. 5.  
M o di ficati o n of t he Pr ot oc ol ....................................................................................... 4 9 
1 5. 6.  
P r ot oc ol De viati o ns .................................................................................................... 5 0 
1 6.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G ....................................................... 5 1  
1 6. 1.  
R ete nti o n of Rec or ds .................................................................................................. 5 1  
1 6. 2.  
C ase Re p ort F or ms ..................................................................................................... 5 1  
1 7.  
P U B LI C A TI O N P O LI C Y .......................................................................................... 5 2  
1 8.  
R E F E R E N C E S ........................................................................................................... 5 3  
1 9.  
A P P E N DI X 1: A T S G UI D E LI N E S F O R T H E SI X- MI N U T E W A L K T E S T .......... 5 5  
2 0.  
A P P E N DI X 2: F U N C TI O N A L C L A S SI FI C A TI O N O F P U L M O N A R Y 
H Y P E R T E N SI O N M O D I FI E D A F T E R T H E N E W Y O R K H E A R T 
A S S O CI A TI O N F U N C T I O N A L C L A S SI FI C A TI O N A C C O R DI N G T O 
T H E W H O 1 9 9 8 ( G A LI E, 2 0 0 9) ............................................................................... 6 3  
2 1.  
A P P E N DI X 3:  B O R G C R 1 0 S C A L E ....................................................................... 6 4  
 


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LI S T O F T A B L E S 
Ta ble 1:  
E mer ge nc y C o nta ct I nf or mati o n ................................................................................... 4  
Ta ble 2:  
A b bre viati o ns a n d S peci alist Ter ms ........................................................................... 1 3  
Ta ble 3:  
Sc he d ule of  Assess me nts ............................................................................................ 2 3 
Ta ble 4:  
Bar d o x ol o ne Me t h yl Dr u g Pr o d uct I nf or mati o n ........................................................ 2 9 
Ta ble 5:  
S A E Re p orti n g C o ntact I nf or mati o n .......................................................................... 4 2  
 


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C o nfi de ntial 
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1 3  
4.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S 
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble 2:  
A b bre vi ati o ns a n d S peci alist Ter ms 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
6 M W D  
6 -mi n ute wal k dista nce  
6 M W T  
6 -mi n ute wal k test  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A S T  
As partate a mi n otra nsferase  
A T P  
A de n osi ne tri p h os p hate  
A T S  
A merica n T h oracic S ociet y  
B MI  
B o d y mass i n de x  
B N P  
B -t y pe natri uretic pe pti de 
C F R  
C o de of Fe deral Re g ulati o ns ( U S)  
C K  
Creati ne ki nase  
C K D  
C hr o nic ki d ne y disease  
C R O  
C o ntract researc h or ga nizati o n  
C T D -P A H  
C o n necti ve ti ss ue disease-ass ociate d p ul m o nar y arterial 
h y perte nsi o n  
E C  
Et hics C o m mittee  
e C R F 
Electr o nic case re p ort f or m  
e G F R 
Esti mate d gl o mer ular filtrati o n rate  
F D A  
F o o d a n d Dr u g A d mi nistrati o n ( U S)  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -gl uta m yl tra ns pe pti dase  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I K K β 
I n hi bit or of n uclear fact or ka p pa β  ki nase beta s u b u nit  
I L D 
Interstitial l u n g disease  
I N R 
I nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal Re vie w B oar d 
Nrf 2  
N uclear fact or ( er yt hr oi d -d eri ve d 2) -relate d fact or 2 
N T -Pr o B N P  
N -T er mi nal Pr o -Brai n Nat ri uretic Pe pti de   


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A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
N Y H A F C  
Ne w Y or k Heart Ass ociati o n F u ncti o nal Classificati o n  
P A H  
P ul m o nar y arterial h y perte nsi o n  
P H  
P ul m o nar y h y perte nsi o n  
R O S  
Reacti ve o x y ge n s pecies  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
T B L  
T otal bilir u bi n  
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
W H O  
W orl d Healt h Or ga nizati o n  
W O C B P  
W o me n of c hil d beari n g p ote ntial  
 


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5.  
I N T R O D U C TI O N 
Bar d o x ol o ne met h yl a n d its a nal o gs are olea n olic aci d- deri ve d s y nt hetic triter pe n oi d c o m p o u n ds 
t hat p ote ntl y i n d uce t he Nrf 2- K ea p 1 p at h wa y (W u , 2 0 1 1; R ojas - Ri vera, 2 0 1 2).  T hr o u g h 
i nteracti o n wit h t he Nrf 2 re press or m olec ule, Kea p 1, bar d o x ol o ne met h yl a n d its a nal o gs 
pr o m ote tra nsl ocati o n of Nrf 2 t o t he n ucle us, w here Nrf 2 bi n ds t o a nti o xi da nt res p o nse ele me nts 
i n t he pr o m oter re gi o n of its tar get ge nes, lea di n g t o i n d ucti o n of ma n y a nti o xi da nt a n d 
c yt o pr ot ecti ve e nz y mes a n d relate d pr ot ei ns ( Lee , 2 0 0 9; Di n k o va - K ost o va, 2 00 5 ).  Bar d o x ol o ne 
met h yl a n d its a nal o gs are als o p ote nt i n hi bit ors of t he N F- κ B i nfla m mat or y pat h wa y t hr o u g h 
b ot h direct ( i.e., i n hi biti o n of I K K β ki nase acti vit y) a n d i n direct mec ha nis ms (i.e., det o xificati o n 
of r eacti ve o x y ge n s peci es [ R O S]) (Os b ur n , 2 0 0 8 ).  Beca use of t his d ual mec ha nis m of acti o n, 
bar d o x ol o ne met h yl a n d its a nal o gs are h y p ot hesi ze d t o ha ve p ote ntial t hera pe utic rel e va nce i n a 
variet y of diseas e setti n gs i n v ol vi n g o xi dati ve stress a n d i nfla m mati o n.  Acti vati o n of t he Nrf 2 
pat h wa y als o tra ns cri pti o nall y re g ulates m ulti ple ge nes t hat pr o m ote t he pr o d ucti o n of cell ular 
e ner g y wit hi n t he mit oc h o n dria a n d facilitates mit oc h o n drial h o me ostasis a n d efficie n c y.   
T hr o u g h i n d u cti o n of  Nrf 2 a n d s u p pressi o n of N F-κ B , bar d o x ol o ne met h yl has br oa d m olec ul ar 
a n d p har mac ol o gi cal effects t hat a d dress m ulti ple facets of t h e pat h o p h ysi ol o g y of p ul m o nar y 
arterial h y p erte nsi o n ( P A H).  I n d ucti o n of N F- κ B is mar ke dl y ele vat e d i n macr o p ha ges, 
e n d ot helial cells a n d s m o ot h m uscle cells of P A H patie nts ( Price , 2 0 1 0).  R ece nt e vi d e nce 
de m o nstrates t hat g e netic or p har mac ol o gi c i n d ucti o n of Nrf 2 s u p presses f or mati o n of t he P A H 
p he n ot y p e i n a m o use m o del of h y p o xic p ul m o nar y h y p erte nsi o n ( P H) ( E b a , 2 0 1 3).   
A d diti o nall y, a n e m er gi n g c o n ce pt i n t he pat h o ge nesis of P H is t he r ole of s yste mic meta b olic 
a n d s keletal m uscle d ysf u ncti o n as a maj or ca use of re d uce d f u ncti o nal ca p acit y a n d fati g ue, as 
well as disease pr o gressi o n.  A hi g h fre q ue n c y of i ns uli n resista nce a n d meta b olic s y n dr o m e-li ke 
feat ur es ha ve b ee n des cri be d i n patie nts wit h P H, a n d gl u c ose i nt olera n ce is ass ociate d wit h a 
decrease i n 6 - mi n ute wal k dista nce ( 6 M W D) (P u g h , 2 0 1 1).  P ul m o nar y h y p erte nsi o n patie nts 
ha ve decrease d a d e n osi ne tri p h os p hate ( A T P) pr o d ucti o n ( S ute n dra , 2 0 1 4), w hic h res ults i n 
s keletal m uscle d ysf u ncti o n a n d i m paire d f u ncti o nal ca pacit y (Mai n g u y , 2 0 1 0; B att, 2 0 1 4 ).  
I n d ee d, t he s k eletal m uscle wit hi n patie nts wit h P H dis pla ys a d ecreas e d e x pressi o n of 
mit oc h o n drial res pirati o n e nz y mes, defects i n mit oc h o n drial o xi dati ve p h os p h or ylati o n, a n d 
i m pair me nts i n mit oc h o n drial bi o ge n esis (Batt , 2 0 1 4; Ma le nfa nt, 2 0 1 5 ).  O verall, t hese d efects i n 
s keletal m uscle c o ntri b ut e t o m uscle wea k n ess a n d fati g u e, as w ell as i m paire d e x ercise ca pacit y 
i n patie nts wit h P H (Batt , 2 0 1 4).  
S e veral li nes of e vi d e nce s u g gest t hat Nrf 2 acti vati o n ca n i ncrease mit oc h o n drial res pirati o n a n d 
bi o ge n esis, i n a d diti o n t o i n d uci n g e x pressi o n of n u mer o us a nti o xi dati ve ge nes t o c o u nter R O S.  
S pecificall y, b y i ncreasi n g t he a vaila bilit y a n d pr o d ucti o n of re d uci n g e q ui vale nts s uc h as 
nic oti na mi de a de ni ne di n ucle oti de a n d fla vi n a de ni ne di n ucle oti de, Nrf 2 acti vati o n i m pr o ves 
mi t oc h o n drial A T P pr o d ucti o n a n d i m pr o ves t he effi cie nc y of mit oc h o n dri al res pirati o n a n d 
o x y ge n c o ns u m pti o n.  I n a d diti o n, Nrf 2 acti vati o n res ults i n i m pr o ve d beta- o xi dati o n of fatt y 
aci ds a n d i m pr o ve d u pta ke of gl uc ose, w hi c h lea ds t o i m pr o ve me nt i n mit oc h o n drial res pir ati o n, 
o x y ge n c o ns u m pti o n, a n d e ner g y pr o d u cti o n.  Si nce Nrf 2 acti vati o n ca n i n creas e mit oc h o n drial 
res pirati o n (H ol mstr ö m , 2 01 3 ; L u dt ma n n , 2 0 1 4 ), bar d o x ol o ne met h yl ma y rest ore meta b olic 
deficits i n P H, t here b y ac utel y i m pr o vi n g e ner g y pr o d ucti o n a n d 6 M W D. 




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patie nts wit h C T D- P A H ha d si milar s ustai ne d i ncreases i n 6 M W D t hr o u g h Wee k 3 2.  O n t he 
basis of t hese data, Reata e x pa n de d t he L A RI A T pr ot oc ol ( Versi o n 5. 0) t o i ncl u de P H patie nts 
wit h I L D, i n cl u di n g W H O Gr o u p III patie nts wit h C T D-ass ociate d I L D, i di o pat hic p ul m o nar y 
fi br osis, n o n-s pecific i nterstitial p ne u m o nia, a n d W H O Gr o u p V patie nts wit h sarc oi d osis.  Reata 
has als o i nitiate d a P hase 3 st u d y i n W H O Gr o u p I C T D- P A H patie nts ( 4 0 2- C- 1 5 0 4, 
C A T A L Y S T, N C T 0 2 6 5 7 3 5 6, E u dra C T 2 0 1 6- 0 0 0 1 9 6- 2 4) t o st u d y t he s afet y a n d effi cac y of 
bar d o x ol o ne met h yl i n t h ose patie nts.   
5. 1.  
St u d y R ati o n ale 
T he esta blis he d p har mac ol o gic effects of bar d o x ol o ne met h yl, i ncl u di n g t he s u p pressi o n of 
pat h ol o gic N F- κ B si g n ali n g a n d i nfla m m ati o n a n d mit oc h o n drial d ysf u ncti o n, are dir ectl y 
a p plica ble t o t he tre at me nt of P H .  Des pite a vaila ble t hera pies, t he pr o g n osis f or P H re mai ns 
p o or,  es peci all y f or patie nts wit h C T D (C h u n g , 2 0 1 4) a n d I L D.  Gi ve n t he se verit y of t he 
u n de rl yi n g dise ase, t his st u d y see ks t o offer patie nts w h o pre vi o usl y p artici pate d i n cli nical 
st u dies e xte n de d access t o bar d o x ol o ne met h yl u ntil it is a vaila ble t hr o u g h c o m mercial c h a n nels 
(i ncl u di n g rei mb urse me nt). 
F or f urt her i nf or m ati o n, refer t o t he I n vesti gat or’s Br oc h ure.  
5. 2.  
Cli nic al E x perie nce wit h B ar d o x ol o ne Met h yl 
A p pr o xi matel y 1 9 5 0 i n di vi d uals ha ve bee n e x p ose d t o bar d o x ol o ne met h yl at t he ti me of 
i nitiati o n of t his st u d y.  Si xtee n st u dies ha ve bee n c o m plete d ( 7 i n patie nts wit h c hr o ni c ki d ne y 
disease ( C K D) w h o a ls o ha d t y p e 2 dia betes, 4 i n n o n- C K D i n dicati o ns, a n d 5 i n healt h y 
s u bjects) a n d 2 st u dies are o n g oi n g i n patie nts wit h P H.   
5. 2. 1.  
S afet y a n d T oler a bilit y 
Please refer t o t he I n v esti gat or ’s Br oc h ure f or a detaile d disc ussi o n of safet y fi n di n gs wit h 
ba r d o x ol o ne met h yl f or st u dies i n healt h y s u bjects, o nc ol o g y, C K D, a n d patie nts wit h P H. 
5. 2. 2.  
F l ui d O verl o a d 
Si milar t o e n d ot heli n rece pt or a nta g o nists i n cert ai n patie nt p o p ulati o ns, i ncl u di n g b ose nta n i n 
a d va nce d c o n gesti ve h eart fail ure a n d a v ose nta n i n a d va nce d C K D, bar d o x ol o ne met h yl 
treat me nt was f o u n d t o b e ass ociate d wit h a n i ncrease d ris k f or fl ui d o verl oa d a n d heart fail ure 
h os pitaliz ati o ns i n a P hase 3 trial ( B E A C O N), w hi c h e nr olle d patie nts wit h Sta ge 4 C K D (e G F R 
of 1 5- 2 9 m L/ mi n/ 1. 7 3 m 2) a n d t y pe 2 dia betes.  T he o verall i ncreas e d ris k f or fl ui d o verl oa d a n d 
heart fail ure e v e nts wit h bar d o x ol o ne met h yl a p peare d t o be li mite d t o t he first t hree t o f o ur 
wee ks after i nitiati o n of treat me nt.  Ele vat e d B-t y pe natri uretic p e pti de ( B N P) a n d pri or 
h os pitaliz ati o n f o r heart fail ure were i de ntifie d as ris k fact ors t hat c o ntri b ute d t o i ncrease d ris k 
f or t hese e v e nts.  T he i ncrease d ris k f or t hes e e ve nts fr o m bar d o x ol o ne met h yl treat me nt ha d n ot 
bee n o bser ve d i n s i x pre vi o us C K D st u dies, w hic h were c o n d ucte d m ostl y i n patie nts wit h Sta ge 
3 b C K D (e G F R of 3 0- 4 4 m L/ mi n/ 1. 7 3 m 2), patie nts wit h he patic d ysf u ncti o n, ca ncer patie nts, or 
healt h y v ol u nteers.  
Re vie w of a d missi o n n otes a n d narrati ve des cri pti o ns f or heart fail ure h os pitalizati o ns i n 
B E A C O N i n dic ates t hat heart fail ure i n bar d o x ol o ne met h yl-treate d patie nts was ofte n prece d e d 
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was n ot ass ociate d wit h ac ute re n al dec o m pe ns ati o n or ac utel y re d uce d left ve ntric ular 
c o ntractilit y.  A v aila ble d ata fr o m B E A C O N a n d ot her st u dies s u g gest t hat bar d o x ol o ne met h yl 
treat me nt can differe ntiall y affect he m o d y na mic st at us acc or di n g t o t he cli nical c o n diti o n of 
patie nts a n d li kel y pr o m ot es fl ui d rete nti o n i n patie nts wit h m ore a d va n ce d re nal d ysf u ncti o n a n d 
ot her  rec o g niz e d ris k fact ors ass ociate d wit h heart fail ure at b aseli ne.   
I n a P hase 2 d ose-ra n gi n g st u d y of t he efficac y a n d safet y of bar d o x ol o ne met h yl i n patie nts wit h 
P H ( L A RI A T), ris k miti gati o n pr oce d ures were e m pl o ye d t o re d u ce t he p ote ntial f or 
bar d o x ol o ne met h yl -i n d u ce d fl ui d o verl o a d; t hese pr oce d ures e x cl u de d pati e nts wit h t he 
i de ntifie d ris k fact ors a n d e ns ure d cl os e m o nit ori n g f or fl ui d rete nti o n wit hi n t he first m o nt h of 
treat me nt.  T o date, t he ris k f or ac ute fl ui d o verl oa d a d verse e ve nts ( A Es) wit h bar d o x ol o ne 
met h yl i n late-sta ge C K D patie nts has n ot bee n o bser ve d i n P A H patie nts.   
5. 2. 3.  
T r a ns a mi n ase a n d G a m m a- Gl ut a m yl Tr a ns pe pti d ase Ele v ati o ns  
I n cli nical st u dies of bar d o x ol o ne met h yl, al m ost all patie nts ha d i ncreas es of tra nsa mi nase 
e nz y mes ab o v e baseli ne u p o n i nitiati o n of treat me nt, w hic h f oll o w e d a c o nsiste nt patter n.  T hese 
i ncreas es were n ot ass oci ate d wit h ele vati o ns i n bilir u bi n or ot her si g ns of li ver t o xicit y.  I n a 
lar ge P hase 3 stu d y t hat e nr olle d 2 1 8 5 patie nts wit h t y pe 2 dia betes a n d sta ge 4 C K D 
( B E A C O N), fe wer he pat o biliar y S A Es w ere o bs er ve d i n t he bar d o x ol o ne met h yl ar m t ha n i n t he 
place b o ar m.  T he ele v ati o ns be gi n i m me diatel y after i nitiati o n of treat me nt or a n i ncrease i n 
d ose; t h e y p ea k a p pr o xi matel y t w o t o f o ur wee ks later.  I n m ost patie nts, tra nsa mi nase ele vati o ns 
we re mil d, b ut a p pr o xi matel y 4 % t o 1 1 % of patie nts e x perie nce d a n ele vati o n greater t h a n 3 X 
t he u p per li mit of n o r mal ( U L N).  T h e ele vati o ns res ol ve d t o le vels less t ha n t he U L N i n m ost all 
patie nts wit h ele vati o ns, wit hi n t w o wee ks after pea k val ues w hile p atie nts c o nti n ue d ta ki n g 
st u d y dr u g.  Patie nts w h o e x perie nce d el e vati o ns t o greater t ha n 3 X t he U L N s o meti mes re q uire d 
a d diti o nal ti me t o res ol ve.  W hile s o me patie nts ha ve ha d ele vati o ns t o a b o ve 3 X t he U L N, 
persiste nt ele vati o ns t o a b o ve 3 X t he U L N ha ve n ot bee n o bser ve d, a n d t he ele vati o ns di d n ot 
rec ur o nce r es ol ve d, u nless ca use d b y ot her fact ors. 
Bar d o x ol o ne met h yl re g ulates ga m ma- gl uta m yl tra ns pe pti dase ( G G T), a k n o w n Nrf 2 tar get 
ge n e.  I n cli nic al st u dies, l o w le vel G G T ele vati o ns d uri n g tr eat me nt were c o m m o n, mil d, a n d 
t y picall y laste d l o n ger t ha n ala ni ne a mi n otra nsferase ( A L T)/as part ate a mi n otra nsferase ( A S T) 
ele vati o ns.  Bilir u bi n l e v els i n patie nts e x peri e nci n g tra ns a mi nase or G G T ele vati o ns d ue t o 
treat me nt wit h bar d o x ol o ne met h yl eit her re mai ne d at baseli ne le vels or d ecreas e d.  T he A L T, 
A S T, a n d G G T ele v ati o ns we re ge nerall y s elf-li miti n g i n patie nts w h o c o nti n ue d treat me nt wit h 
st u d y dr u g.  
5. 2. 4.  
M uscle S p as ms  
M uscle s pas m was t he m ost fre q ue ntl y re p orte d A E i n cli nical st u dies of bar d o x ol o ne met h yl i n 
patie nts wit h C K D  w h o als o ha d t y pe 2 dia betes.  T he m uscle s pas ms m ost ofte n ma nifeste d i n 
t he first t w o m o nt hs of treat me nt a n d res ol ve d s p o nta ne o usl y or wit h e m pirical treat me nt.  T he y 
occ urre d m ostl y at ni g ht, i n t he l o wer e xtre mities, a n d we re ge nerall y mil d t o m o derate i n 
se verit y.  M uscle s pas ms ha ve als o be e n re p orte d i n bar d o x ol o ne met h yl-tr eate d P A H patie nts 
b ut at l o wer i nci de nces t ha n t hat o bser ve d i n pri or C K D st u dies.  M ore o ver, t he i nci de nce of 
m uscle s pas ms is si milar t o t hat o bser ve d i n place b o-treate d P A H patie nts.  M uscle s pas ms ma y 
res ult fr o m i m pr o ve d i ns uli n se nsiti vit y a n d gl uc ose u pta ke i n s keletal m us cle cells.  I n creases i n 


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gl uc ose u pta ke, as assess e d b y t h e h y peri ns uli ne mic-e u gl yce mic cla m p pr o ce d ure, were 
o bser ve d i n res p o ns e t o b ar d o x ol o ne met h yl i n a d efi ne d s u bset of p atie nts e nr olle d i n a P hase 2 a 
st u d y.  T o date, i n t h ose cases w h ere s er u m creati ni ne ki nase ( C K) le vels ha ve bee n me as ure d, 
n o ass ociati o n has bee n o bser ve d bet w ee n m uscle s pas ms a n d ele vate d C K le vels i n patie nts 
treate d wit h bar d o x ol o ne met h yl.  Cli nical si g ns a n d la b orat or y fi n di n gs ass ociate d wit h t he 
re p orts of m uscle s p as ms ha ve n ot bee n c o nsiste nt wit h m uscle t o xicit y.  Bar d o x ol o ne met h yl 
s u bjects s h o we d n o i ncrease i n pr o mi ne nt la b orat or y fi n di n gs ass ociate d wit h m uscle t o xicit y, 
s uc h as i ncrease d le v els of ser u m mar kers, i ncl u di n g creati ni ne, lactate de h y dr o ge nase, bl o o d 
urea nitr o ge n, uric aci d, p h os p h or us, a n d p otassi u m, w hic h were m o nit ore d wee kl y d uri n g t he 
first t w o m o nt hs of a pri or st u d y ( B E A M) w he n m uscle s pas ms were m ost fre q ue ntl y re p orte d.  
I n creases i n t he w h ole- b o d y gl uc os e dis p osal rate ha ve bee n o bser ve d i n mice treat e d wit h 
bar d o x ol o ne met h yl, as well.  I n crease d gl uc os e u pta ke was o bser ve d i n is olate d calf m uscles of 
t he mice, b ut n ot i n w hite a di p ose tiss ue (Sa ha , 2 0 1 0).   
5. 2. 5.  
We i g ht L oss 
De creases i n w ei g ht a n d re p orts of a n ore xia/ decrease d a p petite ha ve bee n o bser ve d f oll o wi n g 
treat me nt wit h bar d o x ol o ne met h yl i n patie nts wit h C K D w h o als o ha d t y p e 2 dia betes.  I n 
st u dies of t hese patie nts, 1 7 % of bar d o x ol o ne met h yl patie nts re p orte d A Es of wei g ht decreas e or 
decrease d a p petite (irres p ecti ve of relati o ns hi p t o treat m e nt).  Wei g ht re d u cti o n was m ore 
pr o n o u nce d i n patie nts tr e ate d wit h bar d o x ol o ne met h yl t ha n i n t h ose gi ve n place b o. 
Wei g ht l oss of a p pr o xi matel y o n e kil o gra m per m o nt h was o bser ve d, wit h patie nts of hi g h er 
b o d y- mass i n d e x at baseli ne l osi n g m ore wei g ht (i n a bs ol ute ter ms) t ha n t h ose of n or mal or 
m o deratel y- ele vate d b o d y- mass i n d e x.   
Bar d o x ol o ne met h yl-treate d P A H patie nts ha ve als o ha d decreases i n wei g ht, wit h mea n wei g ht 
decrease s of a p pr o xi matel y 3 k g vers us place b o at Wee k 1 6.  Wei g ht l oss i n P A H pati e nts has 
n ot c oi nci de d wit h re p orts of de crease d a p petite or a n ore xia A Es. 
5. 2. 6.  
H y p o m a g nes ae mi a 
H y p o ma g n esae mia has n ot bee n re p orte d i n P A H patie nts t o date, b ut was re p orte d as a n A E f or 
1 5. 5 % of patie nts wit h C K D w h o als o ha d t y pe 2 dia betes w h o recei v e d bar d o x ol o ne met h yl.  
T he A E  of h y p o ma g n esae mia ( of a n y re p ort e d rel ati o ns hi p t o st u d y dr u g) was m ore fre q ue ntl y 
re p orte d i n bar d o x ol o ne met hyl-tr eate d patie nts t h a n i n patie nts gi ve n pl ace b o.  T he i n vesti gat ors 
c o nsi dere d al m ost all re p orte d e ve nts t o be mil d.  A d diti o nall y, patie nts treate d wit h bar d o x ol o ne 
met h yl ha d a g reater d ecrease fr o m baseli ne i n ser u m ma g nesi u m le vels t ha n patie nts gi ve n 
place b o; t he decrease w as e vi de nt wit hi n 4 wee ks a n d atte n uate d after 8 wee ks of starti n g 
t hera p y.  In b ar d o x ol o ne met h yl cli nical st u dies perf or me d t o date, a p ost- h oc a nal ysis i de ntifie d 
n o c orrel ati o n bet wee n h y p o ma g n esae mia a n d eit her gastr oi ntesti nal A Es or car di ac A Es, 
i ncl u di n g car diac d ysr h yt h mias a n d pr ol o n ge d Q T c.  T he 2 4- h o ur uri ne c oll ecti o ns fr o m t he 
B E A C O N a m b ulat or y bl o o d press ure m o nit ori n g s u b-st u d y s h o we d n o i ncrease i n uri n ar y 
ma g n esi u m le vels, i n dicati n g t hat re n al l oss of ma g nesi u m di d n ot acc o u nt f or t he re d u cti o ns i n 
ser u m ma g nesi u m o bser ve d wit h bar d o x ol o ne met h yl treat me nt i n C K D patie nts.  N ota bl y, a 
t h or o u g h Q T st u d y t hat teste d d oses of bar d o x ol o ne met h yl u p t o 8 0 m g, b ar d o x ol o ne met h yl 
s h o we d n o i ncrease i n th e Q T i nter val.  


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6.  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S 
6. 1.  
Pri m ar y O bjecti ves 
T o pr o vi de c o nti n ui n g tr eat me nt wit h bar d o x ol o ne met h yl as part of t his e xte n de d access 
pr o gra m w hile c ollecti n g o n g oi n g safet y a n d t olera bilit y data of bar d o x ol o ne met h yl.  
6. 2.  
Pri m ar y  S afet y E n d p oi nt: 
Fre q u e nc y, i nte nsit y, a n d relati o ns hi p t o st u d y dr u g of a d verse e ve nts ( A Es) a n d seri o us a d v erse 
e ve nts ( S A Es), a n d c ha n ge fr o m baseli ne i n t he f oll o wi n g assess me nts: p h ysical e x a mi nati o ns, 
vital si g n meas ur e me nts, B N P, N-ter mi nal p r o- brai n natri uretic pe pti de ( N T- pr o B N P), a n d 
we i g ht. 


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7.  
I N V E S TI G A TI O N A L P L A N 
7. 1.  
O ver all St u d y Desi g n 
T his e xte n de d access st u d y will assess t he l o n g-ter m safet y a n d t olera bilit y of bar d o x ol o ne 
met h yl i n q ua lified patie nts wit h P H w h o pre vi o usl y partici p ate d i n c o ntr olle d cli nical st u dies 
wit h bar d o x ol o ne met h yl. 
Q ualifie d patie nts will start d osi n g at 1 0 m g of bar d o x ol o ne met h yl e ver y ot her da y, t he n be gi n 
o nce dail y d osi n g at W ee k 4 ( u nless c o ntrai n dicate d cli nicall y) a n d c o nti n ue u ntil t he dr u g is 
availa ble t hr o u g h c o m mercial c ha n n els (i ncl u di n g rei m b urse me nt) or u ntil patie nt wit h dra wal, 
w hic he ver is s o o n er.  D ose de-es calati o n ( d o w n t o 5 m g) is per mitte d d uri n g t he st u d y if 
i n dicate d cli nicall y.  Refer t o Secti o n  7. 3. 1  f or a d diti o nal details o n d ose de-escalati o n.  
All patie nts i n t he st u d y will f oll o w t he sa me visit a n d assess me nt sc h e d ule.  Patie nts will be 
sc he d ule d t o be ass esse d i n pers o n d uri n g treat me nt at Da y 1, Wee k 2, Wee k 4, Wee k 6, Wee k 8, 
W ee k 2 4, a n d ever y 2 4 w ee ks t hereafter.  Patie nts will als o be assesse d b y t ele p h o ne c o nt act o n 
Da ys 3, 1 0, 2 1, 3 1, a n d 3 8.  Da y 1 f or t his e xte n de d access st u d y s h o ul d occ ur o n t he sa me d a y 
as t he last visit i n the c o ntr olle d cli nical st u d y.  Patie nt stat us s h o ul d be caref ull y m o nit ore d b y 
t he i n vesti gat or d uri n g t h e first 8 wee ks of st u d y treat me nt.  Assess me nts re q uire d f or b ot h t he 
last visit i n t he c o ntr olle d st u d y a n d Da y 1 f or t his st u d y s h o ul d o nl y b e c o m plete d o nce. 
Patie nts fr o m t he C A T A L Y S T st u d y: 
Da y 1 of t his e xte n de d access st u d y will c oi nci de wit h t he Wee k 2 8 f oll o w- u p visit f or patie nts 
fr o m C A T A L Y S T ( 4 0 2- C- 1 5 0 4, N C T 0 2 6 5 7 3 5 6, E u dra C T 2 0 1 6- 0 0 0 1 9 6- 2 4).  If t his e xte n de d 
access pr o gra m is n ot yet o pe n f or e nr oll me nt at t he ti me of a patie nt’s Wee k 2 8 visit, t he Da y 1 
visit ( i.e., e nr oll me nt) m ust occ ur wit hi n 3 0 da ys of site acti vati o n.  E x ce pti o ns all o wi n g 
C A T A L Y S T patie nts w h o ha ve c o m plete d 2 4 wee ks of treat me nt t o sc he d ule t heir f oll o w- u p 
assess me nts pri or t o W ee k 2 8 a n d still be c o nsi dere d eli gi ble f or t his o pe n-l a bel st u d y s h o ul d be 
disc usse d wit h t he C hief Me dical Offi cer at Reata, or desi g n ee, a n d will be c o nsi dere d o n a cas e-
b y - case b asis.   
Patie nts fr o m t he L A RI A T st u d y: 
Da y 1 of t his e xte n de d access st u d y will c oi nci de wit h t he E n d- of- Treat me nt visit f or patie nts 
fr o m L A RI A T ( 4 0 2- C- 1 3 0 2, N C T 0 2 0 3 6 9 7 0).   
7. 2.  
N u m ber of P atie nts 
Patie nt n u m bers will be deter mi ne d b y t h ose w h o ha ve bee n treat me nt-c o m plia nt a n d w h o ha ve 
pre vi o usl y p a rtici pate d i n cli nical st u dies wit h bar d o x ol o ne met h yl. 
7. 3.  
Tre at me nt Assi g n me nt 
All patie nts will recei ve bar d o x ol o ne met h yl i n t his st u d y. 


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7. 3. 1.  
D ose Esc al ati o n a n d D ose De -Esc al ati o n  
P atie nts will start d osi n g at 1 0 m g of bar d o x ol o ne met h yl e ver y ot her d a y, t he n be gi n o nce d ail y 
d osi n g at Wee k 4 u nless c o ntrai n dicate d cli nicall y.  T he i n vesti gat or s h o ul d disc uss a n y reas o ns 
f or n ot d ose-es calati n g t o o nce dail y d osi n g at Wee k 4 wit h t he me dical m o nit or.  
D ose de- escalati o n is per mitte d d uri n g t he st u d y a n d t he i n vesti gat or m a y c h o ose t o decrease t he 
patie nt’s d ose t o 5 m g  if cli nicall y i n dicat e d.  Reas o ns f or d ose de-escalati o n s h o ul d be disc usse d 
wit h t he me dical m o nit or pri or t o c ha n gi n g d ose.  O nce a p atie nt’s d ose has bee n decrease d t o 
5 m g, t he y ca n n ot d ose- escalate bac k t o 1 0 m g of bar d o x ol o ne met h yl. 
U nsc he d ule d visits d ue t o d ose de-es calati o n s h o ul d i ncl u de assess me nts detaile d i n Secti o n 9. 7 .  
7 . 4. 
Criteri a f or St u d y Ter mi n ati o n 
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y at a n y ti me f or cli nical or a d mi nistrati ve 
reas o ns, or if re q uir e d b y re g ulat or y a ge ncies.  If t he S p o ns or disc o nti n ues t he st u d y, all st u d y 
dr u gs will be disc o nti n ue d a n d t he i n vesti gat or will be res p o nsi ble f or s ec uri n g a n y alter nati ve 
t hera p y t o be a d mi nistere d, as a p pr o pri ate. 
7. 5.  
Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of I n vesti g ati o n al 
Sites 
A st u d y site ma y be t er mi nate d pre mat urel y or s us pe n de d if t he site (i ncl u di n g t he i n vesti gat or) 
is f o u n d i n si g nifica nt vi olati o n of G o o d Cli nical Practice ( G C P), pr ot oc ol, or c o ntract ual 
a gree m e nt wit h S p o ns or or t he site is u na ble t o e ns ure a de q u ate perf or ma n ce of t he st u d y. 
7. 6.  
Pr oce d ures f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of t he St u d y 
or t he P artici p ati o n of I n vesti g ati o n al Sites 
I n t he e ve nt t hat t he S p o ns or, a n i nstit uti o nal re vie w b oar d (I R B)/et hics c o m mittee ( E C), or 
re g ulat or y a ut h orit y el ects t o ter mi nate or s us pe n d t he st u d y or t he p artici pati o n of a n 
i n vesti gati o nal site, a st u d y-s p ecific pr oce d ure f or earl y ter mi nati o n or s us p e nsi o n will be 
pr o vi de d b y t he S p o ns or. 
7. 7.  
Sc he d ule of Assess me nts 
Ta ble 3  lists t he o verall s c he d ule of assess me nts f or t he st u d y. 
 


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T a ble 3:  
Sc he d ule of Assess me nts   
St u d y Wee k  
( D a y) 
Assess me nt  
D a y 1 a We e k 1  
( P h o ne) 
D a y 3 ± 2  
We e k 1   
D a y 7 ± 3  
We e k 2  
( P h o ne) 
D a y 1 0 ± 2  
We e k 2  
D a y 1 4 ± 3  
We e k 3  
( P h o ne) 
D a y 2 1 ± 2  
We e k 4  
D a y 2 8 ± 3  
We e k 4  
( P h o ne) 
D a y 3 1 ± 2  
We e k 5  
( P h o ne) 
 D a y 3 8 ± 2  
We e k 6  
D a y 4 2 ± 3  
We e k 8  
D a y 5 6 ± 3  
We e k 
2 4 ± 3,  
E ver y 2 4 
We e ks  
E n d of  
St u d y  
 Visit b 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d C o nc o mita nt 
me dicati o ns  
X c 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C urre nt P A H bac k gr o u n d 
me dicati o ns  
X c 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Wei g ht at h o me  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Wei g ht i n cli nic  
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
Vital si g n meas ure me nts  
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
P h ysical e xa m i n ati o n 
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
Pre g na nc y test d 
X c 
 
 
 
 
 
 
 
 
 
 
X  
 
Dis pe nse st u d y dr u g  
X  
 
 
 
 
 
X  
 
 
 
 
X  
 
C ollect st u d y dr u g  
 
 
 
 
 
 
X  
 
 
 
 
X  
X  
Tele p h o ne c o ntact  
 
X  
 
X  
 
X  
 
X  
X  
 
 
 
 
A d verse e ve nt c ollecti o n  
X e 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Cli nical C he mistries f 
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
B N P a n d / or N T -Pr o B N P  
X c 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
6 -mi n wal k test  
X c 
 
 
 
 
 
 
 
 
 
 
X  
X  
D ys p nea a n d fati g ue g 
X c 
 
 
 
 
 
 
 
 
 
 
X  
X  
W H O f u ncti o nal class  
X c 
 
 
 
 
 
 
 
 
 
 
X  
X  
a O n Da y 1, all pr oce d ures s h o ul d be perf or me d bef ore st u d y dr u g a d mi nistrati o n f or patie nts w h o are treat me nt-c o m plia nt a n d ha ve pre vi o usl y partici pate d i n 
cli nical st u dies wit h bar d o x ol o ne met h yl. 
b After t he W ee k 2 4 visit, patie nts will c o nti n ue t o be assesse d i n pers o n e ver y 2 4 wee ks u ntil bar d o x ol o ne met h yl b ec o mes c o m m erciall y a vaila ble.  T he 
E n d- of - St u d y visit s h o ul d occ ur wit hi n 3 0 da ys after bar d o x ol o ne met h yl bec o mes a vaila ble t hr o u g h c o m mercial c ha n nels.  P atie nts w h o will be disc o nti n ue d 
fr o m t he st u d y pri or t o c o m mercial a vaila bilit y of bar d o x ol o ne met h yl m ust als o c o m plete all En d -of - St u d y assess me nts.  
c Da y 1 assess me nts s h o ul d be perf or me d as part of E n d-of - Treat me nt or F oll o w- u p visit pr oce d ures fr o m a pri or st u d y wit h bar d o x ol o ne met h yl.  
d A ser u m pre g na nc y test will be perf or me d at a n y p oi nt i n ti me if a pre g na nc y is s us pecte d.  All ot her pre g na nc y assess me nts will be uri ne pre g na nc y t ests.  
A d diti o nal pre g na nc y assess me nts will be perf or me d m ore fr e q ue ntl y if re q uire d b y l ocal l a w or re q ueste d b y l ocal healt h a ut h orities or I R Bs/ E Cs .   


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e A E assess me nts o n Da y 1 s h o ul d be perf or me d f oll o wi n g st u d y dr u g a d mi nistrati o n. 
f Cli nical c he mistries will be a n al yze d l ocall y. 
g D ys p nea a n d fati g ue m ust b e assesse d pri or t o be gi n ni n g a n d i m me diatel y f oll o wi n g c o m pleti o n of t he 6 M W T usi n g t he B or g scale. 
 
A b bre viati o ns: P A H, p ul m o nar y arterial h y perte nsi o n; B N P, B-t y pe natri uretic pe pti de; N T- pr o B N P, N-ter mi nal pr o B-t y pe natri uretic pe pti de; W H O, W orl d 
Healt h Or ga nizati o n; A E, a d verse e ve nt; 6 M W T, 6- mi n ute wal k test.


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8.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S 
8. 1.  
P atie nt I ncl usi o n Criteri a 
Mai n criteria f or i ncl usi o n:  
Treat me nt- c o m plia nt patie nts w h o are p artici pati n g i n q ualif yi n g o n g oi n g st u dies a n d ha ve 
c o m plete d re q uir e d E n d- of- Treat me nt a n d/ or F oll o w- u p visits i n a pri or cli nical st u d y wit h 
bar d o x ol o ne met h yl.   
8. 2.  
P atie nt E xcl usi o n Criteri a 
All patie nts wit h a n y of t he f oll o wi n g c o n diti o ns or c haracteristics m ust be e x cl u de d fr o m t he 
st u d y: 
1.  Partici pati o n i n ot her i n vesti gati o nal cli nical st u dies i n v ol vi n g i nter ve nti o n al pr o d ucts 
bei n g teste d or use d i n a wa y differe nt fr o m t he a p pr o ve d f or m or w he n use d f or a n 
u na p pr o ve d i n dicati o n; 
2.  Patie nts w h o ha ve a n o n g oi n g seri o us a d verse e ve nt ( S A E) fr o m a cli nical st u d y t hat is 
assesse d b y t he i n ve sti gat or as relate d t o b ar d o x ol o ne met h yl; 
3.  U n willi n g t o practice acce pta ble met h o ds of birt h c o ntr ol ( b ot h males w h o ha ve part n ers 
of c hil d beari n g p ote ntial a n d fe males of c hil d beari n g p ote ntial) w hile t a ki n g st u d y dr u g;  
4.  W o me n w h o are pre g na nt or breastf ee di n g; 
5.  Patie nt is, i n t he o pi ni o n of t he i n vesti gat or, u na bl e t o c o m pl y wit h t he re q uire me nts of 
t he st u d y pr ot oc ol or is u ns uita ble f or t he st u d y f or a n y reas o n; 
6.  K n o w n h y p erse nsiti vit y t o a n y c o m p o ne nt of t he st u d y dr u g.  
8. 3.  
P atie nt Disc o nti n u ati o n a n d Ter mi n ati o n 
Patie nts ha ve t he ri g ht t o disc o nti n ue st u d y dr u g or wit h dra w fr o m t he st u d y at a n y ti me f or a n y 
reas o n, wit h o ut prej u dice t o t heir me dical care.  F urt her m ore, t he i n v esti gat or ma y disc o nti n ue a 
patie nt fr o m st u d y dr u g.  C o ns ultati o n wit h t he me dical m o nit or s h o ul d occ ur pri or t o st u d y dr u g 
disc o nti n uati o n or wit h d ra wi n g a patie nt fr o m t he st u d y.  T he reas o n f or a p atie nt’s 
disc o nti n uati o n fr o m st u d y dr u g or st u d y t er mi nati o n will be rec or de d i n t he electr o ni c cas e 
re p ort f or m (e C R F).  
Disc o nti n uati o n refers t o a patie nt’s st o p pi n g a d mi nistrati o n of st u d y dr u g a n d all st u d y 
assess me nts a n d visits.  Reas o ns f or st u d y dr u g disc o nti n uati o n ma y i ncl u de t he f oll o wi n g: 
 Oc c urre nce of a n A E or c ha n ge i n me dical stat us t hat will lea d t he i n vesti gat or t o be 
c o ncer ne d a b o ut t he p atie nt’s welfare; 
 A d mi nistrati ve reas o ns ( e. g., i na bilit y t o c o nti n ue); 
 S p o ns or ter mi nati o n of t he st u d y; 
 V ol u ntar y wit h dra w al; 


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 F e males w h o bec o me pre g na nt d uri n g t he st u d y; 
 P re mat ure ter mi nati o n or s us pe nsi o n of a n i n vesti gati o nal site; 
 L oss t o f oll o w- u p; 
 De at h; 
 W it h dra wal of c o nse nt. 
Patie nts m ust disc o nti n ue st u d y dr u g if a n y of t he f oll o wi n g occ ur. 
 A L T or A S T > 8 X U L N; 
 A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks; 
 A L T or A S T > 3 X U L N a n d (t otal bilir u bi n > 2 X U L N or I nter nati o nal N or malize d 
Rati o [I N R] > 1. 5); 
 A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na us ea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %). 
Patie nts w h o disc o nti n ue fr o m t he st u d y will be as ke d t o c o m plete t he E n d- of- St u d y pr oce d ures 
n ote d i n Ta ble 3 . 


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9.  
T R E A T M E N T O F P A TI E N T S 
9. 1.  
Select M a n a ge me nt G ui deli nes 
T he f oll o wi n g g ui d eli nes a p pl y t o t he ma n a ge me nt of st u d y partici pa nts: 
9. 1. 1.  
M a n a ge me nt of Fl ui d St at us 
S pecific ris k miti gati o n pr oce d ures will be e m pl o ye d t o re d uce t he p ote ntial f or bar d o x ol o ne 
met h yl-i n d uc e d fl ui d o verl oa d.  La b orat or y data, as well as B N P a n d/ or N T - pr o B N P, will als o be 
us e d t o m o nit or fl ui d stat us.  A d diti o nall y, p atie nts will be m o nit ore d f or ra pi d wei g ht gai n 
s u g gesti ve of fl ui d o verl oa d.  Patie nts will be gi v e n a S p o ns or- pr o vi de d s cale t o use at h o me t o 
m o nit or t heir wei g hts dail y d uri n g t he first 8 wee ks of t he treat me nt peri o d .  Patie nts w h o 
ex perie nce a 5- p o u n d ( 2. 3 kil o gra m) or greater i n creas e i n wei g ht si nce t h eir Da y 1 wei g ht 
d uri n g t he first 8 wee ks of t he treat me nt peri o d will be i nstr ucte d t o st o p ta ki n g t heir st u d y 
me dicati o n i m me dia tel y a n d ret ur n t o t he cli nic f or a n u nsc he d ul e d p h ysical e x a mi nati o n a n d 
la b orat or y ass ess me nt b y t he i n vesti gat or.  Patie nts ma y n ot r estart t heir st u d y me dicati o n u ntil 
t he i n vesti gat or h as c o m plete d a n d d oc u me nt e d a n assess me nt of fl ui d o verl oa d.  
In v esti gat or s s h o ul d a d vise patie nts t o watc h f or si g ns a n d s y m pt o ms of fl ui d o verl oa d.  Patie nts 
s h o ul d be i nf or me d t o n otif y t heir p h ysicia ns i m m e diatel y if t he y e x perie nce s w olle n feet, c hest 
pai n, s h ort ness of breat h wit h mil d e x erti o n or w hile l yi n g d o w n, or ot her rele va nt s y m pt o ms.  
T he i n vesti gat or s h o ul d i m me diatel y ass ess s y m pt o ms of fl ui d o verl oa d a n d deter mi ne 
ap pr o priate m e dica l ma n a ge me nt, as necessar y, i n cl u di n g w het her st o p pi n g dr u g a d mi nistrati o n 
will be re q uire d.  At t he earliest si g n of w orse ni n g or ne w o nset peri p heral e de ma, or ot her si g ns 
a n d s y m pt o ms o f ac ute v ol u me o verl oa d, i n vesti gat ors will als o be e x pecte d t o deter mi ne if 
c ha n ges t o a p atie nt’s di uretic re gi me n is nee de d. 
9. 1. 2.  
M a n a ge me nt of Ele v ate d Tr a ns a mi n ase Le vels ( A L T a n d/ or A S T) 
Tra nsa mi nases s h o ul d be m o nit ore d f oll o wi n g patie nt’s sta n dar d of care.  Nearl y all i nsta nces of 
ele vate d tra nsa mi nases are e x pecte d t o be as y m pt o matic.  Tra nsa mi nas e le vels (as well as t otal 
bilir u bi n [ T B L], G G T, al kali ne p h os p hatase, a n d I N R) will be c hec k e d wit hi n 4 8 t o 7 2 h o urs 
d uri n g a n u nsc he d ule d visit if t he f oll o wi n g occ urs: 
 A L T or A S T le vels > 3 X U L N. 
Testi n g will be re peat e d e ver y 7 2 t o 9 6 h o urs u ntil tra nsa mi nase le vels are bel o w 3 X t he U L N 
f or at least o ne wee k or u ntil t he patie nt wit h dra ws c o nse nt. 
St u d y dr u g a d mi nistrati o n will be per ma ne ntl y dis c o nti n ue d if a n y of t he f oll o wi n g occ urs: 
 A L T or A S T > 8 X U L N; 
 A L T or A S T > 5 X U L N f or m ore t ha n 2 wee ks; 
 A L T or A S T > 3 X U L N a n d ( T B L > 2 X U L N or I N R > 1. 5); 
 A L T or A S T > 3 X U L N wit h t he a p peara nce of fati g ue, na us ea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %).  


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T he he pat o biliar y tr ee m ust be vis ualize d ( e. g., ultras o u n d, ma g netic res o n a nce i ma gi n g) a n d 
assesse d if a p atie nt disc o nti n ues ta ki n g st u d y dr u g sec o n dar y t o ele vate d tra nsa mi nase le vels.  
A d diti o nal tests/st u dies ma y b e warra nte d de pe n di n g o n t he cli nical prese ntati o n. 
9. 1. 3.  
M a n a ge me nt of M uscle S p as ms 
Basic s y m pt o matic relief is t he first ste p i n ma na gi n g m uscle s pas m, i ncl u di n g wal ki n g, a d e q uate 
h y drati o n, weari n g s o c ks, a n d stretc hi n g bef ore b e dti me.  Assess me nt of le vels of electr ol ytes 
s uc h as ma g nesi u m, cal ci u m a n d p otassi u m as part of patie nt’s sta n dar d of care ma y i n dicate t he 
nee d f or re pla ce me nt.  If vita mi n D le vels are l o w, s u p ple me ntati o n ma y b e warra nte d.  M uscl e 
rela x a nts ma y als o hel p r elie ve s y m pt o ms. 
9. 1. 4.  
We i g ht L oss 
O n g oi n g ass ess me nts t o e ns ure t hat t he patie nt is recei vi n g a d e q uate n utriti o n a n d c o nsi derati o n 
of ot her eti ol o gies of w ei g ht l oss ma y be warra nte d f or patie nts recei vi n g b ar d o x ol o ne met h yl.   
9. 1. 5.  
H y p o m a g nes ae mi a 
I n i nsta n ces w h ere a pati e nt e x perie nces h y p o ma g nesae mia (e val uate d as p art of patie nt’s 
sta n dar d of care), defi ne d as ser u m ma g nesi u m less t ha n 1. 3 m E q/ L ( 0. 6 5 m m ol/ L), 
c o nsi derati o n s h o ul d be gi ve n t o re pleti o n of ser u m ma g nesi u m. 
9. 1. 6.  
N a us e a 
Na usea ma y o cc ur wit h hi g her d os es of bar d o x ol o ne met h yl.  N a usea A Es are t y picall y mil d a n d 
re versi ble wit hi n a few wee ks aft er treat me nt i nitiati o n.  If s y m pt o ms will n ot res ol ve, d ose 
de-escalati o n, wit h c o ns ultati o n of t he me dical m o nit or, ma y be n ecessar y.   


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9. 2.  
Descri pti o n of St u d y Dr u g 
Bar d o x ol o ne met h yl ( R T A 4 0 2) dr u g pr o d u ct i nf or mati o n is s h o w n i n  Ta ble 4 .   
T a ble 4:  
B ar d o x ol o ne Met h yl Dr u g Pr o d uct I nf or m ati o n 
Descri pti o n  
Bar d o x ol o ne met h yl ca ps ule ( 5  m g , 
1 0  m g ) 
I n gre die nts 
Bar d o x ol o ne met h yl  
Met hacr ylic Aci d –  Et h yl Acr ylate 
C o p ol y mer  
 T y pe A  
Silicifie d Micr ocr ystalli ne Cell ul ose  
H y dr o x y pr o p yl Met h ylcell ul ose  
Lact ose M o n o h y drate  
S o di u m La ur yl S ulfate  
C oll oi dal Silic o n Di o xi de  
Ma g nesi u m Stearate  
Gelati n ca ps ules  
Tita ni u m Di o xi de 
 
R o ute of A d mi nistr ati o n  
Oral  
9. 3.  
C o nc o mit a nt Me dic ati o ns 
9. 3. 1.  
E xcl u de d Me dic ati o ns 
N o ot her i n vesti gati o nal dr u g or de vic e s h o ul d be ta ke n as part of a n i nter ve nti o nal st u d y d uri n g 
t he c o n d uct of t his st u d y. 
Patie nts w h o ta ke i n vesti gati o nal dr u g or de vice d uri n g t he st u d y s h o ul d n ot disc o nti n ue st u d y 
dr u g s olel y o n t his basis.  C o ns ultati o n wit h t he me dical m o nit or s h o ul d occ ur pri or t o st u d y dr u g 
disc o nti n uati o n or wit h dra wi n g a patie nt fr o m t he st u d y. 
9. 3. 2.  
P er mitte d Me dic ati o ns 
P ul m o nar y arterial h y perte nsi o n-s pecific b ac k gr o u n d t hera p y s h o ul d be ta ke n as cli nicall y 
i n dicate d a n d prescri be d b y t he p h ysicia n f or t he d urati o n of t he st u d y. 
Refer t o Secti o n 9. 1 0. 1 5  f or g ui deli nes o n o x y ge n use d uri n g 6 M W Ts.  I nitiati o n of 
s u p ple me ntal l o n g-ter m o x y ge n t h era p y ( o x y ge n a p plicati o n f or m ore t h a n 3 0 c o nsec uti ve da ys ) 
or persiste nt m o dificati o n of a pre-e xisti n g s u p ple me ntal l o n g-ter m o x y ge n t hera p y ( i.e., n ee d f or 
a persiste nt i ncrease of t he a m o u nt of deli vere d o x y ge n f or m ore t ha n 3 0 da ys) d ue t o w orse ni n g 
P A H is per mitte d.  
Di uretics ma y be prescri be d as cli nicall y i n dicate d t hr o u g h o ut t he st u d y.  A n y c ha n ges t o t he 
d oses of o x y ge n or di ur etics t hr o u g h o ut t he c o urse of t he st u d y m ust be rec or de d i n t he 
electr o nic case re p ort f or m (e C R F).   


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9. 4.  
Tre at me nt C o m pli a nce 
T he i n vesti gat or or his/ her desi g nate d a n d q ualifi e d re prese ntati ves will o nl y dis pe nse st u d y dr u g 
t o patie nts e nr olle d i n t he st u d y i n acc or da n ce wit h t he pr ot oc ol.  T he st u d y dr u g m ust n ot be 
use d f or rea s o ns ot her t h a n t hat descri b e d i n t he pr ot oc ol.  
9. 5.  
R a n d o mi z ati o n 
N ot a p plica ble. 
9. 6.  
Bli n di n g 
N ot a p plica ble.  
9. 7.  
U nsc he d ule d Visits 
U nsc he d ule d visits are all o we d f or t he f oll o wi n g reas o ns: 
 Asse ss me nt of wei g ht gai n per Secti o n 9. 1. 1 ;  
 Ma na ge me nt of a n A E or S A E; 
 P erf or ma nce of a d diti o nal la b orat or y tests f or cli nicall y a b n or mal la b orat or y test 
val ues or t o c o nfir m a p ossi ble pre g na nc y; 
 D ose  de- escalati o n; 
 A n y ti me t he i n vesti gat or feels t hat it is cli nicall y a p pr o priate f or patie nt safet y. 
At a mi ni m u m, u nsc he d ule d visits s h o ul d i ncl u de c ollecti o n of A Es, c o n c o mita nt me dicati o ns 
a n d vital si g ns .  A d diti o nal c o n vers ati o ns ma y b e necessar y wit h t he me dical m o nit or f oll o wi n g 
a n u nsc he d ule d visit t o assess patie nt safet y. 
9. 8.  
Pre g n a nc y 
9. 8. 1.  
W o m e n of C hil d be ari n g P ote nti al 
W o me n of c hil d beari n g p ote ntial ( W O C B P) are t h ose w h o are n ot s ur gicall y sterile ( n o hist or y 
of bilateral t u bal li gati o n, h ysterect o m y, or bilateral sal pi n g o- o o p h orect o m y), d o n ot ha ve 
fall o pia n i nserts wit h c o nfir me d bl oc ka ge, ha ve n ot ha d re pr o d ucti ve p ote ntial ter mi nate d b y 
ra diati o n, a n d are n ot p ost me n o pa usal f or at least 1 year. 
9. 8. 2.  
M et h o ds of Birt h C o ntr ol 
W hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys f oll o wi n g a d mi nistrati o n of t he fi nal d ose of st u d y 
me dicati o n, W O C B P m ust practice o n e of t he f oll o wi n g acce pta ble met h o ds of birt h c o ntr ol: 
 Use d o u ble barrier c o ntrace pti o n met h o d defi ne d as male use of a c o n d o m a n d fe male 
use of a barrier m et h o d ( e. g., c o ntrace pti ve s p o n ge, s per mici dal jell y or crea m, or 
dia p hr a g m [ al wa ys use wit h s per mici dal jell y/crea m]); 
 Use  of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi n al, or tra ns der mal) f or at least 
9 0 da ys pri or t o start of st u d y dr u g a d mi nistrati o n; 


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 Use  of a n i ntra uteri ne d e vice; 
 A bsta i n fr o m se x ual i nterc o urse c o m plet el y.  C o m plete a bsti ne nce fr o m se x ual 
i nterc o urse is o nly acce pt a ble if it is t he preferre d a n d us ual lifest yl e of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot per mitte d. 
W hile ta ki n g st u d y dr u g a n d u ntil 3 0 da ys after t h e fi nal d ose of st u d y me dicati o n is ta ke n, males 
w h o ha ve fe male part ners of c hil d beari n g p ote ntial m ust practice o ne of t h e f oll o wi n g met h o ds 
of birt h c o ntr ol: 
 Ha ve ha d a vasect o m y (at least 6 m o nt hs earlier); 
 Use  d o u ble barrier c o ntrace pti o n met h o d, defi ne d as mal e use of a c o n d o m a n d 
fe male use of a barrier met h o d (e. g., c o ntr ace pti ve s p o n ge, s p er mici dal jell y or crea m, 
or dia p hra g m [ al wa ys us e wit h s per mici dal jell y/ crea m]); 
 P art ner use of a n i ntra uteri ne de vice; 
 P art ner use of h or m o nal c o ntrace pti ves ( oral, pare nteral, va gi nal or tr a ns der mal) f or 
at least 9 0 da ys pri or t o start of st u d y dr u g a d mi nistrati o n; 
 A bstai n fr o m se x ual i nterc o urse c o m plet el y.  C o m plete a bsti ne nce fr o m se x ual 
i nterc o urse is o nly acce pt a ble if it is t he preferre d a n d us ual lifest yl e of t he i n di vi d ual.  
Peri o dic a bsti ne nce is n ot per mitte d. 
9. 8. 3.  
S us pecte d Pre g n a nc y 
D uri n g t h e st u d y, all W O C B P m ust be i nstr ucte d t o c o ntact t he i n vesti gat or i m me diatel y if t he y 
s us pect t he y mi g ht be pre g na nt (e. g., late or misse d me nstr ual peri o d).  Mal e patie nts m ust be 
i nstr ucte d t o c o ntact t he i n vesti gat or if a se x ual part ner s us pects s he m a y be pre g na nt. 
If a patie nt or i n v esti gat or s us pects t hat t he patie nt ma y b e pre g n a nt, t he st u d y dr u g m ust be 
wit h hel d u ntil t he res ults of a ser u m pre g na n c y test are a v aila ble.  If t h e ser u m pre g n a nc y test 
c o nfir ms t he pre g n a nc y, t he patie nt m ust per ma ne ntl y disc o nti n ue ta ki n g st u d y dr u g.  T h e 
i n vesti gat or m ust i m me diatel y re p ort t o t he me dical m o nit or a pre g na nc y ass ociate d wit h st u d y 
dr u g e x p os ure.  T he earl y disc o nti n uati o n pr ot oc ol-re q uire d pr oce d ures o utli ne d f or E n d- of-
St u d y visits m ust be perf or me d o n t he patie nt.  
Pre g n a nc y is n ot c o nsi dere d a n A E; h o w e ver, t he i n vesti gat or m ust f oll o w a pre g na nt p atie nt, or 
t he pre g na nt f e male part ner of a m ale patie nt (if c o nse nti n g), a n d re p ort f oll o w- u p i nf or mati o n 
re gar di n g t he c o urse of t he pre g na n c y, i ncl u di n g peri natal a n d n e o natal o utc o me.  I nfa nts 
res ulti n g fr o m s uc h pre g na ncies s h o ul d be f oll o we d f or a mi ni m u m of 8 wee ks.  Reata or 
desi g nee ma y c o nt act t he i n vesti gat or t o re q uest a d diti o nal i nf or mati o n t hr o u g h o ut t he c o urse of 
t he pre g na n c y. 
T he f oll o wi n g pre g na n c y o utc o mes m ust be c o nsi dere d S A Es a n d will re q uire a d diti o nal 
re p orti n g i n t he e C R F a n d re p orte d as a n S A E: 
 C o n ge nital a n o mal y/ birt h defect; 
 Still birt h; 
 S p o nta ne o us mis carria ge. 


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9. 9.  
Seri o us T o xicities 
I n t he cas e of seri o us t o xicities, t he i n vesti gat or m a y c h o ose t o i nterr u pt treat me nt wit h 
bar d o x ol o ne met h yl.  A si n gle d ose re d ucti o n (fr o m 1 0 m g t o 5 m g) is p er mitte d if cli nicall y 
i n dicate d t o ma na ge t olera bilit y iss ues.  O nce a patie nt’s d ose has bee n re d u ce d, t hat d ose m ust 
be mai ntai ne d.  Patie nts w h o res u me t hera p y after a n i nterr u pti o n will f oll o w t he ori gi nall y 
pla n ne d st u d y s c he d ule.  
9. 1 0.  
St u d y Pr oce d ures  
T he f oll o wi n g s ecti o ns d escri be eac h assess me nt.  T he ti mi n g of t h ese assess me nts is n ote d i n 
Ta ble 3 .  All Da y 1 pr oce d ures, e x ce pt A E ass ess me nts, s h o ul d be c o m plete d pri or t o 
a d mi nistrati o n of  first d ose of st u d y dr u g. 
9. 1 0. 1.  
I nf or me d C o nse nt 
Writte n i nf or me d c o nse nt (see  Secti o n 1 5. 3 ) m ust be o btai ne d fr o m t he p atie nt bef ore a n y 
st u dy-relate d pr oce d ures are perf or m e d, a n d a gai n if t here is a c h a n ge i n t h e st u d y pr oce d ures 
t hat w o ul d affect t he pati e nt’s willi n g ness t o parti ci pate. 
9. 1 0. 2.  
I ncl usi o n/ E xcl usi o n 
I n cl usi o n a n d e x cl usi o n criteria m ust be re vi e we d as i n dicate d i n Ta ble 3 .  Patie nts m ust meet all 
of t he i ncl usi o n a n d n o ne of t he e x cl usi o n criteria f or e ntr y i n t he st u d y.   
9. 1 0. 3.  
Pri o r a n d C urre nt C o n c o mit a nt Me dic ati o ns 
T he na me, d ose, a n d fre q ue nc y m ust be rec or de d f or all me dicati o ns t hat t he patie nt is ta ki n g.  
All all o we d a n d e x cl u de d me dicati o ns s h o ul d be rec or de d i ncl u di n g all prescri pti o n dr u gs, her bal 
pr o d ucts, vita mi ns, mi nerals, a n d o ver-t h e-c o u nt er me dicati o ns.  Tra de or ge neric dr u g n a mes 
s h o ul d be use d w here p ossi ble.  C o nc o mita nt me dicati o ns will be re vie we d as i n dicate d i n  
Ta ble 3  a n d all c h a n ges will be rec or de d. 
9. 1 0. 4.  
C urre nt P A H B ac k gr o u n d Me dic ati o ns 
T h e na me, d ose, a n d fre q ue nc y m ust be rec or de d f or all P A H bac k gr o u n d me dicati o ns t hat t he 
patie nt is ta ki n g.  P A H b ac k gr o u n d me dicati o ns are t h ose t hat ha ve bee n a p pr o ve d b y t he U S 
F o o d a n d Dr u g A d mi nistrati o n ( F D A) or t he l o cal healt h a ut h orit y f or t he tre at me nt of P A H.  
Tra de or ge neric dr u g na mes s h o ul d be use d w here p ossi ble.  P A H bac k gr o u n d me dicati o ns will 
be re vie we d as i n dicate d i n Ta ble 3  a n d all c h a n ges will be rec or de d.   
9. 1 0. 5.  
Wei g ht a n d B o d y M ass I n de x  
Wei g ht m ust be meas ure d as i n dicate d i n Ta ble 3 .  B o d y mass i n de x ( B MI) will be calc ulate d i n 
t he eC R F eac h ti me t he wei g ht is r ec or de d.  Patie nts will use S p o ns or- pr o vi de d scales t o meas ure 
wei g ht at h o me.  Patie nts will be i nstr ucte d t o st o p a d mi nisteri n g st u d y dr u g a n d c o ntact t he 
i n vesti gat or if t heir dail y wei g ht i ncreas es per t h e criteria o utli ne d i n Secti o n 9. 1. 1 .  Patie nts will 
be  pr o vi de d i nstr ucti o ns wit hi n t he I nf or me d C o nse nt F or m t o hel p e ns ure c o nsiste nt wei g ht 
c ollecti o n t hr o u g h o ut t he st u d y. 


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9. 1 0. 6.  
Vit al Si g n Me as ure me nts 
Vital si g n meas ur e me nts i ncl u de t he patie nt’s heart rate ( beats/ mi n ute ta ke n f or at least 
1 5 sec o n ds), res pirati o n rate, a n d b o d y te m perat ur e.  Bl o o d pr ess ure s h o ul d be ta ke n after t he 
pa tie nt has reste d i n a sitti n g p ositi o n f or at least 5 mi n utes.  T he sa me ar m ( us uall y t he n o n-
d o mi na nt ar m) a n d t he a p pr o priate size c uff s h o ul d be use d f or eac h meas ure me nt.  Vital si g n 
meas ure me nts s h o ul d be ta ke n as i n dicate d i n T a ble 3 .  
9. 1 0. 7.  
P h ysic al E x a mi n ati o n 
A c o m pre he nsi v e p h ysic al e x a mi nati o n m ust be perf or me d b y a p h ysicia n, p h ysicia n assista nt, or 
re gistere d n urse practiti o ner as i n dicat e d i n Ta ble 3  a n d as d oc u me nte d wit hi n t he ta ble 
f o ot n otes.  T he e x ami nati o n m ust i ncl u de t he f oll o wi n g or ga n or b o d y s yste m assess me nts: hea d, 
e yes, ears, n ose, t hr o at, m usc ul os keletal, car di o v asc ular, l y m p hatic, res pir at or y, a b d o me n, s ki n, 
e xtre mities, a n d ne ur ol o gical.  Assess me nts of a n y s pecific si g ns or s y m pt o ms re p orte d b y t he 
patie nt m ust als o be perf or me d a n d d oc u me nt e d al o n g wit h a n y ot her fi n di n gs of n ote.  Cli nicall y 
si g nifica nt fi n di n gs at D a y 1 m ust be rec or de d as me dical hist or y.  F oll o wi n g t he e x a mi nati o n o n 
Da y 1, ne w or c ha n ge d p h ysical e x a mi nati o n fi n di n gs meeti n g t he criteria f or a n a d verse e v e nt 
m ust be rec or de d as a n a d verse e v e nt.  If p ossi ble, t he sa me i n di vi d ual s h o ul d perf or m eac h 
p h ysical e x a mi nati o n o n a patie nt d uri n g t he st u d y.  
9. 1 0. 8.  
Pre g n a nc y Test 
W O C B P (see  Secti o n 9. 8 ) will c o m plete a pre g na n c y t est as i n dicate d i n Ta ble 3 , or at a n y ti me 
if pre g na n c y is s us pecte d.  Ne gati ve test res ults are re q uir e d o n Da y 1 b ef ore st u d y dr u g 
a d mi nistrati o n.  A n y pati e nt w h o bec o mes pre g na nt d uri n g t he st u d y m ust disc o nti n ue ta ki n g 
st u d y dr u g i m me diatel y.  See Secti o n 9. 8. 3  f or a d escri pti o n of pr oce d ures t o be f oll o we d i n cas e 
of pr e g na n c y. 
9. 1 0. 9.  
St u d y Dr u g A d mi nistr ati o n 
Patie nts s h o ul d self-a d mi nister o ne ca ps ule orall y, o nce a d a y, prefera bl y i n t he m or ni n g, as 
i n dicate d i n Ta ble 3 .  A v o mite d d ose m ust n ot be re place d.  A d o u ble d ose (e. g., misse d d ose 
fro m pre vi o us da y a n d d ose f or c urre nt da y) m ust n ot be ta ke n. 
9. 1 0. 1 0.  
St u d y Dr u g Dis pe ns ati o n a n d C ollecti o n 
St u d y dr u g will be dis pe nse d t o t he patie nt a n d c ollecte d fr o m t he patie nt as i n dicate d i n Ta ble 3 .  
T he patie nt will be dis pe nse d 1 or m ore tr eat me nt kits at Da y 1, Wee k 4, Wee k 2 4, a n d e ver y 
2 4 wee ks t hereaft er f or t he d urati o n of t he st u d y.   Dis pe nse d treat me nt kits fr o m eac h visit 
s h o ul d be ret ur ne d t o t he site f or c ollecti o n at t he s u bse q ue nt visit. 
9. 1 0. 1 1.  
Tele p h o ne C o nt act 
Patie nts will be c o ntacte d b y tele p h o n e as i n dicat e d i n Ta ble 3 .  Patie nts will be as ke d a b o ut t heir 
b o d y w ei g ht a n d ot her si g ns of fl ui d rete nti o n, as well as A Es a n d a n y c ha n ges t o c o nc o mita nt 
me dicati o ns.  If fl ui d ret e nti o n is s us pecte d, t he patie nt m ust be br o u g ht i nt o t he cli nic a n d 
e val uate d b y t he i n v esti gat or as s o o n as p ossi ble, as detaile d i n  Secti o n  9. 1. 1 . 


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9. 1 0. 1 2.  
A d verse E ve nt C ollecti o n 
Patie nts will be o bser ve d f or ge neral a p peara nce, prese nce of ill ness or i nj ur y, or si g ns i n dic ati ve 
of a c o nc urre nt ill ness as i n dicate d i n Ta ble 3 .  Patie nts m ust be i nstr ucte d t o v ol u nteer a n y 
i nf ormati o n re gar di n g A Es o n or after t h e first d ose of st u d y dr u g or q uer y t he patie nts wit h a n 
o pe n q uesti o n re gar di n g a n y A Es t he y ma y be e x perie nci n g ( e. g., “ H o w ha ve y o u bee n feeli n g 
si nce y o ur last visit? ”).  A n y fi n di n gs are t o be d oc u me nte d.  Patie nts m ust be as ke d if t he y h a ve 
bee n h os pitaliz e d, ha d a n y acci de nts, use d a n y ne w me dicati o ns, or c h a n ge d c o nc o mita nt 
me dicati o n re gi me ns (i ncl u di n g pres cri pti o n dr u gs, o ver-t he-c o u nter m e dicati o ns, vita mi ns, 
her bal pr o d u cts, a n d mi nerals).  Res p o nses m ust b e d oc u me nte d i n t he s o urce d oc u me nts. 
9. 1 0. 1 3.  
Cli nic al C he mistr y 
S a m ples will be c ollecte d f or cli nical c he mistr y a nal yses as i n dicate d i n T a ble 3 .  Cli nical 
c he mistries will be a nal yze d l ocall y a n d s h o ul d i n cl u de t h ose r o uti nel y m o nit ore d per patie nt’s 
sta n dar d of care.  
9. 1 0. 1 4.  
N- Ter mi n al Pr o- Br ai n N atri ureti c Pe pti de a n d Br ai n N atri uretic Pe pti de  
Sa m ples will be  c ollecte d f or N T- Pr o B N P a n d/ or B N P as i n dicate d i n T a ble 3 .  As rece nt 
ex ercise ma y affect B N P a n d N T- Pr o B N P le vels, patie nts m ust be all o we d t o rest f or a 
mi ni m u m peri o d of 1 h o ur f oll o wi n g arri val at t he cli nic a n d pri or t o o btai ni n g t his bl o o d 
sa m ple.  Si milarl y, t his sa m ple m ust be ta ke n pri or t o t he 6 M W T or at least o ne h o ur aft er 
6 M W T.  T his sa m ple m ust be ta ke n wit h t he patie nt i n t he sa me p ositi o n at all a p pr o priate visits, 
e. g., sitti n g or se mi-rec u m be nt. 
9. 1 0. 1 5.  
6- Mi n ute W al k Test 
A 6 - mi n ute wal k test ( 6 M W T) will be perf or me d b y t he patie nts as i n dicat e d i n Ta ble 3 .  U nless 
ot her wise i n dicate d as descri be d bel o w, eac h t est m ust be perf or me d i n stri ct acc or da nce wit h t he 
A merica n T h oraci c S ociet y ( A T S) g ui d eli nes ( A T S  State me nt 2 0 0 2) pr o vi de d i n Secti o n 1 9 , 
A p pe n di x 1.  T he a p pr o priate la n g ua ge versi o n will be a p plie d f or patie nts wit h a n o n- E n glis h 
i nf or me d c o nse nt.  T h e wal ki n g c o urse m ust be 3 0 m i n le n gt h, e xce pt at sites gra nte d pri or 
S p o ns or a gree m e nt. 
Patie nts will rate t heir d ys p nea a n d o verall fati g ue usi n g t he B or g scale ( 2 0 0 4 versi o n, pr o vi de d 
i n Secti o n 2 1 , A p pe n di x 3) pri or t o be gi n ni n g a n d i m me diatel y f oll o wi n g c o m pleti o n of eac h 
6 M W T as  i n dicate d i n Ta ble 3 .   
T he  assess or of t he 6 M W T m ust n ot pr o vi de t he patie nt wit h t he res ults of t he assess me nt o nce 
c o m plete.  A patie nt s h o ul d wear t he s a me or si milar s h oes f or all 6 M W Ts.  A d diti o nall y, if a 
patie nt uses a wal ki n g ai d f or t he first test, t his sa me ai de s h o ul d be use d d uri n g all s u bse q ue nt 
tests.  T he s h oes w or n a n d wal ki n g ai d use d f or eac h 6 M W T s h o ul d be n ote d i n s o urce 
d oc u me nts.   
Patie nts w h o re q uire s u p ple me ntal o x y ge n wit h e x ercise ma y us e t heir prescri be d o x y ge n le vel 
d uri n g 6 M W Ts.  If a p atie nt’s healt h stat us deteri orates d uri n g st u d y partici pati o n a n d it is 
deter mi ne d b y  a p h ysici a n t hat t he patie nt re q uires a d diti o nal s u p ple me ntal o x y ge n, t h e patie nt 
ma y c o nti n ue  st u d y p arti ci pati o n.   


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9. 1 0. 1 6.  
W H O/ N Y H A F u ncti o n al Cl ass Assess me nt 
W H O / NY H A  f u ncti o nal class will be assesse d (Secti o n 2 0 , A p pe n di x 2) as i n dicate d i n Ta ble 3 .  
T o t he e xte nt fea si ble, t he sa me e v al uat or s h o ul d assess W H O/ N Y H A F C f or a partic ular p atie nt 
o ver t he e ntire c o urs e of t he st u d y.  


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S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T 
1 0. 1.  
St u d y Dr u g 
Bar d o x ol o ne met h yl ca ps ules, 5 m g  a n d 1 0 m g, will be use d i n t his st u d y. 
1 0. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g 
T he st u d y dr u g will be s u p plie d i n ta m per-e vi de nt kits c o ntai ni n g o ne 3 0-cc ( 5- m g ca ps ules, 
3 0 c o u nt), o ne 6 0- cc ( 5- m g ca ps ules, 9 0 c o u nt), or o ne 1 0 0-cc ( 1 0- m g ca ps ules, 9 0 c o u nt) hi g h-
de nsit y p ol yet h yle ne b ottle.  Eac h b ottle will utilize f oil i n d ucti o n-seal li ners a n d a c hil d-resista nt 
cl os ure.  Eac h b ottle of st u d y dr u g will c o ntai n 3 0 or 9 0 ca ps ules of 5 m g  or 1 0 m g stre n gt h 
ba r d o x ol o ne met h yl.  Eac h b ottle will als o c o ntai n a desicca nt i nsert t hat m ust n ot be i n geste d.  
La b eli n g o n eac h kit b ottle will c o ntai n at mi ni m u m t he f oll o wi n g i nf or mati o n: 
 Me dicati o n i de ntificati o n n u m ber; 
 P r ot oc ol 4 0 2- C- 1 6 0 2; 
 C a uti o n State me nt: Ne w Dr u g – Li mite d b y Fe d eral La w t o I n vesti gati o nal Use.  
Kee p o ut of si g ht a n d re ac h of c hil dre n; 
 C o ntr ol or l ot n u m ber 
 S t ore at 2 0° - 2 5° C ( 6 8° - 7 7° F), s h ort ter m e x c ursi o ns all o we d t o 
1 5° - 3 0° C ( 5 9° - 8 6° F); 
 R eata P har ma ce uticals, I nc., Ir vi n g, T X. 
A d o u ble pa nel la b el will be prese nt e d o n t he treat me nt b ottle c o ntai ni n g t his a n d ot her 
i nf or mati o n as well.  A d diti o nall y, l a beli n g i n t he rele va nt l ocal la n g ua ges f or i n vesti gati o nal 
me dici nal pr o d uct f or us e a n d distri b uti o n i n t he E U s hall a d here t o c urre nt E u drale x, V ol u me 4 
A n ne x 1 3 g ui da nce a n d re q uire me nts.   
1 0. 3.  
St u d y Dr u g St or a ge 
T he sta bilit y of t he dr u g pr o d uct has bee n a n d is c urre ntl y bei n g e v al uate d i n o n g oi n g st u dies. 
I n v esti gati ve sites m ust st ore t he i n vesti gati o nal pr o d uct i n a sec ure l ocati o n wit h r o o m 
te m perat ur e c o n diti o ns of 2 0° C t o 2 5° C ( 6 8° F t o 7 7° F), wit h brief e x c ursi o ns all o we d t o 
1 5° C t o 3 0° C ( 5 9° F t o 8 6° F).   
1 0. 4.  
St u d y Dr u g A d mi nistr ati o n 
Please refer t o  Secti o n  9. 1 0. 9  f or details o n st u d y dr u g a d mi nistrati o n.  Clear i nstr ucti o ns will be 
pr o vi de d t o t he patie nt re gar di n g t h e n u m ber a n d t y p e of ca ps ul es t o be i n geste d at eac h st u d y 
dr u g a d mi nistrati o n ti me p oi nt liste d i n Ta ble 3 .  Patie nts m ust be i nstr ucte d t o c o nti n ue ta ki n g 
st u d y dr u g u nless: ( 1) patie nt has bee n ot her wise i nstr u cte d b y t he i n vesti gat or or ( 2) t h e patie nt 
has bee n f or mall y dis c o nti n ue d fr o m t he st u d y.  


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1 0. 5.  
St u d y Dr u g Acc o u nt a bilit y 
T he i n vesti gat or, or desi g nee, will mai ntai n a rec or d of all st u d y dr u g recei v e d, dis pe nse d, a n d 
ret ur ne d t o t he S p o ns ors’ desi g nee.  N o st u d y dr u g s hall be destr o ye d b y t he cli nical site u nless 
directe d i n writi n g t o d o s o b y t he S p o ns or’s q u alit y ass ur a nce d e part me nt.  St u d y dr u g b ottles 
a n d a n y u n use d ca ps ules s h o ul d be ret ur ne d t o t he st u d y staff f or e v e nt ual dis p ositi o n b y t he 
S p o ns or.  T he n u m ber of ca ps ules ret ur ne d at eac h visit will be rec or de d f or eac h b ottle i n t he 
kit. 
1 0. 6.  
St u d y Dr u g H a n dli n g a n d Dis p os al 
At t he c o ncl usi o n of t he st u d y or i n a n i nsta nce of pla n ne d st u d y dr u g re place me nt, t he S p o ns or 
or its desi g nee will direct t he site re gar di n g t he fi n al dis p ositi o n of st u d y dr u g. 


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1 1.  
S A F E T Y A S S E S S M E N T S 
1 1. 1.  
S afet y P ar a meters 
T o a v oi d i nter- o bser v er varia bilit y, e v er y eff ort s h o ul d be ma de t o e ns ure t hat t he sa me 
i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o ns will c o m plete all safet y assess me nts.  
Safet y p ara meters will i n cl u de vital si g n meas ure me nts, p h ysical e x a mi nati o n res ults, A Es, 
S A Es, wei g ht, a n d assess me nt of B N P a n d/ or N T - Pr o B N P.  
1 1. 2.  
A d verse a n d Seri o us A d verse E ve nts 
1 1. 2. 1.  
Defi niti o n of A d verse E ve nts 
1 1. 2. 1. 1.  A d verse E ve nt 
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a patie nt re gar dless of its ca usal 
relati o ns hi p t o st u d y dr u g.  A n A E ca n b e a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n y 
cli nicall y si g nifica nt a b n or mal la b orat or y test res ult), s y m pt o m, or disease te m p orall y ass ociate d 
wit h t he use of t he st u d y dr u g, w het her or n ot it is c o nsi dere d t o be st u d y- dr u g relate d.  I n cl u d e d 
i n t his defi niti o n are a n y ne wl y- occ urri n g e v e nts or pre vi o us c o n diti o n t hat has i ncrease d i n 
se verit y or fre q ue n c y si nce t he a d mi nistrati o n of st u d y dr u g. 
All A Es t hat are o bser ve d or re p orte d b y t he patie nt d uri n g t he st u d y (fr o m ti me of 
a d mi nistrati o n of t he first d ose at t he Da y 1 visit u ntil t he fi nal visit i n dicate d i n Ta ble 3 ) m ust be 
rep orte d, re gar dless of t h eir relati o ns hi p t o st u d y dr u g or t heir cli nical si g nifica nce. 
1 1. 2. 1. 2.  Seri o us A d verse E ve nt 
A n S A E is a n y A E occ urri n g at a n y d ose a n d re gar dless of ca us alit y t hat: 
 R es ults i n deat h; 
 Is life-t hreate ni n g; 
 R e q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; 
 R es ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u ncti o ns; 
 Is a c o n ge nital a n o mal y or birt h defect i n a n offs pri n g of a patie nt ta ki n g st u d y dr u g; 
 Is a n i m p orta nt me dical e ve nt.  
T he ter m "life-t hr eate ni n g" refers t o a n e ve nt i n w hic h t he patie nt was at i m me diate ris k of deat h 
at t he ti me of t he e ve nt.  It d oes n ot refer t o a n e v e nt t hat h y p ot heticall y mi g ht ha ve ca us e d deat h 
if it were m ore s e vere. 
I m p ort a nt me dical e v e nts are t h ose t hat ma y n ot m eet a n y of t he criteri a defi ne d a b o ve; h o we v er, 
t he y ma y b e c o nsi dere d s eri o us w he n, bas e d u p o n a p pr o priate m e dical j u d g me nt, t he y ma y 
je o par dize t he patie nt a n d ma y re q uire m e dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
ot her o utc o mes liste d i n t he S A E defi niti o n. 


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Pre g n a nc y is n ot c o nsi dere d a n A E; h o w e ver, i nf or mati o n will be c ollecte d f or a n y pre g na nci es 
t hat occ ur d uri n g t he st u dy (fr o m t he ti me of t he first d ose of st u d y dr u g u ntil t he fi nal visit 
i n dicate d i n Ta ble 3 , as a p pr o priate).  Certai n pre g na nc y o utc o mes will re q uire s u b missi o n as a n 
S A E ( See  Secti o n 9. 8 ). 
T he i n vesti gat or is res p o nsi ble f or re p orti n g t o Reata or desi g nee all A Es a n d S A Es t hat are 
o bser ve d or re p ort e d b y t he patie nt d uri n g t he st u d y (fr o m t he ti me of a d mi nistrati o n of t he first 
d ose of st u d y dr u g u ntil t he fi nal visit i n dicate d i n Ta ble 3 , as a p pr o priate), re gar dl ess of t heir 
relati o ns hi p t o st u d y dr u g or t heir cli nical si g nifica nce.   
T he S p o ns or, or t he C o ntract Rese arc h Or ga nizati o n ( C R O) o n t he be half of t he S p o ns or, m ust 
be n otifie d i m me diatel y re gar di n g t he occ urre nce of a n y S A E t hat occ urs after t he patie nt 
recei v es t he first d ose of st u d y dr u g a n d t hr o u g h o ut t he st u d y, re gar dless of st u d y dr u g 
a d mi nistrati o n, i ncl u di n g S A Es res ulti n g fr o m pr ot oc ol-ass ociate d pr oce d ures, as defi ne d i n 
rele va nt le gislati o n.  T he pr oce d ures f or re p orti n g all S A Es, re gar dless of ca usal relati o ns hi p, are 
as f oll o ws: 
 R ec or d t he S A E o n t he A E e C R F a n d c o m plete t h e “ Seri o us A d verse E v e nt Re p ort” 
f or m wit hi n t he electr o ni c data bas e; 
 In t he e ve nt t he electr o ni c data bas e is n ot f u ncti o nal, a pa per S A E f or m will be 
a vaila ble f or t he re p orti n g of S A Es. 
T he S p o ns or ma y re q u est a d diti o nal i nf or mati o n fr o m t he i n vesti gat or t o e ns ure t he ti mel y 
c om pleti o n of acc urate s afet y re p orts. 
All S A Es re p orte d or o bs er ve d d uri n g t he st u d y m ust be f oll o we d t o res ol uti o n or u ntil t he 
i n vesti gat or d ee ms t he e v e nt t o be c hr o nic or t he p atie nt t o be sta ble.  Reata or desi g n ee ma y 
c o ntact t he i n vesti gat or t o o btai n a d diti o nal i nf or mati o n o n a n y S A E w hic h has n ot res ol ve d at 
t he ti me t he patie nt c o m pletes t he st u d y. 
1 1. 3.  
Eliciti n g A d verse E ve nt I nf or m ati o n  
At e ver y st u d y visit, patie nts m ust be as ke d a sta n dar d, n o n directe d q uesti o n, s uc h as, “ H o w 
ha ve y o u bee n feeli n g si n ce y o ur last visit? ” t o elicit a n y me dicall y relate d c ha n ges i n t heir 
well- bei n g.  T he y ma y als o be as ke d if t he y h a ve bee n h os pitalize d, ha d a n y acci de nts, use d a n y 
ne w me dicati o ns, or c ha n ge d c o nc o mita nt me dicati o n re gi me ns (i ncl u di n g prescri pti o n dr u gs, 
o ver-t he- c o u nter m e dicati o ns, vita mi ns, her bal pr o d ucts, a n d mi nerals).  Res p o nses m ust be 
d oc u me nte d i n t he s o urce d oc u me nts. 
I n a d diti o n t o patie nt o bser vati o ns, A Es m ust be d oc u me nte d f or a n y cli nicall y si g nifica nt 
dia g n osis r es ulti n g fr o m a b n or mal la b orat or y test val ues t hat are m o nit ore d per patie nt’s sta n d ar d 
of care, p h ysical e x a mi nati o n fi n di n gs, or fr o m ot h er d oc u me nts t hat are rel e va nt t o patie nt 
safet y. 


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Assess me nt of C a us alit y  
T he i n vesti gat or m ust use t he f oll o wi n g classificati o ns a n d criteria t o c haracterize t he 
relati o ns hi p or ass ociati o n of t he st u d y dr u g i n ca usi n g or c o ntri b uti n g t o t he A E: 
N ot Relate d: T his relati o ns hi p s u g gests t hat t here is n o ass ociati o n bet wee n t he st u d y dr u g a n d 
t he re p orte d e ve nt. 
U nli kel y Relate d: T his r elati o ns hi p s u g gests t hat t he te m p oral se q u e nce of t he e ve nt wit h st u d y 
dr u g a d mi nistrati o n ma kes a ca us al relati o ns hi p i m pr o ba ble a n d/ or ot her fact ors als o pr o vi de 
pla usi ble e x pla nati o ns. 
P ossi bl y Relate d: T his r elati o ns hi p s u g gests t hat treat me nt wit h t he st u d y dr u g ca use d or 
c o ntri b ute d t o t he A E.  T hat is, t he e ve nt f oll o ws a reas o na bl e te m p oral se q ue nce fr o m t he ti me 
of st u d y dr u g a d mi nistrati o n, a n d/ or, f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g, b ut 
c o ul d ha ve bee n pr o d uce d b y ot her fact ors. 
Pr o ba bl y Relat e d: T his relati o ns hi p s u g gests t hat a reas o n a ble te m p or al se q ue nce of t h e e ve nt 
wit h st u d y dr u g a d mi nistrati o n e xists a n d, base d u p o n t he k n o w n p har mac ol o gical acti o n of t he 
dr u g, k n o w n or pre vi o usl y re p orte d a d verse reacti o ns t o t he dr u g or class of dr u gs, or j u d g me nt 
base d o n t he i n vesti ga t or’s cli nical e x perie nce, t he ass ociati o n of t he e v e nt wit h st u d y dr u g 
a d mi nistrati o n see ms li kel y. 
Defi nitel y R elate d: T his relati o ns hi p s u g gests t hat a defi nite ca usal rel ati o ns hi p e xists bet wee n 
t he dr u g a d mi nistrati o n a n d t he A E, a n d ot her c o n diti o ns (e. g., c o nc urre nt ill ness, 
pr o gr essi o n/e x pressi o n of disease state, or c o nc urre nt me dicati o n reacti o n) d o n ot a p pear t o 
e x plai n t he e ve nt.  
1 1. 5.  
Assess me nt of Se verit y 
T he i n vesti gat or will gra de t he se verit y of t h e A Es as mil d, m o derate, or se vere usi n g t he 
f oll o wi n g defi niti o ns: 
Mil d: S y m pt o ms ca usi n g n o or mi ni mal i nterfere n ce wit h us ual s ocial a n d f u ncti o nal acti vities; 
M o derate: S y m pt o ms c a usi n g greater t ha n mi ni m al i nterfere nce wit h us ual s ocial a n d f u ncti o nal 
acti vities; 
Se vere: S y m pt o ms c a usi n g i na bilit y t o p erf or m us ual s ocial a n d f u n cti o nal acti vities.  
1 1. 6.  
Rec or di n g A d verse E ve nts 
All c o n diti o ns prese nt pri or t o t he a d mi nistrati o n of t he first d ose of st u d y dr u g ( Da y 1) i n a 
pre vi o us st u d y wit h bar d o x ol o ne met h yl s ho ul d b e d oc u me nte d as me dical hist or y i n a pre vi o us 
st u d y wit h bar d o x ol o ne met hyl.  After t he first d ose, d oc u me ntati o n of A Es s hall c o nti n ue u ntil 
3 0 da ys f oll o wi n g a d mi nistrati o n of t he fi nal d ose of st u d y me dicati o n u n der t his pr ot oc ol or 
t hr o u g h 3 0 d a ys after c o m mercial a vaila bilit y of bar d o x ol o ne met h yl (i.e., t hr o u g h t he E n d- of-
Tr eat me nt visit), re gar dless of t he relati o ns hi p of t he A E t o st u d y dr u g.  I nf or mati o n t o be 
c ollecte d will i ncl u de t y p e of e ve nt, d ate of o nset, date of res ol uti o n, i n vesti gat or-s pecifie d 
assess me nt of se verit y a n d relati o ns hi p t o st u d y dr u g, seri o us ness, as well as a n y acti o n ta ke n.  


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W hile a n A E is o n g oi n g, c ha n ges i n t he se v erit y ( e. g., w orse ni n g a n d i m pr o vi n g) s h o ul d be 
n ote d i n t he s o urce d o c u me nts, b ut w he n d oc u me nti n g t he A E, o nl y t he t ot al d urati o n a n d 
greatest se v erit y s h o ul d be rec or de d i n t he e C R F.  A Es c haracterize d as i nter mitte nt will re q uire 
d oc u me ntati o n of o nset a n d d urati o n. 
All dr u g-relate d ( p ossi bl y, pr o ba bl y, or defi nitel y relate d, see  Secti o n 1 1. 4 ) A Es a n d a b n or m al 
la b orat or y test r es ults re p orte d or o bser ve d d uri n g t he st u d y m ust be f oll o w e d t o res ol uti o n 
(eit her ret ur n t o baseli ne or wit hi n n or mal li mits).  All ot her A Es will be f oll o we d t hr o u g h t he 
fi nal visit i n dicate d i n Ta ble 3 , as a p pr o priate. 
A E s res ulti n g fr o m c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt ill nesses, reacti o ns t o c o nc urre nt 
me dicati o ns, or pr o gressi o n of disease states m ust als o be re p ort e d.  Pree xisti n g c o n diti o ns 
( prese nt bef ore t h e start of t he A E c ollecti o n peri o d) will be c o nsi dere d c o n c urre nt me di cal 
c o n diti o ns a n d s h o ul d N O T be rec or de d as A Es.  H o we ver, if t he patie nt e x perie nces a 
w orse ni n g or c o m plicati o n of s uc h a c o n c urre nt c o n diti o n, t he w orse ni n g or c o m plicati o n s hall 
be rec or de d as a n A E.  I n vesti gat ors s h all e ns ure t hat t he A E ter m r ec or de d ca pt ures t he c ha n ge 
i n t he c o n diti o n (e. g., “ w orse ni n g of …”).  A n y i m pr o ve me nt i n c o n diti o n s hall be d oc u me nte d 
pe r Secti o n 9. 1 0. 7 . 
Eac h A E s hall be rec or de d t o re prese nt a si n gl e dia g n osis.  A cc o m pa n yi n g si g ns (i ncl u di n g 
a b n or mal la b orat or y test val ues) or s y m pt o ms s hall N O T be rec or de d as a d diti o nal A Es.  If a 
dia g n osis is u n k n o w n, si g n(s) or s y m pt o m(s) s hall be rec or de d as a n A E(s).  C ha n ges i n 
la b orat or y test val ues will o nl y be c o nsi dere d A Es if t he y are j u d ge d t o be cli nicall y si g nifica nt 
(i.e., if s o me acti o n or i nt er ve nti o n is re q uir e d or if t he i n vesti gat or j u d ges t he c ha n ge t o be 
be y o n d t h e ra n ge of n or mal p h ysi ol o gi cal fl uct uati o n).  If a b n or mal la b orat or y test val u es will be 
t he res ult of pat h ol o g y f or w hic h t here will be a n o verall dia g n osis (e. g., i ncrease d creati ni ne 
le vels i n re nal f ail ure), o nl y t he dia g n osis s hall be re p orte d as a n A E. 
Electi ve pr oce d ures (s ur geries or t hera pies) t h at will be sc he d ule d pri or t o t he start of A E 
c ollecti o n will n ot be c o nsi dere d A Es.  T h ese electi ve pr oce d ures s hall n ot be rec or de d as A Es, 
b ut s hall be d oc u me nte d i n t he patie nt’s s o urce d o c u me nts as electi ve ( e. g.,  electi ve peri o d o ntal 
s ur ger y).  H o we ver, if a pre- pla n n e d pr oce d ure will be perf or me d earl y (e. g., as a n e mer ge nc y) 
be ca use of a w orse ni n g of t he pree xisti n g c o n diti o n, t he w orse ni n g of t he c o n diti o n s hall be 
ca pt ure d as a n A E. 
1 1. 7.  
Re p orti n g Seri o us A d verse E ve nts 
A n y A E t he i n vesti gat or will c o nsi der seri o us acc or di n g t o t he pre vi o usl y descri be d criteria m ust 
be re p ort e d wit hi n 2 4 h o urs fr o m t he ti me t he site pers o n nel first lear n a b o ut t he e ve nt.  
T o r e p ort t he S A E, t he i n vesti gat or will c o m plete t he S A E f or m i n t he cli nical data b ase a n d s e n d 
t o  
 (fa x n u m bers liste d i n Ta ble 5 ) wit hi n 2 4 h o urs of a ware ness.  If t he cli nical 
da ta base is d o w n f or an y reas o n, t he ma n ual S A E f or ms will be utilize d; h o we ver sites are 
res p o nsi ble f or e ns uri n g t he i nf or mati o n o n t he ma n ual S A E f or ms is e ntere d i nt o t he cli nical 
data base o n ce a v aila ble. 


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T a ble 5:  
S A E Re p orti n g C o nt act I nf or m ati o n 
 
 
 
  
N o n -N ort h A merica n  sites will use access c o des 
s pecific t o t heir c o u ntr y.  C o ntact i nf or mati o n f or 
n o n -N ort h A merica n sites f or S A E re p orti n g will 
be pr o vi de d b y t he cli nical tea m directl y t o t he 
sites. 
F or q uesti o ns re g a r di n g S A E re p orti n g, c o nt act y o ur st u d y m a n a g er, m o nit or, o r  
 
 
F oll o w- U p Re p orts 
T he i n vesti gat or m ust c o nti n ue t o f oll o w t he patie nt u ntil t he S A E has s u bsi de d or u ntil t he 
c o n diti o n bec o mes c hr o nic i n nat ure , sta bilizes (i n t he case of persiste nt i m pair me nt), or t he 
patie nt dies. 
W it hi n 2 4 h o urs of receipt of ne w i nf or mati o n, t h e S A E f or m s h o ul d be u p date d wit hi n t he 
cli nical data bas e a n d s u b mitte d al o n g wit h a n y s u p p orti n g d oc u me nt ati o n ( e. g., patie nt disc har ge 
s u m mar y or a ut o ps y re p orts).  If t he cli nical data b ase is d o w n f or a n y reas o n, t he ma n ual S A E 
f or ms s h o ul d be use d; h o we ver, sites are res p o nsi ble f or e ns uri n g t he u p date d i nf or mati o n o n t he 
ma n ual S A E f or ms is e ntere d i nt o t he cli nical d ata base o nce a vaila ble. 
T he S p o ns or or desi g nee will n otif y re g ulat or y a ge ncies of a n y fatal or life-t hreate ni n g 
u ne x pecte d e ve nts ass oci ate d wit h t he use of t he st u d y dr u g as s o o n as p ossi ble b ut n o later t ha n 
7 cale n dar da ys after t he i nitial recei pt of t he i nf or mati o n.  I nitial n otificati o n will be f oll o we d b y 
a writte n re p ort wit hi n t he ti mefra me esta blis he d b y t he a p pr o priat e re g ulat or y a ge nc y.  F or ot her 
S A Es t hat d o n ot meet t he fatal or life-t hreate ni n g u ne x pecte d criteria, b ut are re p orte d t o be 
ass ociate d wit h t he use of t he st u d y dr u g, Reata or desi g nee will n otif y t h e a p pr o priate re g ulat or y 
a ge ncies i n writi n g wit hi n t he ti mefra me est a blis he d b y t h os e re g ulat or y a ge ncies.  Reat a or 
desi g nee will pr o vi de c o pies of a n y re p orts t o re g ulat or y a ge nci es re gar di n g seri o us a n d 
u ne x pecte d S A Es t o t he i n vesti gat ors f or re vie w a n d s u b missi o n t o t heir I R B or E C, as 
a p pr o priate.  
Pri nci pal i n vesti gat ors will be res p o nsi ble f or i nf or mi n g t heir I R B/ E C of a n y S A Es at t heir site.  
S A E c orres p o n d e nce wit h re g ulat or y a ut h orities or I R Bs/ E Cs m ust be s u b mitte d t o t he S p o ns or 
or desi g n ee f or rec or di n g i n t he st u d y file. 
N ote t hat t he f oll o wi n g A Es w hic h are c o m m o nl y o bser ve d i n t his patie nt p o p ulati o n will n ot be 
re p orte d t o r e g ulat or y a ut h orities as i n di vi d ual e x pe dite d re p orts, e x ce pt i n u n us ual 
circ u msta nc es: 
 S h ort ness of breat h; 
 Li g ht hea d e d ness/ dizzi ness; 
 S y nc o pe; 


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 C hest pai n; 
 P al pitati o ns; 
 F ati g ue; 
 E de ma/fl ui d rete nti o n; 
 E x erti o nal d ys p n ea; 
 H y p o x e mia. 
T hese e v e nts will be re vi e we d o n a re g ular basis i n a g gre gat e a n d will be re p orte d i n a n 
e x pe dite d ma n ner if a safet y si g nal is detecte d.  Re g ular s afet y st u d y u p dat es will be re p orte d t o 
re g ulat or y a ut h orities acc or di n g t o l ocal g ui deli nes. 


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1 2.  
S T A TI S TI C S 
1 2. 1.  
S a m ple Size 
T he ai m of t his l o n g-t er m e xte n de d access st u d y is pri maril y t o pr o vi de c o nti n ui n g treat me nt t o 
patie nts wit h bar d o x ol o ne met h yl a n d t o assess l o n g-ter m safet y a n d t olera bilit y, h e nce n o si n gle 
pri mar y varia bl e has bee n i de ntifie d.  Patie nt n u m bers will be deter mi ne d b y t h ose w h o h a ve 
bee n treat me nt-c o m plia nt a n d w h o ha ve pre vi o usl y partici pate d i n cli nical st u dies wit h 
ba r d o x ol o ne met hyl.  
1 2. 2.  
St u d y V ari a bles 
1 2. 2. 1.  
S afet y V ari a bles 
T he safet y v aria bles will i ncl u de res ults of p h ysical e xa mi nati o ns, la b orat or y test res ults ( B N P 
a n d N T- Pr o B N P), vital si g n meas ure me nts, wei g ht, A Es, a n d S A Es. 
1 2. 3.  
St atistic al A n al yses 
A statistical a nal ysis pla n ( S A P) detaili n g t he a nal ys es will be d e vel o pe d pri or t o t he data base 
l oc k.  All statistical a nal yses a n d data s u m mari es will be perf or me d usi n g S A S® ( Versi o n 9. 1 or 
hi g her) or ot her vali date d s oft ware.  T h e S A P will ser ve as t h e fi nal ar biter of all statistical 
a nal ys es.  Dat a will be s u m mariz e d o verall usi n g d escri pti ve statistics.  C o nti n u o us data will be 
s u m marize d wit h n u m ber of patie nts ( n), mea n, me dia n, mi ni m u m, ma xi m u m, rele va nt q uartiles, 
sta n dar d de viati o n, c o effi cie nt of vari ati o n, a n d ge o metric mea n ( w here a p plica ble).  Cate g ori cal 
data will be s u m mariz e d usi n g fre q ue n c y c o u nts a n d perce nt a ges.  
1 2. 3. 1.  
Pri m ar y A n al ysis of S afet y 
As t he e xte nsi o n is of a n o pe n-la bel desi g n wit h n o c o m parat or gr o u p, all statistical a nal ys es wi ll 
be descri pti ve.  Patie nts will be i ncl u de d i n t hese a nal ys es if t he y are i ncl u de d i n t he safet y 
a nal ysis a n d ha ve b ot h b aseli ne a n d p ost- bas eli ne data a vaila ble f or t he varia ble bei n g a nal yz e d.  
T he s u m mar y ta bles will be prese nt e d f or t he o verall gr o u p of patie nts, a n d als o s plit b y pre vi o us 
treat me nt gr o u ps i n pri or bar d o x ol o ne met h yl cli nical st u dies.   
 


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1 3.  
DI R E C T A C C E S S T O S O U R C E D A T A/ D O C U M E N T S 
1 3. 1.  
St u d y- S pecific C o m mittees  
N o steeri n g c o m mittee, d ata safet y m o nit ori n g c o m mittee, a dj u dicati o n c o m mittee, or cli nical 
e n d p oi nt c o m m ittee will be use d i n t his st u d y. 
1 3. 2.  
St u d y M o nit ori n g 
T he st u d y site will be m o nit ore d re m otel y b y t he C R O peri o dicall y d uri n g t he st u d y t o e ns ure 
t hat all as pects of t he pr ot oc ol will be f oll o we d a n d will i ncl u de a n electr o nic data c ollecti o n 
w hic h has a set of a ut o matic data c h ec ks wit h dat a q ueries f or pr o gra m me d data c ollecti o n.  
T here will be m o nit ori n g of st u d y site b y tele p h o n e t o e ns ure t hat t he dr u g s u p plies ha ve bee n 
pr o vi de d a n d pr ot oc ol i nstr ucti o ns are well u n derst o o d a n d a p plie d. 
T he S p o ns or or desi g nee will m o nit or all as pects of t he st u d y f or c o m plia nce wit h a p plica ble 
g o ver n me nt re g ul ati o n wit h res pect t o t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) 
g ui deli ne E 6( R 1): G o o d C li nical Practice: C o ns oli date d G ui deli ne a n d c urre nt sta n dar d o perati n g 
pr oce d ures. 
1 3. 3.  
A u dits a n d I ns pecti o ns 
Pri nci pal i n vesti gat ors a n d i nstit uti o ns i n v ol ve d i n t he st u d y will per mit st u d y-relate d 
m o nit ori n g, a u dits, a n d I R B/ E C re vie w, a n d re g ul at or y i ns p ecti o ns, b y pr o vi di n g direct access t o 
all st u d y re c or ds.  I n t he e ve nt of a n a u dit, t he pri nci pal i n vesti gat or will a gree t o all o w t he 
S p o ns or, re pres e ntati ves of t he S p o ns or, t he F D A, a n d ot her rele va nt r e g ulat or y a ut h orities 
access t o all st u d y rec or ds. 
T he pri nci pal i n vesti gat or s hall pr o m ptl y n otif y t h e S p o ns or or desi g nee of a n y a u dits sc he d ule d 
b y a n y re g ulat or y a ut h orities a n d s hall pr o m ptl y f or war d c o pies of a n y a u dit re p orts recei ve d t o 
t he S p o ns or or desi g n ee. 


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1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E 
1 4. 1.  
Q u alit y Ass ur a nce 
T o e ns ure c o m plia n ce wit h G o o d Cli nical Practices a n d all a p plica ble re g ul at or y re q uir e me nts, 
Reata ma y c o n d u ct a q ualit y ass ura n ce a u dit of t h e i n vesti gat or’s cli nical site, i ncl u di n g 
C T M/I M P st ora ge facilities.   
1 4. 2.  
Fi n a nci al Discl os ure  
Pri nci pal i n vesti gat ors a n d s u b-i n vesti gat ors are re q uire d t o pr o vi de fi na n cial discl os ure 
i nf or mati o n pri or t o starti n g t he st u d y.  I n a d diti o n, t he pri nci pal i n vesti gat or a n d s u b-
i n vesti gat ors m ust pr o vi d e t he S p o ns or or desi g nee wit h u p date d i nf or mati o n, if a n y rele va nt 
c ha n ges occ ur d uri n g t he c o urse of t he i n v esti gati o n a n d f or o ne year f oll o wi n g t he c o m pleti o n 
of t he st u d y. 
N o  p ote ntial i n vesti gat or w h o has a veste d fi na nci al i nterest i n t he s uccess of t his st u d y ma y 
pa rtici pate i n t his st u d y. 
1 4. 3.  
S p o ns or O bli g ati o ns  
T he S p o ns or or desi g nee is n ot fi na nciall y res p o nsi ble f or f urt her testi n g/treat me nt of a n y 
me dical c o n diti o n t hat ma y b e dete cte d d uri n g t he Scree ni n g pr ocess.  I n a d diti o n, i n t he a bse nce 
of s pecific arr a n ge me nts, t he S p o ns or or desi g n ee is n ot fi na nciall y res p o nsi ble f or treat me nt of 
t he patie nt’s u n derl yi n g disease. 
1 4. 4.  
I n vesti g at or D oc u me nt ati o n 
Bef ore be gi n ni n g t he st u d y, t he pri n ci pal i n vesti gat or will be as ke d t o c o m pl y wit h I C H E 6( R 1) 
8. 2 a n d Title 2 1 of t he C o de  of Fe deral Re g ulati o ns ( C F R) b y pr o vi di n g t h e esse ntial d oc u me nts 
t o t he S p o ns or or desi gn ee, w hic h i ncl u de b ut are n ot li mite d t o t he f oll o wi n g: 
 A n or i gi n al i n vesti gat or-si g ne d i n vesti gat or a gree me nt pa ge of t he pr ot oc ol;  
 T he  I R B/ E C a p pr o val of t he pr ot oc ol; 
 T he  I R B- or E C-a p pr o ve d i nf or me d c o nse nt, sa m ples of site a d vertise me nts f or 
recr uit me nt f or t his st u d y, a n d a n y ot her writte n i nf or mati o n re gar di n g t his st u d y t hat 
is t o be pr o vi de d t o t he patie nt or le gal g uar dia ns; 
 A F or m F D A 1 5 7 2, f ull y e x ec ute d, a n d all u p dates o n a n e w f ull y e x ec ute d F or m 
F D A 1 5 7 2; 
 C urric ula vitae f or t he pri nci pal i n vesti gat or a n d eac h s u b-i n vesti gat or liste d o n F or m 
F D A 1 5 7 2.  A c urric ul a vitae a n d c urre nt lice ns ure, as a p plica bl e, m ust be pr o vi de d.  
T he c urri c ula vitae  m ust ha ve bee n si g n e d a n d dat e d b y t h e pri nci pal i n vesti gat ors 
a n d s u b-i n vesti gat ors wit hi n 2 years bef ore st u d y start- u p t o i n dicate t he d o c u me nts 
are acc urate a n d c urre nt; 


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 C o m plete d fi na ncial discl os ure f or ms ( Secti o n  1 4. 2 ) t o all o w t he S p o ns or or desi g n ee 
t o s u b mit c o m plete a n d acc urat e certificati o n or discl os ure state me nts re q uire d u n der 
U S Title 2 1 C F R 5 4.  I n a d diti o n, t he i n vesti gat ors m ust pr o vi de t o t he S p o ns or or 
desi g nee a c o m mit me nt t o u p date t his i nf or mati o n pr o m ptl y if a n y rele va nt c ha n ges 
occ ur d uri n g t he c o urse of t he i n vesti gati o n a n d f or 1 year f oll o wi n g t he c o m pleti o n 
of t he st u d y; 
 L a b orat or y certificati o ns a n d n or mal ra n ges f or a n y la b orat ories use d b y t h e site f or 
t he c o n d uct of t his st u d y. 
1 4. 5.  
Cli nic al St u d y I ns ur a nce 
I n acc or da n ce wit h t he res pecti ve nati o nal dr u g la ws, t he S p o ns or has ta ke n o ut patie nt lia bilit y 
i ns ura nce f or all patie nts w h o gi ve t h eir c o nse nt a n d e nr oll i n t his st u d y.  T his i ns ura nce c o v ers 
p ote ntial fatalities, p h ysi cal i nj uries, or da ma ge t o healt h t hat ma y occ ur d uri n g t he cli nical 
st u d y. 
1 4. 6.  
Use of I nf or m ati o n  
All i nf or mati o n re gar di n g bar d o x ol o ne met h yl s u p plie d b y t he S p o ns or t o t he i n vesti gat or is 
pri vile ge d a n d c o nfi de ntial.  T he i n vesti gat or a grees t o use t his i nf or mati o n t o acc o m plis h t he 
st u d y a n d will n ot use it f or ot her p ur p oses wit h o ut c o nse nt fr o m t he S p o ns or.  F urt her m ore, t he 
i n vesti gat or is o bli gate d to pr o vi de t he S p o ns or wit h c o m plete data o btai ne d d uri n g t he st u d y.  
T he i nf or mati o n o btai ne d fr o m t he cli nical st u d y will be use d t o war ds t he de vel o p me nt of 
bar d o x ol o ne met h yl a n d ma y b e discl ose d t o re g ul at or y a ut h orities, ot her i n vesti gat ors, c or p orate 
part ners, or c o ns ul ta nts as re q uire d. 


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1 5.  
E T HI C S 
1 5. 1.  
I nstit uti o n al Re vie w B o ar d or Et hics C o m mittee Re vie w 
T he pr ot oc ol a n d t he pr o p ose d i nf or me d c o ns e nt f or m m ust be re vie we d a n d a p pr o ve d b y a 
pr o perl y c o nstit ute d I R B/ E C bef ore st u d y start.  E ac h i n vesti gat or m ust pr o vi de t he S p o ns or or 
its desi g nee a si g n e d a n d date d state me nt t hat t he pr ot oc ol a n d i nf or me d c o nse nt ha ve bee n 
a p pr o ve d b y t he I R B/ E C f or t hat site bef ore c o ns e nti n g patie nts.  Pri or t o st u d y i nitiati o n, t he 
i n vesti gat or is r e q uire d to si g n a pr ot o c ol si g nat ure pa ge c o nfir mi n g a gree me nt t o c o n d uct t he 
st u d y i n acc or da n ce wit h t his pr ot oc ol a n d t o gi ve access t o all rele va nt d ata a n d rec or ds t o t he 
S p o ns or, its desi g nee, a n d re g ulat or y a ut h orities as re q uire d. 
T he I R B/ E C c h air pers o n or desi g n ee m ust si g n all I R B/ E C a p pr o vals a n d m ust i de ntif y t he 
I R B/ E C b y na me a n d a d dress, t he cli nical pr ot o c ol, a n d t he date a p pr o val a n d/ or fa v ora ble 
o pi ni o n was gra nte d. 
T he pri nc i pal i n vesti gat or is res p o nsi ble f or o btai ni n g re vi e ws of t he cli nical researc h at i nter v als 
s pecifie d b y t he IR B/ E C, b ut n ot e x cee di n g 1 year.  T he pri nci pal i n vesti gat or m ust s u p pl y t he 
S p o ns or or desi g n ee  wit h writte n d oc u me ntati o n of re vie ws of t he cli nical r esearc h. 
1 5. 2.  
Et hic al C o n d uct of t he St u d y 
T his cli nical st u d y was d esi g ne d a n d s hall be i m pl e me nte d a n d re p orte d i n acc or da nce wit h t he 
I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble l ocal 
re g ulati o ns (e. g., U S  C o d e of Fe deral Re g ulati o ns Title 2 1, E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C), 
a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarati o n of Helsi n ki.  
T he pri nci pal i n vesti gat or a grees t o c o n d uct t he st u d y i n acc or da nce wit h t he I nter n ati o nal 
C o nfere nce o n Har m o niz ati o n (I C H) f or G ui da nce f or I n d ustr y o n G C P I C H E 6( R 1) 
[htt p:// w w w.ic h. or g/file a d mi n/ P u blic
We b Site/I C H Pr o d ucts/ G ui deli nes/ Efficac y/ E 6/ E 6
R 1
G ui deli ne. p df ] a n d t he pri nci ples of t he Declarati o n of Helsi n ki 
[htt p:// w w w. w ma. net/e n/ 3 0 p u blicati o ns/ 1 0 p olicies/ b 3/ ].  T he pri nci pal i n vesti gat or m ust c o n d u ct 
all as pects of t his st u d y i n acc or da nce wit h all n ati o nal, state, a n d l ocal la ws or re g ulati o ns. 
1 5. 3.  
Writte n I nf or me d C o nse nt 
Beca use t he st u d y will be c o n d ucte d u n der a U S  I n vesti gati o nal N e w Dr u g A p plicati o n, a si g n e d 
i nf or me d c o nse nt f or m, i n c o m plia nce wit h Title 2 1 of t he U S C F R Part 5 0, will be o btai ne d 
fr o m eac h patie nt bef ore t he patie nt e nters t he st u d y.  F or sites o utsi de of t h e U S , t he si g n e d 
c o nse nt will be o bta i ne d i n acc or d wit h l ocal re g ul ati o ns, I C H E 6 ( R 1), a n d pri nci ples of t he 
Declarati o n of Helsi n ki.  A n i nf or me d c o ns e nt te m plate ma y be pr o vi de d b y t he S p o ns or or 
desi g nee t o t he i n vesti gat ors.  T he c o nse nt m ust be re vie we d b y t h e S p o ns or or desi g n ee b ef ore 
I R B/ E C s u b missi o n.  O nce re vi e we d, t he c o nse nt will be s u b mitte d b y t h e pri nci pal i n vesti gat or 
t o his or her I R B/ E C f or re vie w a n d a p pr o v al bef ore t he start of t h e st u d y.  If t he i nf or me d 
c o nse nt f or m is re vise d d uri n g t he c o urse of t he st u d y, all partici pa nts affecte d b y t he re visi o n 
m ust si g n t he re vise d I R B/ E C-a p pr o ve d c o nse nt f or m. 


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Bef ore e nr oll me nt, eac h pr os pecti ve patie nt will b e gi v e n a f ull e x pla nati o n of t he st u d y a n d be 
all o we d t o rea d t h e a p pr o ve d i nf or me d c o ns e nt f or m.  O nce t he pri nci p al i n vesti gat or or desi g nee 
is ass ure d t hat t he patie nt u n dersta n ds t he i m plicati o ns of partici pati n g i n t h e st u d y, t he patie nt 
will be as ke d t o gi v e c o nse nt t o partici pate i n t he st u d y b y si g ni n g t he i nf or me d c o nse nt f or m.  
Eli gi ble patie nts ma y o nl y be i n cl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n), I R B/ E C-a p pr o ve d i nf or me d c o ns e nt.  I nf or m e d c o nse nt m ust be 
o btai ne d bef ore c o n d u cti n g a n y st u d y-s p ecific pr oce d ures ( i.e., all of t he pr oce d ures d escri b e d i n 
t he prot oc ol).  T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust be d oc u me nte d i n t he patie nt 
s o urce d oc u m e nts. 
A n y c ha n ges t o t he pr o p ose d c o nse nt f or m s u g geste d b y t he i n vesti gat or m ust be a gree d t o b y 
t he S p o ns or bef ore s u b missi o n t o t he I R B/ E C, a n d a c o p y of t he a p pr o ve d versi o n a n d t he n otice 
of a p pr o val m ust be pr o vi de d t o t he S p o ns or’s desi g nate d m o nit or after I R B/ E C a p pr o val. 
T he pri nci pal i n vesti ga t or or desi g nee will pr o vi de a c o p y of t h e i nf or me d c o nse nt f or m (si g ne d 
c o p y t o b e pr o v i de d per a p plica ble la w) t o t he p atie nt a n d/ or le gal g uar dia n.  T he ori gi nal f or m 
will be mai ntai ne d i n t he pa tie nt’s me dical r ec or ds at t he site. 
1 5. 4.  
C o nfi de nti alit y 
All la b orat or y s peci me ns, e val uati o n f or ms, r e p orts, a n d ot her rec or ds will be i de ntifie d i n a 
ma n ner desi g ne d t o mai ntai n patie nt c o nfi de ntialit y.  All rec or ds will be ke pt i n a sec ure st or a ge 
area wit h l i mite d access.  Cli nical i nf or mati o n will n ot be releas e d wit h o ut t he writte n 
per missi o n of t he patie nt ( or t he patie nt’s g u ar dia n), e x ce pt as necessar y f or m o nit ori n g a n d 
a u diti n g b y t he S p o ns or, its desi g nee, t h e F D A or a p plica ble re g ulat or y a ut h orities, or t he 
I R B/ E C. 
T he pri nci pal i n vesti gat o r a n d all e m pl o yees a n d c o w or kers i n v ol ve d wit h t his st u d y m a y n ot 
discl ose or use f or a n y p ur p ose ot her t ha n perf or ma nce of t he st u d y, a n y data, rec or d, or ot her 
u n p u blis he d c o nfi de ntial i nf or mati o n discl ose d t o t he m f or t he p ur p ose of t he st u d y.  Pri or 
writte n a gre e me nt fr o m t he S p o ns or or desi g nee m ust be o btai ne d f or t he discl os ure of a n y s ai d 
c o nfi de ntial i nf or mati o n t o ot her parties. 
1 5. 5.  
M o dific ati o n of t he Pr ot oc ol 
A n y c ha n ges t h at arise after t he a p pr o val of t he pr ot oc ol m ust be d oc u me nte d as pr ot oc ol 
a me n d me nts.  T he F D A or ot her a p plica ble re g ul at or y a ge n cies m ust be n otifie d of pr ot oc ol 
a me n d me nts.  T he c h a n ges will bec o me effecti ve o nl y aft er a p pr o val of t he S p o ns or, t he 
i n vesti gat or, t he IR B/ E C, a n d w here necessar y, t h e a p plica ble re g ulat or y a ge n c y.  I n cases w he n 
t he prot oc ol is m o difie d t o e n ha nce patie nt safet y, c ha n ges ma y b e i m ple me nte d a n d t he 
a me n d me nt m ust be i m me diatel y s u b mitte d t o t he I R B/ E C. 
T he i n vesti gat or is res p o nsi ble f or i nf or mi n g t h e I R B/ E C of all pr o ble ms i n v ol vi n g ris ks t o 
pa tie nts acc or di n g t o n ati o nal le gislati o n.  I n case of ur ge nt safet y meas ures, t he S p o ns or will 
i m me diatel y n otif y t he i n vesti gat ors a n d rel e va nt r e g ul at or y a ge n cies, i ncl u di n g F D A i n acc or d 
wit h 2 1 C F R 3 1 2. 3 2. 


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1 5. 6.  
Pr ot oc ol De vi ati o ns 
T he pri nci pal i n vesti gat or or desi g nee m ust d oc u me nt a n y pr ot oc ol de viati o n.  T he I R B/ E C m ust 
be n otifie d of all pr ot oc ol de viati o ns i n a ti mel y m a n ner b y t he pri nci pal i n vesti gat or or desi g nee 
as a p pr o priat e.  Pr ot oc ol de viati o ns will be d oc u me nte d b y t he res p o nsi ble m o nit or d uri n g 
m o nit ori n g visits, a n d t h ose o bser vati o ns will be c o m m u nicate d t o t he i n vesti gat or. 
If t here is an i m me diate hazar d t o a patie nt t he pri nci pal i n vesti gat or ma y d e viate fr o m t he 
pr ot oc ol wit h o ut pri or S p o ns or a n d I R B/ E C a p pr o val.  T he S p o ns or a n d I R B/ E C m ust be 
n otifie d of t he de viati o n. 


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1 6.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G 
1 6. 1.  
Rete nti o n of Rec or ds 
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H- G C P a n d a p plica ble re g ulat or y 
req uire me nt(s).  R ec or ds will be retai ne d f or at least 2 years aft er t he last m ar keti n g a p plicati o n 
s u b missi o n or 2 years aft er f or mal disc o nti n uati o n of t he cli nical de vel o p me nt of t he 
i n vesti gati o nal pr o d u ct.  If t he i n vesti gat or wit h dr a ws fr o m t he res p o nsi bilit y of kee pi n g t he 
st u d y recor ds, c ust o d y m ust be tra nsferre d t o a pers o n willi n g t o acce pt t he res p o nsi bilit y.  T he 
S p o ns or m ust be n otifie d i n wr iti n g if a c ust o dial c ha n ge o cc urs.  
1 6. 2.  
C ase Re p ort F or ms 
All case re p ort f or m dat a will be e ntere d i n pa p er or electr o ni c f or ms at t he i n vesti gati o nal site.  
A 2 1 C F R Part 1 1 c o m plia nt Electr o nic Dat a Ca pt ure s yste m will be use d t o ca pt ure d ata 
electr o nicall y f or all e nr olle d patie nts. 


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1 7.  
P U B LI C A TI O N P O LI C Y 
T he S p o ns or s u p p orts c o m m u nicati o n a n d p u blicati o n of st u d y res ults w hat e ver t he fi n di n gs of 
t he st u d y.   
T he S p o ns or reser ves t he ri g ht t o re vi e w all pla n ne d c o m m u nicati o ns a n d ma n uscri pts base d o n 
t he res ults of t his st u d y.  T his reser vati o n of t h e ri g ht is n ot i nte n de d t o restrict or hi n der 
p u blicati o n or a n y ot her disse mi nati o n of st u d y res ults, b ut t o all o w t he S p o ns or t o c o nfir m t he 
acc urac y of t he data, t o pr otect pr o priet ar y i nf or m ati o n, a n d t o pr o vi de c o m me nts base d o n 
i nf or mati o n t hat ma y n ot yet b e a vaila ble t o t he st u d y i n vesti gat ors.  T h e S p o ns or als o 
e nc o ura ges discl os ure of a n y c o nflict of i nterest fr o m all a ut h ors or i n vesti gat ors w he n 
ma n uscri pts are s u b mitte d f or p u blicati o n.  T h ose i n di vi d uals, w h o ha ve c o ntri b ute d greatl y t o 
t his st u d y, i ncl u di n g le a d e xter nal a d vis ors a n d sel ect pri nci pal i n vesti gat ors, ma y ser ve o n a n y 
p ote ntial p u blicati o ns c o m mittee f or t he st u d y. 


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1 8.  
R E F E R E N C E S 
A T S C o m mittee o n Pr oficie nc y Sta n dar ds f or Cli nical P ul m o nar y F u ncti o n La b orat ories. A T S 
State me nt: G ui deli nes f or t he si x- mi n ute wal k test.  A m J Res pir Crit Care Me d. 
2 0 0 2; 1 6 6( 1): 1 1 1- 7. 
Batt J, A h me d S S, C orrea J, et al. S keletal m uscle d ysf u ncti o n i n i di o pat hic p ul m o nar y art erial 
h y perte nsi o n. A m J  Res pir Cell M ol Bi ol. 2 0 1 4; 5 0( 1): 7 4- 8 6. 
C h u n g L, D o msi c R T, Li n gal a B, et al.  S ur vi val a n d pre dict ors of m ortalit y i n s yste mic 
scler osis-ass oci ate d p ul m o nar y art erial h y perte nsi o n: o utc o mes fr o m t he p ul m o nar y h y p erte nsi o n 
assess me nt a n d rec o g niti o n of o utc o mes i n scler o der ma re gistr y. Art hritis Care Res ( H o b o k e n). 
2 0 1 4; 6 6( 3): 4 8 9- 9 5. 
Di n k o va- K ost o va A T, L i b y K T, Ste p he ns o n K K, et al. E xtre mel y p ote nt triter pe n oi d i n d ucers of 
t he p hase 2 res p o nse: c orrelati o ns of pr otecti o n a gai nst o xi da nt a n d i nfla m mat or y str ess.  
Pr oc Natl Aca d Sci U S A. 2 0 0 5; 1 0 2( 1 2): 4 5 8 4- 9. 
E ba  S, H os hi ka wa Y, M ori g uc hi T, et al. T he n u clear fact or er yt hr oi d 2-rel ate d fact or 2 acti vat or 
olti praz  atten uates c hr o ni c h y p o xia-i n d uce d car di o p ul m o nar y alterati o ns i n mice. A m J Res p ir 
Cell M ol Bi ol. 2 0 1 3; 4 9( 2): 3 2 4- 3 3. 
Galiè N, H oe p er M M, H u m bert M, et al. G ui deli n es f or t he dia g n osis a n d treat me nt of 
p ul m o nar y  h y p erte nsi o n: t he Tas k F orce f or t he Dia g n osis a n d Treat me nt of P ul m o nar y 
H y p erte nsi o n of t he E ur o pea n S ociet y of Car di ol o g y ( E S C) a n d t h e E ur o pea n Res pirat or y 
S ociet y ( E R S), e n d orse d b y t he I nt er nati o nal S oci et y of Heart a n d L u n g Tra ns pla ntati o n 
(I S H L T). E ur Heart J. 2 0 0 9; 3 0: 2 4 9 3- 5 3 7. 
G h ofra ni H A, Ga liè N, Gri m mi n ger F, et al. Ri oci g uat f or t he treat me nt of p ul m o nar y arteri al 
h y perte nsi o n . N E n gl J Me d. 2 0 1 3; 3 6 9( 4): 3 3 0- 4 0. 
H ol mstr ö m K M, Bair d L, Z ha n g Y, et al. Nrf 2 i m pacts cell ular bi oe ner getics b y c o ntr olli n g 
s u bstrate a vailabilit y f or mit oc h o n drial res pirati o n. Bi ol O pe n. 2 0 1 3; 0: 1- 1 0. 
Lee D F, K u o H P, Li u M, et al. K E A P 1 E 3 li gase- me diate d d o w nre g ul ati o n of N F- k B si g nali n g 
b y tar geti n g  I K K b eta. M ol Cell. 2 0 0 9; 3 6( 1): 1 3 1- 4 0. 
L u dt ma n n M H, A n ge l o v a P R, Z ha n g Y, et al. Nrf 2 i m pacts t he effici e nc y of mit oc h o n drial fatt y 
aci d o xi dati o n. Bi oc he m J. 2 0 1 4; 4 5 7( 3): 4 1 5- 2 4. 
Ma i n g u y V, M altais F, S ae y D, et al. Peri p heral m uscle d ysf u ncti o n i n i di o pat hic p ul m o nar y 
h y perte nsi o n. T h ora x. 2 0 1 0; 6 5( 2): 1 1 3- 7. 
Male nfa nt S, P ot us F, F o ur nier F, et al. S keletal m uscle pr ote o mic si g nat ur e a n d m eta b olic 
i m pair me nt i n p ul m o nar y h y perte nsi o n. J M ol Me d ( Berl). 2 0 1 5; 9 3( 5): 5 7 3- 8 4. 
Os b ur n W Oa n d, Ke nsler T W. Nrf 2 si g nali n g: A n a da pti ve res p o ns e pat h w a y f or pr otecti o n 
a gai nst e n vir o n me ntal t o xic i ns ults. M utat Res. 2 0 0 8; 6 5 9( 1- 2): 3 1- 9. 
Price L, Cara m ori G, D orf m uller P, et al.  E n d ot helial cell N F- k B acti vati o n is i ncrease d i n 
h u ma n i di o pat hic P A H. T h ora x. 2 0 1 0; 6 5( 4): A 8 8 - A 8 9. 


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P u g h M E; R o b bi ns, I M; Rice T W, et al. U nrec o g nize d gl uc ose i nt olera nce is c o m m o n i n 
p ul m o nar y a rteri al h y p ert e nsi o n. J Heart L u n g Tra ns pla nt. 2 0 1 1; 3 0( 8): 9 0 4- 1 1. 
R ojas- Ri vera J, Ortiz A, E gi d o J. A nti o xi da nts i n ki d ne y dise ases: T he i m p act of bar d o x ol o ne 
met h yl. I nt J Ne p hr ol. 2 0 1 2; 2 0 1 2: 1- 1 1. 
Sa ha P K, Re d d y  V T, K o n o ple va M, et al. T he trit er pe n oi d 2-c ya n o- 3, 1 2- di o x o olea na- 1, 9- die n-
2 8- o ic-aci d met h yl ester has p ote nt a nti dia betic effects i n diet-i n d uce d di a b etic mice a n d 
Le pr( d b/ d b) mice. J Bi ol C he m. 2 0 1 0; 2 8 5( 5 2): 4 0 5 8 1- 9 2. 
S ute n dra G, Mic hela kis E D. T he meta b olic b asis of p ul m o nar y arterial h y perte nsi o n. Cell Meta b. 
2 0 1 4; 1 9( 4): 5 5 8- 7 3. 
Ta ps o n V F, Ji n g Z C, X u K F, et al. Oral tre pr osti nil f or t he treat me nt of p ul m o nar y arterial 
h y perte nsi o n i n patie nts r ecei vi n g bac k gr o u n d e n d ot heli n rece pt or a nta g o nist a n d 
p h os p h o diesterase t y pe 5 i n hi bit or t hera p y (t he F R E E D O M- C 2 st u d y): a ra n d o mize d c o ntr olle d 
trial. C hest. 2 0 1 3; 1 4 4( 3): 9 5 2- 8. 
W u Q Q, Wa n g Y, Se nit k o M, et al. Bar d o x ol o ne met h yl ( B A R D) a meli orates isc he mic A KI a n d 
i ncreas es ex pressi o n of pr otecti ve ge n es Nrf 2, P P A R , a n d H O- 1. A m J P h ysi ol Re nal P h ysi ol. 
2 0 1 1; 3 0 0( 5): F 1 1 8 0- F 1 1 9 2. 
 


Pr ot oc ol 4 0 2- C- 1 6 0 2 
Reata P har mace uticals, I nc. 
C o nfi de ntial 
Versi o n 3. 0 
5 5   
1 9.  
A P P E N DI X 1: A T S G UI D E LI N E S F O R T H E SI X- MI N U T E W A L K 
T E S T  


A m eric a n T h or acic S oci et y
 
A m J R es pir Crit C ar e M e d 
V ol 1 6 6. p p 1 1 1 – 1 1 7, 2 0 0 2
D OI: 1 0. 1 1 6 4 /r c c m. 1 6 6 / 1 / 1 1 1
I nt er n et a d dr ess: w w w. atsj o ur n als. or g
 
A T S S t a t e m e n t: G ui d eli n e s f o r t h e Si x- Mi n u t e W al k T e s t
 
T
 
HI S
 
 O
 
F FI CI A L
 
 S
 
T A T E M E N T
 
 
 
O F
 
 
 
T H E
 
 A
 
M E RI C A N
 
 T
 
H O R A CI C
 
 S
 
O CI E T Y
 
 
 
W A S
 
 
 
A P P R O V E D
 
 
 
B Y
 
 
 
T H E
 
 A T S B
 
O A R D
 
 
 
O F
 
 D
 
I R E C T O R S
 
M
 
A R C H
 
 2 0 0 2
 
C O N T E N T S
 
P ur p os e a n d Sc o p e
B ac k gr o u n d
I n dic ati o ns a n d Li mit ati o ns
C o ntr ai n dic ati o ns
S af et y Iss u es
T ec h nic al As p ects of t h e 6
 
-
 
Mi n ut e W al k T est
R e q uir e d E q ui p m e nt
P ati e nt Pr e p ar ati o n
M e as ur e m e nts
Q u alit y Ass ur a nc e
I nt er pr et ati o n
R ef er e nc es
 
P U R P O S E A N D S C O P E
 
T his st at e m e nt pr o vi d es pr actic al g ui d eli n es f or t h e 6- mi n ut e
w al k t est ( 6 M W T). S p ecific all y, it r e vi e ws i n dic ati o ns, d et ails
f act ors t h at i nfl u e nc e r es ults, pr es e nts a bri ef st e p- b y-st e p pr o-
t oc ol, o utli n es s af et y m e as ur es, d escri b es pr o p er p ati e nt pr e p-
ar ati o n a n d pr oc e d ur es, a n d off ers g ui d eli n es f or cli nic al i nt er-
pr et ati o n of r es ults. T h es e r ec o m m e n d ati o ns ar e n ot i nt e n d e d
t o li mit t h e us e of alt er n ati v e pr ot oc ols f or r es e arc h st u di es.
W e d o n ot disc uss t h e g e n er al t o pic of cli nic al e x ercis e t esti n g.
As wit h ot h er A m eric a n T h or acic S oci et y st at e m e nts o n
p ul m o n ar y f u ncti o n t esti n g, t h es e g ui d eli n es c o m e o ut of a
c o ns e ns us c o nf er e nc e. Dr afts w er e pr e p ar e d b y t w o m e m b ers
( P. L. E. a n d R.J. Z.) a n d w er e b as e d o n a c o m pr e h e nsi v e M e d-
li n e lit er at ur e s e arc h fr o m 1 9 7 0 t hr o u g h 2 0 0 1, a u g m e nt e d b y
s u g g esti o ns fr o m ot h er c o m mitt e e m e m b ers. E ac h dr aft r e-
s p o n d e d t o c o m m e nts fr o m t h e w or ki n g c o m mitt e e. T h e g ui d e-
li n es f oll o w pr e vi o usl y p u blis h e d m et h o ds as cl os el y as p ossi-
bl e a n d pr o vi d e a r ati o n al e f or e ac h s p ecific r ec o m m e n d ati o n.
T h e fi n al r ec o m m e n d ati o ns r e pr es e nt a c o ns e ns us of t h e c o m-
mitt e e. T h e c o m mitt e e r ec o m m e n ds t h at t h es e g ui d eli n es b e
r e vi e w e d i n fi v e y e ars a n d i n t h e m e a nti m e e nc o ur a g es f urt h er
r es e arc h i n ar e as of c o ntr o v ers y.
 
B A C K G R O U N D
 
T h er e ar e s e v er al m o d aliti es a v ail a bl e f or t h e o bj ecti v e e v al u-
ati o n  of  f u ncti o n al  e x ercis e  c a p acit y.  S o m e  pr o vi d e  a  v er y
c o m pl et e ass ess m e nt of all s yst e ms i n v ol v e d i n e x ercis e p er-
f or m a nc e ( hi g h t ec h), w h er e as ot h ers pr o vi d e b asic i nf or m a-
ti o n b ut ar e l o w t ec h a n d ar e si m pl er t o p erf or m. T h e m o d alit y
us e d s h o ul d b e c h os e n b as e d o n t h e cli nic al q u esti o n t o b e a d-
dr ess e d a n d o n a v ail a bl e r es o urc es. T h e m ost p o p ul ar cli nic al
e x ercis e t ests i n or d er of i ncr e asi n g c o m pl e xit y ar e st air cli m b-
i n g, a 6 M W T, a s h uttl e- w al k t est, d et ecti o n of e x ercis e-i n d uc e d
ast h m a, a c ar di ac str ess t est ( e. g., Br uc e pr ot oc ol), a n d a c ar di o-
p ul m o n ar y e x ercis e t est ( 1, 2). Ot h er pr of essi o n al or g a niz a-
ti o ns h a v e p u blis h e d st a n d ar ds f or c ar di ac str ess t esti n g ( 3, 4).
Ass ess m e nt  of  f u ncti o n al  c a p acit y  h as  tr a diti o n all y  b e e n
d o n e  b y  m er el y  as ki n g  p ati e nts  t h e  f oll o wi n g:  “ H o w  m a n y
fli g hts of st airs c a n y o u cli m b or h o w m a n y bl oc ks c a n y o u
w al k ? ” H o w e v er, p ati e nts v ar y i n t h eir r ec oll ecti o n a n d m a y
r e p ort o v er esti m ati o ns or u n d er esti m ati o ns of t h eir tr u e f u nc-
ti o n al  c a p acit y.  O bj ecti v e  m e as ur e m e nts  ar e  us u all y  b ett er
t h a n s elf-r e p orts. I n t h e e arl y 1 9 6 0s, B al k e d e v el o p e d a si m pl e
t est t o e v al u at e t h e f u ncti o n al c a p acit y b y m e as uri n g t h e dis-
t a nc e w al k e d d uri n g a d efi n e d p eri o d of ti m e ( 5). A 1 2- mi n ut e
fi el d  p erf or m a nc e  t est  w as  t h e n  d e v el o p e d  t o  e v al u at e  t h e
l e v el of p h ysic al fit n ess of h e alt h y i n di vi d u als ( 6). T h e w al ki n g
t est  w as  als o  a d a pt e d  t o  ass ess  dis a bilit y  i n  p ati e nts  wit h
c hr o nic br o nc hitis ( 7). I n a n att e m pt t o acc o m m o d at e p ati e nts
wit h r es pir at or y dis e as e f or w h o m w al ki n g 1 2 mi n ut es w as t o o
e x h a usti n g, a 6- mi n ut e w al k w as f o u n d t o p erf or m as w ell as
t h e 1 2- mi n ut e w al k ( 8). A r ec e nt r e vi e w of f u ncti o n al w al ki n g
t ests c o ncl u d e d t h at “t h e 6 M W T is e as y t o a d mi nist er, b ett er
t ol er at e d, a n d m or e r efl ecti v e of acti viti es of d ail y li vi n g t h a n
t h e ot h er w al k t ests ” ( 9).
T h e 6 M W T is a pr actic al si m pl e t est t h at r e q uir es a 1 0 0-ft
h all w a y  b ut  n o  e x ercis e  e q ui p m e nt  or  a d v a nc e d  tr ai ni n g  f or
t ec h nici a ns. W al ki n g is a n acti vit y p erf or m e d d ail y b y all b ut
t h e m ost s e v er el y i m p air e d p ati e nts. T his t est m e as ur es t h e dis-
t a nc e t h at a p ati e nt c a n q uic kl y w al k o n a fl at, h ar d s urf ac e i n a
p eri o d of 6 mi n ut es (t h e 6 M W D). It e v al u at es t h e gl o b al a n d i n-
t e gr at e d r es p o ns es of all t h e s yst e ms i n v ol v e d d uri n g e x ercis e,
i ncl u di n g t h e p ul m o n ar y a n d c ar di o v asc ul ar s yst e ms, s yst e mic
circ ul ati o n, p eri p h er al circ ul ati o n, bl o o d, n e ur o m usc ul ar u nits,
a n d m uscl e m et a b olis m. It d o es n ot pr o vi d e s p ecific i nf or m a-
ti o n o n t h e f u ncti o n of e ac h of t h e diff er e nt or g a ns a n d s yst e ms
i n v ol v e d i n e x ercis e or t h e m ec h a nis m of e x ercis e li mit ati o n, as
is p ossi bl e wit h m a xi m al c ar di o p ul m o n ar y e x ercis e t esti n g. T h e
s elf- p ac e d 6 M W T ass ess es t h e s u b m a xi m al l e v el of f u ncti o n al
c a p acit y. M ost p ati e nts d o n ot ac hi e v e m a xi m al e x ercis e c a p ac-
it y d uri n g t h e 6 M W T; i nst e a d, t h e y c h o os e t h eir o w n i nt e nsit y
of e x ercis e a n d ar e all o w e d t o st o p a n d r est d uri n g t h e t est.
H o w e v er, b ec a us e m ost acti viti es of d ail y li vi n g ar e p erf or m e d
at s u b m a xi m al l e v els of e x erti o n, t h e 6 M W D m a y b ett er r efl ect
t h e f u ncti o n al e x ercis e l e v el f or d ail y p h ysic al acti viti es.
 
I N DI C A TI O N S A N D LI MI T A TI O N S
 
T h e str o n g est i n dic ati o n f or t h e 6 M W T is f or m e as uri n g t h e r e-
s p o ns e t o m e dic al i nt er v e nti o ns i n p ati e nts wit h m o d er at e t o
s e v er e h e art or l u n g dis e as e. T h e 6 M W T h as als o b e e n us e d as
a o n e-ti m e m e as ur e of f u ncti o n al st at us of p ati e nts, as w ell as a
pr e dict or of m or bi dit y a n d m ort alit y (
 
see
 
 T a bl e 1 f or a list of
t h es e i n dic ati o ns). T h e f act t h at i n v esti g at ors h a v e us e d t h e
6 M W T i n t h es e s etti n gs d o es n ot pr o v e t h at t h e t est is cli nic all y
us ef ul ( or t h e b est t est) f or d et er mi ni n g f u ncti o n al c a p acit y or
c h a n g es i n f u ncti o n al c a p acit y d u e t o a n i nt er v e nti o n i n p a-
ti e nts wit h t h es e dis e as es. F urt h er st u di es ar e n ec ess ar y t o d e-
t er mi n e t h e utilit y of t h e 6 M W T i n v ari o us cli nic al sit u ati o ns.
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
5 6


 
1 1 2
 
A M E RI C A N J O U R N A L O F R E S PI R A T O R Y A N D C RI TI C A L C A R E M E DI CI N E 
V O L 1 6 6 
2 0 0 2
 
F or m al c ar di o p ul m o n ar y e x ercis e t esti n g pr o vi d es a gl o b al
ass ess m e nt of t h e e x ercis e r es p o ns e, a n o bj ecti v e d et er mi n a-
ti o n of f u ncti o n al c a p acit y a n d i m p air m e nt, d et er mi n ati o n of
t h e a p pr o pri at e i nt e nsit y n e e d e d t o p erf or m pr ol o n g e d e x er-
cis e, q u a ntific ati o n of f act ors li miti n g e x ercis e, a n d a d efi ni-
ti o n of t h e u n d erl yi n g p at h o p h ysi ol o gic m ec h a nis ms s uc h as
t h e c o ntri b uti o n of diff er e nt or g a n s yst e ms i n v ol v e d i n e x er-
cis e. T h e 6 M W T d o es n ot d et er mi n e p e a k o x y g e n u pt a k e, di-
a g n os e  t h e  c a us e  of  d ys p n e a  o n  e x erti o n,  or  e v al u at e  t h e
c a us es or m ec h a nis ms of e x ercis e li mit ati o n ( 1, 2). T h e i nf or-
m ati o n pr o vi d e d b y a 6 M W T s h o ul d b e c o nsi d er e d c o m pl e-
m e nt ar y t o c ar di o p ul m o n ar y e x ercis e t esti n g, n ot a r e pl ac e-
m e nt f or it. D es pit e t h e diff er e nc e b et w e e n t h es e t w o f u ncti o n al
t ests,  s o m e  g o o d  c orr el ati o ns  b et w e e n  t h e m  h a v e  b e e n  r e-
p ort e d. F or e x a m pl e, a si g nific a nt c orr el ati o n (r 
  
 0. 7 3) b e-
t w e e n 6 M W D a n d p e a k o x y g e n u pt a k e h as b e e n r e p ort e d f or
p ati e nts wit h e n d-st a g e l u n g dis e as es ( 3 6, 3 7).
I n s o m e cli nic al sit u ati o ns, t h e 6 M W T pr o vi d es i nf or m a-
ti o n t h at m a y b e a b ett er i n d e x of t h e p ati e nt’s a bilit y t o p er-
f or m d ail y acti viti es t h a n is p e a k o x y g e n u pt a k e; f or e x a m pl e,
6 M W D c orr el at es b ett er wit h f or m al m e as ur es of q u alit y of
lif e ( 3 8). C h a n g es i n 6 M W D aft er t h er a p e utic i nt er v e nti o ns
c orr el at e  wit h  s u bj ecti v e  i m pr o v e m e nt  i n  d ys p n e a  ( 3 9,  4 0).
T h e r e pr o d uci bilit y of t h e 6 M W D ( wit h a c o effici e nt of v ari a-
ti o n of a p pr o xi m at el y 8 %) a p p e ars t o b e b ett er t h a n t h e r e-
pr o d uci bilit y of 1-s ec o n d f orc e d e x pir at or y v ol u m e i n p ati e nts
wit h c hr o nic o bstr ucti v e p ul m o n ar y dis e as e ( C O P D) ( 8, 4 1 –
4 3). Q u esti o n n air e i n dic es of f u ncti o n al st at us h a v e a l ar g er
s h ort-t er m v ari a bilit y ( 2 2 – 3 3 %) t h a n d o es t h e 6 M W D ( 3 7).
T h e s h uttl e- w al ki n g t est is si mil ar t o t h e 6 M W T, b ut it us es
a n a u di o si g n al fr o m a t a p e c ass ett e t o dir ect t h e w al ki n g p ac e
of t h e p ati e nt b ac k a n d f ort h o n a 1 0- m c o urs e ( 4 4 – 4 7). T h e
w al ki n g s p e e d is i ncr e as e d e v er y mi n ut e, a n d t h e t est e n ds w h e n
t h e p ati e nt c a n n ot r e ac h t h e t ur n ar o u n d p oi nt wit hi n t h e r e-
q uir e d ti m e. T h e e x ercis e p erf or m e d is si mil ar t o a s y m pt o m-
li mit e d, m a xi m al, i ncr e m e nt al tr e a d mill t est. A n a d v a nt a g e of
t h e s h uttl e w al ki n g t est is t h at it h as a b ett er c orr el ati o n wit h
p e a k o x y g e n u pt a k e t h a n t h e 6 M W D. Dis a d v a nt a g es i ncl u d e
l ess v ali d ati o n, l ess wi d es pr e a d us e, a n d m or e p ot e nti al f or
c ar di o v asc ul ar pr o bl e ms.
 
C O N T R AI N DI C A TI O N S
 
A bs ol ut e c o ntr ai n dic ati o ns f or t h e 6 M W T i ncl u d e t h e f oll o w-
i n g: u nst a bl e a n gi n a d uri n g t h e pr e vi o us m o nt h a n d m y oc ar-
di al i nf arcti o n d uri n g t h e pr e vi o us m o nt h. R el ati v e c o ntr ai n di-
c ati o ns i ncl u d e a r esti n g h e art r at e of m or e t h a n 1 2 0, a s yst olic
bl o o d pr ess ur e of m or e t h a n 1 8 0 m m H g, a n d a di ast olic bl o o d
pr ess ur e of m or e t h a n 1 0 0 m m H g.
P ati e nts wit h a n y of t h es e fi n di n gs s h o ul d b e r ef err e d t o t h e
p h ysici a n or d eri n g or s u p er visi n g t h e t est f or i n di vi d u al cli ni-
c al ass ess m e nt a n d a d ecisi o n a b o ut t h e c o n d uct of t h e t est.
T h e r es ults fr o m a r esti n g el ectr oc ar di o gr a m d o n e d uri n g t h e
pr e vi o us 6 m o nt hs s h o ul d als o b e r e vi e w e d b ef or e t esti n g. St a-
bl e e x erti o n al a n gi n a is n ot a n a bs ol ut e c o ntr ai n dic ati o n f or a
6 M W T, b ut p ati e nts wit h t h es e s y m pt o ms s h o ul d p erf or m t h e
t est aft er usi n g t h eir a nti a n gi n a m e dic ati o n, a n d r esc u e nitr at e
m e dic ati o n s h o ul d b e r e a dil y a v ail a bl e.
 
R ati o n al e
 
P ati e nts wit h t h e pr e vi o usl y m e nti o n e d ris k f act ors m a y b e at
i ncr e as e d ris k f or arr h yt h mi as or c ar di o v asc ul ar c oll a ps e d uri n g
t esti n g. H o w e v er, e ac h p ati e nt d et er mi n es t h e i nt e nsit y of t h eir
e x ercis e, a n d t h e t est ( wit h o ut el ectr oc ar di o gr a m m o nit ori n g)
h as b e e n p erf or m e d i n t h o us a n ds of ol d er p ers o ns ( 3 1, 4 8 – 5 0)
a n d t h o us a n ds of p ati e nts wit h h e art f ail ur e or c ar di o m y o p at h y
( 3 2, 5 1, 5 2) wit h o ut s eri o us a d v ers e e v e nts. T h e c o ntr ai n dic a-
ti o ns list e d pr e vi o usl y h er e w er e us e d b y st u d y i n v esti g at ors
b as e d o n t h eir i m pr essi o ns of t h e g e n er al s af et y of t h e 6 M W T
a n d t h eir d esir e t o b e pr u d e nt, b ut it is u n k n o w n w h et h er a d-
v ers e e v e nts w o ul d occ ur if s uc h p ati e nts p erf or m e d a 6 M W T;
t h e y ar e, t h er ef or e, list e d as r el ati v e c o ntr ai n dic ati o ns.
 
S A F E T Y I S S U E S
 
1. T esti n g s h o ul d b e p erf or m e d i n a l oc ati o n w h er e a r a pi d,
a p pr o pri at e r es p o ns e t o a n e m er g e nc y is p ossi bl e. T h e a p-
pr o pri at e l oc ati o n of a cr as h c art s h o ul d b e d et er mi n e d b y
t h e p h ysici a n s u p er visi n g t h e f acilit y.
2. S u p pli es t h at m ust b e a v ail a bl e i ncl u d e o x y g e n, s u bli n g u al
nitr o gl yc eri n e, as piri n, a n d al b ut er ol ( m et er e d d os e i n h al er
or n e b uliz er). A t el e p h o n e or ot h er m e a ns s h o ul d b e i n
pl ac e t o e n a bl e a c all f or h el p.
3. T h e t ec h nici a n s h o ul d b e c ertifi e d i n c ar di o p ul m o n ar y r e-
s uscit ati o n wit h a mi ni m u m of B asic Lif e S u p p ort b y a n
A m eric a n H e alt h Ass oci ati o n – a p pr o v e d c ar di o p ul m o n ar y
r es uscit ati o n c o urs e. A d v a nc e d c ar di ac lif e s u p p ort c ertifi-
c ati o n is d esir a bl e. Tr ai ni n g, e x p eri e nc e, a n d c ertific ati o n
i n r el at e d h e alt h c ar e fi el ds (r e gist er e d n urs e, r e gist er e d r e-
s pir at or y  t h er a pist,  c ertifi e d  p ul m o n ar y  f u ncti o n  t ec h ni-
ci a n, etc.) ar e als o d esir a bl e. A c ertifi e d i n di vi d u al s h o ul d
b e r e a dil y a v ail a bl e t o r es p o n d if n e e d e d.
4. P h ysici a ns ar e n ot r e q uir e d t o b e pr es e nt d uri n g all t ests.
T h e p h ysici a n or d eri n g t h e t est or a s u p er visi n g l a b or at or y
p h ysici a n  m a y  d eci d e  w h et h er  p h ysici a n  att e n d a nc e  at  a
s p ecific t est is r e q uir e d.
5. If a p ati e nt is o n c hr o nic o x y g e n t h er a p y, o x y g e n s h o ul d b e
gi v e n at t h eir st a n d ar d r at e or as dir ect e d b y a p h ysici a n or
a pr ot oc ol.
R e as o ns f or i m m e di at el y st o p pi n g a 6 M W T i ncl u d e t h e f oll o w-
i n g: (
 
1
 
) c h est p ai n, (
 
2
 
) i nt ol er a bl e d ys p n e a, (
 
3
 
) l e g cr a m ps, (
 
4
 
)
st a g g eri n g, (
 
5
 
) di a p h or esis, a n d (
 
6
 
) p al e or as h e n a p p e ar a nc e.
T ec h nici a ns m ust b e tr ai n e d t o r ec o g niz e t h es e pr o bl e ms
a n d t h e a p pr o pri at e r es p o ns es. If a t est is st o p p e d f or a n y of
t h es e r e as o ns, t h e p ati e nt s h o ul d sit or li e s u pi n e as a p pr o pri-
at e d e p e n di n g o n t h e s e v erit y or t h e e v e nt a n d t h e t ec h nici a n’s
ass ess m e nt of t h e s e v erit y of t h e e v e nt a n d t h e ris k of s y nc o p e.
T h e f oll o wi n g s h o ul d b e o bt ai n e d b as e d o n t h e j u d g m e nt of
t h e t ec h nici a n: bl o o d pr ess ur e, p uls e r at e, o x y g e n s at ur ati o n,
a n d a p h ysici a n e v al u ati o n. O x y g e n s h o ul d b e a d mi nist er e d as
a p pr o pri at e.
 
T A B L E 1. I N DI C A TI O N S F O R T H E SI X- MI N U T E  W A L K T E S T
 
Pr etr e at m e nt a n d p osttr e at m e nt c o m p aris o ns
L u n g tr a ns pl a nt ati o n ( 9, 1 0)
L u n g r es e cti o n ( 1 1)
L u n g v ol u m e r e d u cti o n s ur g er y ( 1 2, 1 3)
P ul m o n ar y r e h a bilit ati o n ( 1 4, 1 5)
C O P D ( 1 6 – 1 8)
P ul m o n ar y h y p ert e nsi o n
H e art f ail ur e ( 1 9, 2 0)
F u n cti o n al st at us (si n gl e m e as ur e m e nt)
C O P D ( 2 1, 2 2)
C ysti c fi br osis ( 2 3, 2 4)
H e art f ail ur e ( 2 5 – 2 7)
P eri p h er al v as c ul ar dis e as e ( 2 8, 2 9)
Fi br o m y al gi a ( 3 0)
Ol d er p ati e nts ( 3 1)
Pr e di ct or of m or bi dit y a n d m ort alit y
H e art f ail ur e ( 3 2, 3 3)
C O P D ( 3 4, 3 5)
Pri m ar y p ul m o n ar y h y p ert e nsi o n ( 1 0, 3 6)
D efi niti o n of a b br e vi ati o n
 
: C O P D 
  
 c hr o ni c o bstr u cti v e p ul m o n ar y dis e as e.
Pr ot oc ol 4 0 2- C- 1 6 0 2
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C o nfi de ntial
Versi o n 3. 0
5 7


 
A m eri c a n T h or a ci c S o ci et y
1 1 3
 
T E C H NI C A L A S P E C T S O F T H E 6 M W T
 
L o c ati o n
 
T h e 6 M W T s h o ul d b e p erf or m e d i n d o ors, al o n g a l o n g, fl at,
str ai g ht, e ncl os e d c orri d or wit h a h ar d s urf ac e t h at is s el d o m
tr a v el e d. If t h e w e at h er is c o mf ort a bl e, t h e t est m a y b e p er-
f or m e d o ut d o ors. T h e w al ki n g c o urs e m ust b e 3 0 m i n l e n gt h.
A 1 0 0-ft h all w a y is, t h er ef or e, r e q uir e d. T h e l e n gt h of t h e c or-
ri d or s h o ul d b e m ar k e d e v er y 3 m. T h e t ur n ar o u n d p oi nts s h o ul d
b e m ar k e d wit h a c o n e (s uc h as a n or a n g e tr affic c o n e). A st art-
i n g li n e, w hic h m ar ks t h e b e gi n ni n g a n d e n d of e ac h 6 0- m l a p,
s h o ul d b e m ar k e d o n t h e fl o or usi n g bri g htl y c ol or e d t a p e.
 
R ati o n ale.  
 
A s h ort er c orri d or r e q uir es p ati e nts t o t a k e m or e
ti m e t o r e v ers e dir ecti o ns m or e oft e n, r e d uci n g t h e 6 M W D.
M ost st u di es h a v e us e d a 3 0- m c orri d or, b ut s o m e h a v e us e d
2 0-  or  5 0- m  c orri d ors  ( 5 2 – 5 5).  A  r ec e nt  m ultic e nt er  st u d y
f o u n d n o si g nific a nt eff ect of t h e l e n gt h of str ai g ht c o urs es
r a n gi n g fr o m 5 0 t o 1 6 4 ft, b ut p ati e nts w al k e d f art h er o n c o n-
ti n u o us ( o v al) tr ac ks ( m e a n 9 2 ft f art h er) ( 5 4).
T h e us e of a tr e a d mill t o d et er mi n e t h e 6 M W D mi g ht s a v e
s p ac e a n d all o w c o nst a nt m o nit ori n g d uri n g t h e e x ercis e, b ut
t h e us e of a tr e a d mill f or 6- mi n ut e w al k t esti n g is n ot r ec o m-
m e n d e d. P ati e nts ar e u n a bl e t o p ac e t h e ms el v es o n a tr e a d-
mill. I n o n e st u d y of p ati e nts wit h s e v er e l u n g dis e as e, t h e
m e a n dist a nc e w al k e d o n t h e tr e a d mill d uri n g 6 mi n ut es ( wit h
t h e s p e e d a dj ust e d b y t h e p ati e nts) w as s h ort er b y a m e a n of
1 4 % w h e n c o m p ar e d wit h t h e st a n d ar d 6 M W D usi n g a 1 0 0-ft
h all w a y ( 5 7). T h e r a n g e of diff er e nc es w as wi d e, wit h p ati e nts
w al ki n g b et w e e n 4 0 0 – 1, 3 0 0 ft o n t h e tr e a d mill w h o w al k e d
1, 2 0 0 ft i n t h e h all w a y. Tr e a d mill t est r es ults, t h er ef or e, ar e
n ot i nt erc h a n g e a bl e wit h c orri d or t ests.
 
R E Q UI R E D E Q UI P M E N T
 
1.  C o u nt d o w n ti m er ( or st o p w atc h)
2.  M ec h a nic al l a p c o u nt er
3. T w o s m all c o n es t o m ar k t h e t ur n ar o u n d p oi nts
4.  A c h air t h at c a n b e e asil y m o v e d al o n g t h e w al ki n g c o urs e
5.  W or ks h e ets o n a cli p b o ar d
6.  A s o urc e of o x y g e n
7. S p h y g m o m a n o m et er
8. T el e p h o n e
9.  A ut o m at e d el ectr o nic d efi brill at or
 
P A TI E N T P R E P A R A TI O N
 
1.  C o mf ort a bl e cl ot hi n g s h o ul d b e w or n.
2.  A p pr o pri at e s h o es f or w al ki n g s h o ul d b e w or n.
3. P ati e nts s h o ul d us e t h eir us u al w al ki n g ai ds d uri n g t h e t est
(c a n e, w al k er, etc.).
4. T h e p ati e nt’s us u al m e dic al r e gi m e n s h o ul d b e c o nti n u e d.
5.  A li g ht m e al is acc e pt a bl e b ef or e e arl y m or ni n g or e arl y af-
t er n o o n t ests.
6. P ati e nts s h o ul d n ot h a v e e x ercis e d vi g or o usl y wit hi n 2 h o urs
of b e gi n ni n g t h e t est.
 
M E A S U R E M E N T S
 
1.  R e p e at t esti n g s h o ul d b e p erf or m e d a b o ut t h e s a m e ti m e
of d a y t o mi ni miz e i ntr a d a y v ari a bilit y.
2.  A “ w ar m- u p ” p eri o d b ef or e t h e t est s h o ul d n ot b e p erf or m e d.
3. T h e p ati e nt s h o ul d sit at r est i n a c h air, l oc at e d n e ar t h e
st arti n g p ositi o n, f or at l e ast 1 0 mi n ut es b ef or e t h e t est
st arts. D uri n g t his ti m e, c h ec k f or c o ntr ai n dic ati o ns, m e a-
s ur e p uls e a n d bl o o d pr ess ur e, a n d m a k e s ur e t h at cl ot h-
i n g a n d s h o es ar e a p pr o pri at e. C o m p et e t h e first p orti o n
of t h e w or ks h e et (
 
see
 
 t h e A
 
P P E N DI X
 
).
4. P uls e o xi m etr y is o pti o n al. If it is p erf or m e d, m e as ur e a n d
r ec or d b as eli n e h e art r at e a n d o x y g e n s at ur ati o n ( S p O
 
2
 
)
a n d f oll o w m a n uf act ur er’s i nstr ucti o ns t o m a xi miz e t h e si g-
n al a n d t o mi ni miz e m oti o n artif act ( 5 6, 5 7). M a k e s ur e t h e
r e a di n gs ar e st a bl e b ef or e r ec or di n g. N ot e p uls e r e g ul arit y
a n d w h et h er t h e o xi m et er si g n al q u alit y is acc e pt a bl e.
 
T h e r ati o n al e f or m e as uri n g o x y g e n s at ur ati o n is t h at al-
t h o u g h t h e dist a nc e is t h e pri m ar y o utc o m e m e as ur e, i m-
pr o v e m e nt d uri n g s eri al e v al u ati o ns m a y b e m a nif est eit h er
b y a n i ncr e as e d dist a nc e or b y r e d uc e d s y m pt o ms wit h t h e
s a m e dist a nc e w al k e d ( 3 9). T h e S p O
 
2
 
 s h o ul d n ot b e us e d f or
c o nst a nt  m o nit ori n g  d uri n g  t h e  e x ercis e.  T h e  t ec h nici a n
m ust n ot w al k wit h t h e p ati e nt t o o bs er v e t h e S p O
 
2
 
. If w or n
d uri n g t h e w al k, t h e p uls e o xi m et er m ust b e li g ht w ei g ht (l ess
t h a n 2 p o u n ds), b att er y p o w er e d, a n d h el d i n pl ac e ( p er h a ps
b y a “f a n n y p ac k ”) s o t h at t h e p ati e nt d o es n ot h a v e t o h ol d
or st a biliz e it a n d s o t h at stri d e is n ot aff ect e d. M a n y p uls e
o xi m et ers h a v e c o nsi d er a bl e m oti o n artif act t h at pr e v e nts
acc ur at e r e a di n gs d uri n g t h e w al k. ( 5 7)
 
5.  H a v e t h e p ati e nt st a n d a n d r at e t h eir b as eli n e d ys p n e a
a n d o v er all f ati g u e usi n g t h e B or g sc al e (
 
see
 
 T a bl e 2 f or
t h e B or g sc al e a n d i nstr ucti o ns [ 5 8]).
6. S et t h e l a p c o u nt er t o z er o a n d t h e ti m er t o 6 mi n ut es. As-
s e m bl e all n ec ess ar y e q ui p m e nt (l a p c o u nt er, ti m er, cli p-
b o ar d, B or g Sc al e, w or ks h e et) a n d m o v e t o t h e st arti n g
p oi nt.
7. I nstr uct t h e p ati e nt as f oll o ws:
 
“ T h e o bj ect of t his t est is t o w al k as f ar as p ossi bl e f or 6
mi n ut es. Y o u will w al k b ac k a n d f ort h i n t his h all w a y. Si x
mi n ut es is a l o n g ti m e t o w al k, s o y o u will b e e x erti n g y o ur-
s elf.  Y o u  will  pr o b a bl y  g et  o ut  of  br e at h  or  b ec o m e  e x-
h a ust e d. Y o u ar e p er mitt e d t o sl o w d o w n, t o st o p, a n d t o
r est as n ec ess ar y. Y o u m a y l e a n a g ai nst t h e w all w hil e r est-
i n g, b ut r es u m e w al ki n g as s o o n as y o u ar e a bl e.
Y o u will b e w al ki n g b ac k a n d f ort h ar o u n d t h e c o n es.
Y o u s h o ul d pi v ot bris kl y ar o u n d t h e c o n es a n d c o nti n u e
b ac k t h e ot h er w a y wit h o ut h esit ati o n. N o w I’ m g oi n g t o
s h o w y o u. Pl e as e w atc h t h e w a y I t ur n wit h o ut h esit ati o n. ”
D e m o nstr at e  b y  w al ki n g  o n e  l a p  y o urs elf.  W al k  a n d
pi v ot ar o u n d a c o n e bris kl y.
“ Ar e  y o u  r e a d y  t o  d o  t h at ?  I  a m  g oi n g  t o  us e  t his
c o u nt er t o k e e p tr ac k of t h e n u m b er of l a ps y o u c o m pl et e. I
will clic k it e ac h ti m e y o u t ur n ar o u n d at t his st arti n g li n e.
R e m e m b er t h at t h e o bj ect is t o w al k A S F A R A S P O S SI-
B L E f or 6 mi n ut es, b ut d o n’t r u n or j o g.
St art n o w, or w h e n e v er y o u ar e r e a d y. ”
 
T A B L E 2. T H E B O R G S C A L E
 
0  
N ot hi n g at all
0. 5 V er y, v er y sli g ht (j ust n oti c e a bl e)
1 
V er y sli g ht
2 
Sli g ht (li g ht)
3  
M o d er at e
4 
S o m e w h at s e v er e
5 
S e v er e ( h e a v y)
6
7 
V er y s e v er e
8
9
1 0 
V er y, v er y s e v er e ( m a xi m al)
T his B or g s c al e s h o ul d b e pri nt e d o n h e a v y p a p er ( 1 1 i n c h es hi g h a n d p er h a ps l a mi-
n at e d) i n 2 0- p oi nt t y p e siz e. At t h e b e gi n ni n g of t h e 6- mi n ut e e x er cis e, s h o w t h e s c al e
t o t h e p ati e nt a n d as k t h e p ati e nt t his: “ Pl e as e gr a d e y o ur l e v el of s h ort n ess of br e at h
usi n g t his s c al e. ” T h e n as k t his: “ Pl e as e gr a d e y o ur l e v el of f ati g u e usi n g t his s c al e. ”
At t h e e n d of t h e e x er cis e, r e mi n d t h e p ati e nt of t h e br e at hi n g n u m b er t h at t h e y
c h os e b ef or e t h e e x er cis e a n d as k t h e p ati e nt t o gr a d e t h eir br e at hi n g l e v el a g ai n. T h e n
as k t h e p ati e nt t o gr a d e t h eir l e v el of f ati g u e, aft er r e mi n di n g t h e m of t h eir gr a d e b e-
f or e t h e e x er cis e.
Pr ot oc ol 4 0 2- C- 1 6 0 2
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1 1 4
 
A M E RI C A N J O U R N A L O F R E S PI R A T O R Y A N D C RI TI C A L C A R E M E DI CI N E 
V O L 1 6 6 
2 0 0 2
 
8. P ositi o n t h e p ati e nt at t h e st arti n g li n e. Y o u s h o ul d als o
st a n d n e ar t h e st arti n g li n e d uri n g t h e t est. D o n ot w al k
wit h t h e p ati e nt. As s o o n as t h e p ati e nt st arts t o w al k,
st art t h e ti m er.
9.  D o n ot t al k t o a n y o n e d uri n g t h e w al k. Us e a n e v e n t o n e
of v oic e w h e n usi n g t h e st a n d ar d p hr as es of e nc o ur a g e-
m e nt. W atc h t h e p ati e nt. D o n ot g et distr act e d a n d l os e
c o u nt of t h e l a ps. E ac h ti m e t h e p artici p a nt r et ur ns t o t h e
st arti n g li n e, clic k t h e l a p c o u nt er o nc e ( or m ar k t h e l a p
o n t h e w or ks h e et). L et t h e p artici p a nt s e e y o u d o it. E x-
a g g er at e t h e clic k usi n g b o d y l a n g u a g e, li k e usi n g a st o p-
w atc h at a r ac e.
 
Aft er t h e first mi n ut e, t ell t h e p ati e nt t h e f oll o wi n g (i n
e v e n t o n es): “ Y o u ar e d oi n g w ell. Y o u h a v e 5 mi n ut es t o
g o. ”
W h e n t h e ti m er s h o ws 4 mi n ut es r e m ai ni n g, t ell t h e p a-
ti e nt t h e f oll o wi n g: “ K e e p u p t h e g o o d w or k. Y o u h a v e 4
mi n ut es t o g o. ”
W h e n t h e ti m er s h o ws 3 mi n ut es r e m ai ni n g, t ell t h e p a-
ti e nt t h e f oll o wi n g: “ Y o u ar e d oi n g w ell. Y o u ar e h alf w a y
d o n e. ”
W h e n t h e ti m er s h o ws 2 mi n ut es r e m ai ni n g, t ell t h e p a-
ti e nt t h e f oll o wi n g: “ K e e p u p t h e g o o d w or k. Y o u h a v e o nl y
2 mi n ut es l eft. ”
W h e n t h e ti m er s h o ws o nl y 1 mi n ut e r e m ai ni n g, t ell t h e
p ati e nt: “ Y o u ar e d oi n g w ell. Y o u h a v e o nl y 1 mi n ut e t o
g o. ”
D o n ot us e ot h er w or ds of e nc o ur a g e m e nt ( or b o d y l a n-
g u a g e t o s p e e d u p).
If t h e p ati e nt st o ps w al ki n g d uri n g t h e t est a n d n e e ds a
r est, s a y t his: “ Y o u c a n l e a n a g ai nst t h e w all if y o u w o ul d
li k e; t h e n c o nti n u e w al ki n g w h e n e v er y o u f e el a bl e. ” D o
n ot st o p t h e ti m er. If t h e p ati e nt st o ps b ef or e t h e 6 mi n ut es
ar e  u p  a n d  r ef us es  t o  c o nti n u e  ( or  y o u  d eci d e  t h at  t h e y
s h o ul d n ot c o nti n u e), w h e el t h e c h air o v er f or t h e p ati e nt t o
sit o n, disc o nti n u e t h e w al k, a n d n ot e o n t h e w or ks h e et t h e
dist a nc e, t h e ti m e st o p p e d, a n d t h e r e as o n f or st o p pi n g pr e-
m at ur el y.
W h e n t h e ti m er is 1 5 s ec o n ds fr o m c o m pl eti o n, s a y t his:
“I n a m o m e nt I’ m g oi n g t o t ell y o u t o st o p. W h e n I d o, j ust
st o p ri g ht w h er e y o u ar e a n d I will c o m e t o y o u. ”
W h e n t h e ti m er ri n gs ( or b uzz es), s a y t his: “ St o p! ” W al k
o v er t o t h e p ati e nt. C o nsi d er t a ki n g t h e c h air if t h e y l o o k
e x h a ust e d. M ar k t h e s p ot w h er e t h e y st o p p e d b y pl aci n g a
b e a n b a g or a pi ec e of t a p e o n t h e fl o or.
 
1 0. P ost-t est: R ec or d t h e p ost w al k B or g d ys p n e a a n d f ati g u e
l e v els a n d as k t his: “ W h at, if a n yt hi n g, k e pt y o u fr o m w al k-
i n g f art h er ? ”
1 1. If usi n g a p uls e o xi m et er, m e as ur e S p O
 
2
 
 a n d p uls e r at e
fr o m t h e o xi m et er a n d t h e n r e m o v e t h e s e ns or.
1 2.  R ec or d t h e n u m b er of l a ps fr o m t h e c o u nt er ( or tic k m ar ks
o n t h e w or ks h e et).
1 3.  R ec or d t h e a d diti o n al dist a nc e c o v er e d (t h e n u m b er of m et ers
i n t h e fi n al p arti al l a p) usi n g t h e m ar k ers o n t h e w all as dis-
t a nc e g ui d es. C alc ul at e t h e t ot al dist a nc e w al k e d, r o u n di n g t o
t h e n e ar est m et er, a n d r ec or d it o n t h e w or ks h e et.
1 4.  C o n gr at ul at e t h e p ati e nt o n g o o d eff ort a n d off er a dri n k
of w at er.
 
Q U A LI T Y A S S U R A N C E
 
S o ur c es of V ari a bilit y
 
T h er e ar e m a n y s o urc es of 6 M W D v ari a bilit y (
 
see
 
 T a bl e 3).
T h e s o urc es of v ari a bilit y c a us e d b y t h e t est pr oc e d ur e its elf
s h o ul d b e c o ntr oll e d as m uc h as p ossi bl e. T his is d o n e b y f ol-
l o wi n g t h e st a n d ar ds f o u n d i n t his d oc u m e nt a n d b y usi n g a
q u alit y- ass ur a nc e pr o gr a m.
 
Pr a cti c e T ests
 
A  pr actic e  t est  is  n ot  n e e d e d  i n  m ost  cli nic al  s etti n gs  b ut
s h o ul d b e c o nsi d er e d. If a pr actic e t est is d o n e, w ait f or at l e ast
1 h o ur b ef or e t h e s ec o n d t est a n d r e p ort t h e hi g h est 6 M W D as
t h e p ati e nt’s 6 M W D b as eli n e.
 
R ati o n ale.  
 
T h e 6 M W D is o nl y sli g htl y hi g h er f or a s ec o n d
6 M W T p erf or m e d a d a y l at er. T h e m e a n r e p ort e d i ncr e as e
r a n g es fr o m 0 t o 1 7 % ( 2 3, 2 7, 4 0, 4 1, 5 4, 5 9). A m ultic e nt er
st u d y of 4 7 0 hi g hl y m oti v at e d p ati e nts wit h s e v er e C O P D p er-
f or m e d t w o 6 M W Ts 1 d a y a p art, a n d o n a v er a g e, t h e 6 M W D
w as o nl y 6 6 ft ( 5. 8 %) hi g h er o n t h e s ec o n d d a y ( 5 4).
P erf or m a nc e ( wit h o ut a n i nt er v e nti o n) us u all y r e ac h es a
pl at e a u aft er t w o t ests d o n e wit hi n a w e e k ( 8, 6 0). T h e tr ai ni n g
eff ect m a y b e d u e t o i m pr o v e d c o or di n ati o n, fi n di n g o pti m al
stri d e  l e n gt h,  a n d  o v erc o mi n g  a n xi et y.  T h e  p ossi bilit y  of  a
pr actic e or tr ai ni n g eff ect fr o m t ests r e p e at e d aft er m or e t h a n
a m o nt h h as n ot b e e n st u di e d or r e p ort e d; h o w e v er, it is li k el y
t h at t h e eff ect of tr ai ni n g w e ars off ( d o es n ot p ersist) aft er a
f e w w e e ks.
 
T e c h ni ci a n Tr ai ni n g a n d E x p eri e n c e
 
T ec h nici a ns w h o p erf or m 6 M W Ts s h o ul d b e tr ai n e d usi n g t h e
st a n d ar d pr ot oc ol a n d t h e n s u p er vis e d f or s e v er al t ests b ef or e
p erf or mi n g t h e m al o n e. T h e y s h o ul d als o h a v e c o m pl et e d c ar-
di o p ul m o n ar y r es uscit ati o n tr ai ni n g.
 
R ati o n ale.  
 
O n e  m ultic e nt er  st u d y  of  ol d er  p e o pl e  f o u n d
t h at aft er c orr ecti o n f or m a n y ot h er f act ors, t w o of t h e t ec h ni-
ci a ns h a d m e a n 6 M W Ds t h at w er e a p pr o xi m at el y 7 % l o w er
t h a n t h e ot h er t w o sit es ( 3 1).
 
E n c o ur a g e m e nt
 
O nl y t h e st a n d ar diz e d p hr as es f or e nc o ur a g e m e nt ( as s p eci-
fi e d pr e vi o usl y h er e) m ust b e us e d d uri n g t h e t est.
 
R ati o n ale.  
 
E nc o ur a g e m e nt si g nific a ntl y i ncr e as es t h e dis-
t a nc e w al k e d ( 4 2). R e pr o d uci bilit y f or t ests wit h a n d wit h o ut
e nc o ur a g e m e nt is si mil ar. S o m e st u di es h a v e us e d e nc o ur a g e-
m e nt e v er y 3 0 s ec o n ds, e v er y mi n ut e, or e v er y 2 mi n ut es. W e
h a v e c h os e n e v er y mi n ut e a n d st a n d ar d p hr as es. S o m e st u di es
( 5 3) h a v e i nstr uct e d p ati e nts t o w al k as f ast as p ossi bl e. Al-
t h o u g h l ar g er m e a n 6 M W Ds m a y b e o bt ai n e d t h er e b y, w e r ec-
o m m e n d t h at s uc h p hr as es n ot b e us e d, as t h e y e m p h asiz e i ni-
ti al  s p e e d  at  t h e  e x p e ns e  of  e arli er  f ati g u e  a n d  p ossi bl e
e xc essi v e c ar di ac str ess i n s o m e p ati e nts wit h h e art dis e as e.
 
T A B L E 3. 6 M W D S O U R C E S  O F V A RI A BI LI T Y
 
F a ct ors r e d u ci n g t h e 6 M W D
S h ort er h ei g ht
Ol d er a g e
Hi g h er b o d y w ei g ht
F e m al e s e x
I m p air e d c o g niti o n
A s h ort er c orri d or ( m or e t ur ns)
P ul m o n ar y dis e as e ( C O P D, ast h m a, c ysti c fi br osis, i nt erstiti al l u n g dis e as e)
C ar di o v as c ul ar dis e as e ( a n gi n a, MI, C H F, str o k e, TI A, P V D, A AI)
M us c ul osk el et al dis or d ers ( art hritis, a nkl e, k n e e, or hi p i nj uri es, m us cl e w asti n g, etc.)
F a ct ors i n cr e asi n g t h e 6 M W D
T all er h ei g ht (l o n g er l e gs)
M al e s e x
Hi g h m oti v ati o n
A p ati e nt w h o h as pr e vi o usl y p erf or m e d t h e t est
M e di c ati o n f or a dis a bli n g dis e as e t a k e n j ust b ef or e t h e t est
O x y g e n s u p pl e m e nt ati o n i n p ati e nts wit h e x er cis e-i n d u c e d h y p o x e mi a
D efi niti o n of a b br e vi ati o ns
 
: C O P D 
  
 c hr o ni c o bstr u cti v e p ul m o n ar y dis e as e; 6 M W D 
  
 
6- mi n ut e w al ki n g dist a n c e.
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
5 9


 
A m eri c a n T h or a ci c S o ci et y
1 1 5
S u p pl e m e nt al O x y g e n
 
If o x y g e n s u p pl e m e nt ati o n is n e e d e d d uri n g t h e w al ks a n d s e-
ri al t ests ar e pl a n n e d ( aft er a n i nt er v e nti o n ot h er t h a n o x y g e n
t h er a p y), t h e n d uri n g all w al ks b y t h at p ati e nt o x y g e n s h o ul d
b e d eli v er e d i n t h e s a m e w a y wit h t h e s a m e fl o w. If t h e fl o w
m ust b e i ncr e as e d d uri n g s u bs e q u e nt visits d u e t o w ors e ni n g
g as e xc h a n g e, t his s h o ul d b e n ot e d o n t h e w or ks h e et a n d c o n-
si d er e d d uri n g i nt er pr et ati o n of t h e c h a n g e n ot e d i n 6 M W D.
T h e t y p e of o x y g e n d eli v er y d e vic e s h o ul d als o b e n ot e d o n
t h e r e p ort: f or i nst a nc e, t h e p ati e nt c arri e d li q ui d o x y g e n or
p us h e d or p ull e d a n o x y g e n t a n k, t h e d eli v er y w as p uls e d or
c o nti n u o us, or a t ec h nici a n w al k e d b e hi n d t h e p ati e nt wit h t h e
o x y g e n s o urc e ( n ot r ec o m m e n d e d). M e as ur e m e nts of p uls e
a n d S p O
 
2
 
 s h o ul d b e m a d e aft er w aiti n g at l e ast 1 0 mi n ut es af-
t er a n y c h a n g e i n o x y g e n d eli v er y.
 
R ati o n ale.  
 
F or p ati e nts wit h C O P D or i nt erstiti al l u n g dis-
e as e, o x y g e n s u p pl e m e nt ati o n i ncr e as es t h e 6 M W D ( 1 7, 5 9,
6 1, 6 3). C arr yi n g a p ort a bl e g as c o nt ai n er ( b ut n ot usi n g it f or
s u p pl e m e nt al o x y g e n) r e d uc e d t h e m e a n 6 M W D b y 1 4 % i n
o n e st u d y of p ati e nts wit h s e v er e r es pir at or y dis a bilit y, b ut us-
i n g t h e c o nt ai n er t o d eli v er s u p pl e m e nt al o x y g e n d uri n g t h e
e x ercis e i ncr e as e d t h e m e a n 6 M W D b y 2 0 – 3 5 % ( 5 9).
 
M e di c ati o ns
 
T h e t y p e of m e dic ati o n, d os e, a n d n u m b er of h o urs t a k e n b e-
f or e t h e t est s h o ul d b e n ot e d.
 
R ati o n ale.  
 
Si g nific a nt i m pr o v e m e nt i n t h e dist a nc e w al k e d,
or t h e d ys p n e a sc al e, aft er a d mi nistr ati o n of br o nc h o dil at ors
h as b e e n d e m o nstr at e d i n p ati e nts wit h C O P D ( 6 2, 6 3), as w ell
as c ar di o v asc ul ar m e dic ati o ns i n p ati e nts wit h h e art f ail ur e ( 1 9).
 
I N T E R P R E T A TI O N
 
M ost 6 M W Ts will b e d o n e b ef or e a n d aft er i nt er v e nti o n, a n d
t h e  pri m ar y  q u esti o n  t o  b e  a ns w er e d  aft er  b ot h  t ests  h a v e
b e e n c o m pl et e d is w h et h er t h e p ati e nt h as e x p eri e nc e d a cli ni-
c all y si g nific a nt i m pr o v e m e nt. Wit h a g o o d q u alit y- ass ur a nc e
pr o gr a m, wit h p ati e nts t est e d b y t h e s a m e t ec h nici a n, a n d af-
t er o n e or t w o pr actic e t ests, s h ort-t er m r e pr o d uci bilit y of t h e
6 M W D is e xc ell e nt ( 3 7). It is n ot k n o w n w h et h er it is b est f or
cli nic al p ur p os es t o e x pr ess c h a n g e i n 6 M W D as (
 
1
 
) a n a bs o-
l ut e v al u e, (
 
2
 
) a p erc e nt a g e c h a n g e, or (
 
3
 
) a c h a n g e i n t h e p er-
c e nt a g e of pr e dict e d v al u e. U ntil f urt h er r es e arc h is a v ail a bl e,
w e r ec o m m e n d t h at c h a n g e i n 6 M W D b e e x pr ess e d as a n a b-
s ol ut e v al u e ( e. g., t h e p ati e nt w al k e d 5 0 m f art h er).
A  st atistic all y  si g nific a nt  m e a n  i ncr e as e  i n  6 M W D  i n  a
gr o u p of st u d y p artici p a nts is oft e n m uc h l ess t h a n a cli nic all y
si g nific a nt i ncr e as e i n a n i n di vi d u al p ati e nt. I n o n e st u d y of
1 1 2 p ati e nts ( h alf of t h e m w o m e n) wit h st a bl e, s e v er e C O P D,
t h e s m all est diff er e nc e i n 6 M W D t h at w as ass oci at e d wit h a
n otic e a bl e cli nic al diff er e nc e i n t h e p ati e nts’ p erc e pti o n of e x-
ercis e p erf or m a nc e w as a m e a n of 5 4 m ( 9 5 % c o nfi d e nc e i n-
t er v al, 3 7 – 7 1 m) ( 6 4). T his st u d y s u g g ests t h at f or i n di vi d u al
p ati e nts wit h C O P D, a n i m pr o v e m e nt of m or e t h a n 7 0 m i n
t h e 6 M W D aft er a n i nt er v e nti o n is n ec ess ar y t o b e 9 5 % c o nfi-
d e nt t h at t h e i m pr o v e m e nt w as si g nific a nt. I n a n o bs er v ati o n al
st u d y of 4 5 ol d er p ati e nts wit h h e art f ail ur e, t h e s m all est dif-
f er e nc e i n 6 M W D t h at w as ass oci at e d wit h a n otic e a bl e diff er-
e nc e i n t h eir gl o b al r ati n g of w ors e ni n g w as a m e a n of 4 3 m
( 2 0). T h e 6 M W D w as m or e r es p o nsi v e t o d et eri or ati o n t h a n
t o i m pr o v e m e nt i n h e art f ail ur e s y m pt o ms.
 
R e p ort e d M e a n C h a n g es i n 6 M W D Aft er I nt er v e nti o ns
 
S u p pl e m e nt al o x y g e n ( 4 L/ mi n) d uri n g e x ercis e i n p ati e nts wit h
C O P D or i nt erstiti al l u n g dis e as e i ncr e as e d m e a n 6 M W D b y
a p pr o xi m at el y 9 5 m ( 3 6 %) i n o n e st u d y ( 5 9). P ati e nts t a ki n g
 
a n i n h al e d c ortic ost er oi d e x p eri e nc e d a m e a n 3 3 m ( 8 %) i n-
cr e as e i n 6 M W D i n a n i nt er n ati o n al C O P D st u d y ( 1 6). P a-
ti e nts wit h C O P D i n a st u d y of t h e eff ects of e x ercis e a n d di a-
p hr a g m atic str e n gt h tr ai ni n g e x p eri e nc e d a m e a n i ncr e as e i n
6 M W D of 5 0 m ( 2 0 %) ( 6 5). L u n g v ol u m e r e d ucti o n s ur g er y i n
p ati e nts wit h v er y s e v er e C O P D h as b e e n r e p ort e d t o i ncr e as e
6 M W D b y a m e a n of 5 5 m ( 2 0 %) ( 1 3).
C ar di ac r e h a bilit ati o n i n p ati e nts r ef err e d wit h v ari o us h e art
dis e as es i ncr e as e d 6 M W D b y a m e a n of 1 7 0 m ( 1 5 %) i n a r ec e nt
st u d y ( 6 6). I n 2 5 ol d er p ati e nts wit h h e art f ail ur e, a n a n gi ot e nsi n-
c o n v erti n g  e nz y m e  i n hi bit or  m e dic ati o n  ( 5 0  m g  c a pt o pril  p er
d a y) i m pr o v e d 6 M W D a m e a n of 6 4 m ( 3 9 %) c o m p ar e d wit h a
m e a n i ncr e as e of o nl y 8 % i n t h os e r ec ei vi n g a pl ac e b o ( 1 9).
 
I nt er pr eti n g Si n gl e M e as ur e m e nts of F u n cti o n al St at us
 
O pti m al r ef er e nc e e q u ati o ns fr o m h e alt h y p o p ul ati o n- b as e d
s a m pl es usi n g st a n d ar diz e d 6 M W T m et h o ds ar e n ot y et a v ail-
a bl e. I n o n e st u d y, t h e m e di a n 6 M W D w as a p pr o xi m at el y 5 8 0
m f or 1 1 7 h e alt h y m e n a n d 5 0 0 m f or 1 7 3 h e alt h y w o m e n ( 5 0).
A m e a n 6 M W D of 6 3 0 m w as r e p ort e d b y a n ot h er st u d y of 5 1
h e alt h y ol d er a d ults ( 5 5). Diff er e nc es i n t h e p o p ul ati o n s a m-
pl e d, t y p e a n d fr e q u e nc y of e nc o ur a g e m e nt, c orri d or l e n gt h,
a n d n u m b er of pr actic e t ests m a y acc o u nt f or r e p ort e d diff er-
e nc es i n m e a n 6 M W D i n h e alt h y p ers o ns. A g e, h ei g ht, w ei g ht,
a n d  s e x  i n d e p e n d e ntl y  aff ect  t h e  6 M W D  i n  h e alt h y  a d ults;
t h er ef or e,  t h es e  f act ors  s h o ul d  b e  t a k e n  i nt o  c o nsi d er ati o n
w h e n i nt er pr eti n g t h e r es ults of si n gl e m e as ur e m e nts m a d e t o
d et er mi n e f u ncti o n al st at us. W e e nc o ur a g e i n v esti g at ors t o p u b-
lis h r ef er e nc e e q u ati o ns f or h e alt h y p ers o ns usi n g t h e pr e vi-
o usl y m e nti o n e d st a n d ar diz e d pr oc e d ur es.
A l o w 6 M W D is n o ns p ecific a n d n o n di a g n ostic. W h e n t h e
6 M W D is r e d uc e d, a t h or o u g h s e arc h f or t h e c a us e of t h e i m-
p air m e nt is w arr a nt e d. T h e f oll o wi n g t ests m a y t h e n b e h el p-
f ul: p ul m o n ar y f u ncti o n, c ar di ac f u ncti o n, a n kl e – ar m i n d e x,
m uscl e str e n gt h, n utriti o n al st at us, ort h o p e dic f u ncti o n, a n d
c o g niti v e f u ncti o n.
 
C o n cl usi o ns
 
T h e 6 M W T is a us ef ul m e as ur e of f u ncti o n al c a p acit y t ar g et e d
at p e o pl e wit h at l e ast m o d er at el y s e v er e i m p air m e nt. T h e t est
h as b e e n wi d el y us e d f or pr e o p er ati v e a n d p ost o p er ati v e e v al-
u ati o n a n d f or m e as uri n g t h e r es p o ns e t o t h er a p e utic i nt er-
v e nti o ns f or p ul m o n ar y a n d c ar di ac dis e as e. T h es e g ui d eli n es
pr o vi d e a st a n d ar diz e d a p pr o ac h t o p erf or mi n g t h e 6 M W T.
T h e c o m mitt e e h o p es t h at t h es e g ui d eli n es will e nc o ur a g e f ur-
t h er r es e arc h i nt o t h e 6 M W T a n d all o w dir ect c o m p aris o ns
a m o n g diff er e nt st u di es.
 
T his st at e m e nt w as d e v el o p e d b y t h e A T S C o m mitt e e o n Pr ofi ci e n c y St a n-
d ar ds f or Cli ni c al P ul m o n ar y F u n cti o n L a b or at ori es.
M e m b ers of t h e c o m mitt e e ar e:
R
 
O B E R T
 
 O. C
 
R A P O
 
, M. D., 
 
C h air
 
*
R
 
I C H A R D
 
 C
 
A S A B U RI
 
, P
 
H
 
. D, M. D.
A
 
L L A N
 
 L. C
 
O A T E S
 
, M. D.
P
 
A U L
 
 L. E
 
N RI G H T
 
, M. D.*
N
 
EI L
 
 R. M
 
A C
 
I
 
N T Y R E
 
, M. D.
R
 
O Y
 
 T. M
 
C
 
K
 
A Y
 
, P
 
H
 
. D.
D
 
O U G L A S
 
 J
 
O H N S O N
 
, M. D.
J
 
A C K
 
 S. W
 
A N G E R
 
, M. S.
R. J
 
O R G E
 
 Z
 
E B A L L O S
 
, M. D.*
A d H o c C o m mitt e e m e m b ers ar e:
V
 
E R A
 
 B
 
I T T N E R
 
, M. D.
C
 
A R L
 
 M
 
O T T R A M
 
, R. R. T.
* Writi n g C o m mitt e e M e m b ers
 
R ef er e n c es
 
1.  W ass er m a n K, H a ns e n J E, S u e D Y, C as a b uri R, W hi p p BJ. Pri nci pl es of
e x ercis e t esti n g a n d i nt er pr et ati o n, 3r d e diti o n. P hil a d el p hi a: Li p pi n-
c ott, Willi a ms & Wil ki ns; 1 9 9 9.
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
6 0


 
1 1 6
 
A M E RI C A N J O U R N A L O F R E S PI R A T O R Y A N D C RI TI C A L C A R E M E DI CI N E 
V O L 1 6 6 
2 0 0 2
 
2.  W eis m a n I M, Z e b all os RJ. A n i nt e gr at e d a p pr o ac h t o t h e i nt er pr et ati o n
of c ar di o p ul m o n ar y e x ercis e t esti n g. 
 
Cli n C hest Me d
 
 1 9 9 4; 1 5: 4 2 1 – 4 4 5.
3. Fl etc h er G F, B al a d y G, Fr o elic h er V F, H artl e y L H, H as k ell W L, P ol-
l oc k M L. E x ercis e st a n d ar ds: a st at e m e nt f or h e alt hc ar e pr of essi o n als
fr o m t h e A m eric a n H e art Ass oci ati o n: writi n g gr o u p. 
 
Circ ul ati o n
 
 1 9 9 5;
9 1: 5 8 0 – 6 1 5.
4. Pi n a I L, B al a d y GJ, H a ns o n P, L a b o vitz AJ, M a d o n n a D W, M y ers J. G ui d e-
li n es f or cli nic al e x ercis e t esti n g l a b or at ori es: a st at e m e nt f or h e alt hc ar e
pr of essi o n als fr o m t h e C o m mitt e e o n E x ercis e a n d C ar di ac R e h a bilit a-
ti o n, A m eric a n H e art Ass oci ati o n. 
 
Circ ul ati o n
 
 1 9 9 5; 9 1: 9 1 2 – 9 2 1.
5.  B al k e B. A si m pl e fi el d t est f or t h e ass ess m e nt of p h ysic al fit n ess. 
 
C A RI
Re p ort
 
 1 9 6 3; 6 3: 1 8.
6.  C o o p er K H. A m e a ns of ass essi n g m a xi m al o x y g e n i nt a k e: c orr el ati o n
b et w e e n fi el d a n d tr e a d mill t esti n g. 
 
J A M A
 
 1 9 6 8; 2 0 3: 2 0 1 – 2 0 4.
7.  Mc G a vi n C R, G u pt a S P, Mc H ar d y GJ R. T w el v e- mi n ut e w al ki n g t est f or
ass essi n g dis a bilit y i n c hr o nic br o nc hitis. 
 
B MJ
 
 1 9 7 6; 1: 8 2 2 – 8 2 3.
8.  B utl a n d RJ A, P a n g J, Gr oss E R, W o o dc oc k A A, G e d d es D M. T w o-,
si x-, a n d 1 2- mi n ut e w al ki n g t ests i n r es pir at or y dis e as e. 
 
B MJ
 
 1 9 8 2;
2 8 4: 1 6 0 7 – 1 6 0 8.
9. S ol w a y S, Br o o ks D, L ac ass e Y, T h o m as S. A q u alit ati v e s yst e m atic
o v er vi e w of t h e m e as ur e m e nt pr o p erti es of f u ncti o n al w al k t ests us e d
i n t h e c ar di or es pir at or y d o m ai n. 
 
C hest
 
 2 0 0 1; 1 1 9: 2 5 6 – 2 7 0.
1 0.  K a di k ar A, M a ur er J, K est e n S. T h e si x- mi n ut e w al k t est: a g ui d e t o as-
s ess m e nt f or l u n g tr a ns pl a nt ati o n. 
 
J He art L u n g Tr a ns pl a nt
 
 1 9 9 7; 1 6:
3 1 3 – 3 1 9.
1 1.  H ol d e n D A, Ric e T W, St el m ac h K, M e e k er D P. E x ercis e t esti n g, 6 mi n
w al k, a n d st air cli m b i n t h e e v al u ati o n of p ati e nts at hi g h ris k f or p ul-
m o n ar y r es ecti o n. 
 
C hest
 
 1 9 9 2; 1 0 2: 1 7 7 4 – 1 7 7 9.
1 2. Sci ur b a F C, R o g ers R M, K e e n a n RJ, Sli v k a W A, G orcs a n J 3r d, F ers o n
P F, H ol b ert J M, Br o w n M L, L a n dr e n e a u RJ. I m pr o v e m e nt i n p ul m o-
n ar y f u ncti o n a n d el astic r ec oil aft er l u n g-r e d ucti o n s ur g er y f or diff us e
e m p h ys e m a. 
 
N E n gl J Me d
 
 1 9 9 6; 3 3 4: 1 0 9 5 – 1 0 9 9.
1 3.  Cri n er GJ, C or d o v a F C, F ur u k a w a S, K uz m a A M, Tr a v ali n e J M, L e y e n-
s o n V, O’ Bri e n G M. Pr os p ecti v e r a n d o miz e d tri al c o m p ari n g bil at er al
l u n g v ol u m e r e d ucti o n s ur g er y t o p ul m o n ar y r e h a bilit ati o n i n s e v er e
C O P D. 
 
A m J Res pir Crit C are Me d
 
 1 9 9 9; 1 6 0: 2 0 1 8 – 2 0 2 7.
1 4. Si ncl air DJ M, I n gr a m C G. C o ntr oll e d tri al of s u p er vis e d e x ercis e tr ai n-
i n g i n c hr o nic br o nc hitis. 
 
B MJ
 
 1 9 8 0; 2 8 0: 5 1 9 – 5 2 1.
1 5.  R o o mi J, J o h ns o n M M, W at ers K, Y o h a n n es A, H el m A, C o n n oll y MJ.
R es pir at or y  r e h a bilit ati o n,  e x ercis e  c a p acit y  a n d  q u alit y  of  lif e  i n
c hr o nic air w a ys dis e as e i n ol d a g e. 
 
A ge A gei n g
 
 1 9 9 6; 2 5: 1 2 – 1 6.
1 6. P a g gi ar o P L, D a hl e R, B a kr a n I, Frit h L, H olli n g w ort h K, Eft hi mi o u J.
M ultic e ntr e  r a n d o mis e d  pl ac e b o-c o ntr oll e d  tri al  of  i n h al e d  fl utic a-
s o n e pr o pi o n at e i n p ati e nts wit h C O P D. 
 
L a ncet
 
 1 9 9 8; 3 5 1: 7 7 3 – 7 8 0.
1 7. L e g g ett RJ, Fl e nl e y D C. P ort a bl e o x y g e n a n d e x ercis e t ol er a nc e i n p a-
ti e nts wit h c hr o nic h y p o xic c or p ul m o n al e. 
 
B MJ
 
 1 9 7 7; 2: 8 4 – 8 6.
1 8. S p e nc e D P S, H a y J G, C art er J, P e ars o n M G, C al v erl e y P M A. O x y g e n
d es at ur ati o n a n d br e at hl ess n ess d uri n g c orri d or w al ki n g i n C O P D: ef-
f ect of o xitr o pi u m br o mi d e. 
 
T h or a x
 
 1 9 9 3; 4 8: 1 1 4 5 – 1 1 5 0.
1 9.  D e B oc k V, M ets T, R o m a g n oli M, D er d e M P. C a pt o pril tr e at m e nt of
c hr o nic h e art f ail ur e i n t h e v er y ol d. 
 
J Ger o nt ol
 
 1 9 9 4; 4 9: M 1 4 8 – M 1 5 2.
2 0.  O’ K e eff e S T, L y e M, D o n n n ell a n C, C ar mic h a el D N. R e pr o d uci bilit y
a n d r es p o nsi v e n ess of q u alit y of lif e ass ess m e nt a n d si x mi n ut e w al k
t est i n el d erl y h e art f ail ur e p ati e nts. 
 
He art
 
 1 9 9 8; 8 0: 3 7 7 – 3 8 2.
2 1.  B er nst ei n M L, D es p ars J A, Si n g h N P, A v al os K, St a ns b ur y D W, Li g ht
R W. R e- a n al ysis of t h e 1 2 mi n ut e w al k i n p ati e nts wit h C O P D. 
 
C hest
 
1 9 9 4; 1 0 5: 1 6 3 – 1 6 7.
2 2.  H ajir o T, Nis hi m ur a K, Ts u ki n o M, I k e d a A, K o y a m a H, Iz u mi T. A n al-
ysis  of  cli nic al  m et h o ds  us e d  t o  e v al u at e  d ys p n e a  i n  p ati e nts  wit h
C O P D. 
 
A m J Res pir Crit C are Me d
 
 1 9 9 8; 1 5 8: 1 1 8 5 – 1 1 8 9.
2 3.  G ul m a ns V A M, v a n V el d h o v e n N H MJ, d e M e er K, H el d ers PJ M. T h e
si x- mi n ut e w al ki n g t est i n c hil dr e n wit h c ystic fi br osis: r eli a bilit y a n d
v ali dit y. 
 
Pe di atr P ul m o n ol
 
 1 9 9 6; 2 2: 8 5 – 8 9.
2 4.  Ni x o n P A, J os wi a k M L, Fric k er FJ. A si x- mi n ut e w al k t est f or ass essi n g
e x ercis e t ol er a nc e i n s e v er el y ill c hil dr e n. 
 
J Pe di atr
 
 1 9 9 6; 1 2 9: 3 6 2 – 3 6 6.
2 5.  Bitt n er V. Si x- mi n ut e w al k t est i n p ati e nts wit h c ar di ac d ysf u ncti o n. 
 
C ar-
di ol o gi a
 
 1 9 9 7; 4 2: 8 9 7 – 9 0 2.
2 6. P e et ers P, M ets T. T h e 6 mi n ut e w al k as a n a p pr o pri at e e x ercis e t est i n
el d erl y  p ati e nts  wit h  c hr o nic  h e art  f ail ur e.  
 
J  Ger o nt ol
 
 1 9 9 6; 5 1 A:
M 1 4 7 – M 1 5 1.
2 7.  Z u gc k  C,  Kr u g er  C,  D urr  S,  G er b er  S H,  H a u nst ett er  A,  H or ni g  K,
K u bl er W, H a ass M. Is t h e 6- mi n ut e w al k t est a r eli a bl e s u bstit ut e f or
p e a k  o x y g e n  u pt a k e  i n  p ati e nts  wit h  dil at e d  c ar di o m y o p at h y ?  
 
E ur
He art J
 
 2 0 0 0; 2 1: 5 4 0 – 5 4 9.
2 8.  M o nt o g o m er y P S, G ar d n er A W. T h e cli nic al utilit y of a si x- mi n ut e w al k
t est i n p eri p h er al art eri al occl usi v e dis e as e p ati e nts. 
 
J A m Geri atr S oc
 
1 9 9 8; 4 6: 7 0 6 – 7 1 1.
 
2 9.  C a h a n M A, M o nt g o m er y P, Otis R B, Cl a nc y R, Fli n n W, G ar d n er A.
T h e eff ect of ci g ar ett e s m o ki n g st at us o n si x- mi n ut e w al k dist a nc e i n
p ati e nts wit h i nt er mitt e nt cl a u dic ati o n. 
 
A n gi ol o g y
 
 1 9 9 9; 5 0: 5 3 7 – 5 4 6.
3 0.  Ki n g S, W ess el J, B h a m b h a ni Y, M ai k al a R, S h olt er D, M a ks y m o w yc h
W. V ali dit y a n d r eli a bilit y of t h e 6 mi n ut e w al k i n p ers o ns wit h fi br o-
m y al gi a. J R he u m at ol 1 9 9 9; 2 6: 2 2 3 3 – 2 2 3 7.
3 1.  E nri g ht P L, Mc B ur ni e M A, Bitt n er V, Tr ac y R P, Mc N a m ar a R, N e w-
m a n A B, t h e C ar di o v asc ul ar H e alt h St u d y. T h e si x mi n ut e w al k t est: a
q uic k m e as ur e of f u ncti o n al st at us i n el d erl y a d ults. C hest  (I n pr ess)
3 2.  Bitt n er V, W ei n er D H, Y us uf S, R o g ers WJ, McI nt yr e K M, B a n g di w al a
SI, Kr o n e n b er g M W, K ostis J B, K o h n R M, G uill ott e M, et al. Pr e dic-
ti o n of m ort alit y a n d m or bi dit y wit h a 6- mi n ut e w al k t est i n p ati e nts
wit h l eft v e ntric ul ar d ysf u ncti o n. J A M A 1 9 9 3; 2 7 0: 1 7 0 2 – 1 7 0 7.
3 3.  C a h ali n L P, M at hi er M A, S e mi gr a n MJ, D ec G W, Di S al v o T G. T h e si x-
mi n ut e w al k t est pr e dicts p e a k o x y g e n u pt a k e a n d s ur vi v al i n p ati e nts
wit h a d v a nc e d h e art f ail ur e. C hest  1 9 9 6; 1 1 0: 3 2 5 – 3 3 2.
3 4.  C ot e C G, C elli B R. I n p ati e nts wit h C O P D, t h e 6 mi n ut e w al ki n g dis-
t a nc e is a b ett er pr e dict or of h e alt h c ar e utiliz ati o n t h a n F E V 1, bl o o d
g as es, a n d d ys p n e a [ a bstr act]. E ur Res pir J  1 9 9 8; 3 8 3.
3 5.  K essl er R, F all er M, F o ur g a ut G, M e n n eci er B, W eitz e n bl u m E. Pr e dic-
ti v e f act ors of h os pit aliz ati o n f or ac ut e e x ac er b ati o n i n a s eri es of 6 4
p ati e nts wit h c hr o nic o bstr ucti v e p ul m o n ar y dis e as e. A m J Res pir Crit
C are Me d  1 9 9 9; 1 5 9: 1 5 8 – 1 6 4.
3 6.  C a h ali n L, P a p p a gi a n o p o ul os P, Pr e v ost S, W ai n J, Gi n ns L. T h e r el ati o n-
s hi p of t h e 6- mi n w al k t est t o m a xi m al o x y g e n c o ns u m pti o n i n tr a ns-
pl a nt c a n di d at es wit h e n d-st a g e l u n g dis e as e. C hest  1 9 9 5; 1 0 8: 4 5 2 – 4 5 9.
3 7.  G u y att  G H,  T h o m ps o n  PJ,  B er m a n  L B,  S ulli v a n  MJ,  T o w ns e n d  M,
J o n es N L, P u gsl e y S O. H o w s h o ul d w e m e as ur e f u ncti o n i n p ati e nts
wit h c hr o nic h e art a n d l u n g dis e as e ? J C hr o nic Dis 1 9 8 5; 3 8: 5 1 7 – 5 2 4.
3 8.  G u y att G H, T o w ns e n d M, K ell er J, Si n g er J, N o gr a di S. M e as uri n g f u nc-
ti o n al st at us i n c hr o nic l u n g dis e as e: c o ncl usi o ns fr o m a r a n d o m c o n-
tr ol tri al. Res pir Me d  1 9 9 1; 8 5( S u p pl B): 1 7 – 2 1.
3 9.  Ni e d er m a n M S, Cl e m e nt e P H, F ei n A M, F ei nsil v er S H, R o bi ns o n D A,
Il o wit e J S, B er nst ei n M G. B e n efits of a m ulti disci pli n ar y p ul m o n ar y
r e h a bilit ati o n pr o gr a m: i m pr o v e m e nts ar e i n d e p e n d e nt of l u n g f u nc-
ti o n. C hest  1 9 9 1; 9 9: 7 9 8 – 8 0 4.
4 0.  N os e d a A, C ar pi a u x J, Pri g o gi n e T, Sc h m er b er J. L u n g f u ncti o n, m a xi-
m u m a n d s u b m a xi m u m e x ercis e t esti n g i n C O P D p ati e nts: r e pr o d uc-
i bilit y o v er a l o n g i nt er v al. L u n g  1 9 8 9; 1 6 7: 2 4 7 – 2 5 7.
4 1.  K n o x AJ, M orris o n J F, M u ers M F. R e pr o d uci bilit y of w al ki n g t est r e-
s ults i n c hr o nic o bstr ucti v e air w a ys dis e as e. T h or a x  1 9 8 8; 4 3: 3 8 8 – 3 9 2.
4 2.  G u y att G H, P u gsl e y S O, S ulli v a n MJ, T h o m ps o n PJ, B er m a n L B, J o n es
N L, F all e n E L, T a yl or D W. Eff ect of e nc o ur a g e m e nt o n w al ki n g t est
p erf or m a nc e. T h or a x  1 9 8 4; 3 9: 8 1 8 – 8 2 2.
4 3. L e g er L A. A m a xi m al m ultist a g e 2 0- m s h uttl e r u n t est t o pr e dict V O 2
m a x. E ur J A p pl P h ysi ol  1 9 8 2; 4 9: 1 – 1 2.
4 4. Si n g h SJ, M or g a n M D L, Sc ott S, W alt ers D, H ar d m a n A E. D e v el o p-
m e nt of a s h uttl e w al ki n g t est of dis a bilit y i n p ati e nts wit h c hr o nic air-
w a ys o bstr ucti o n. T h or a x  1 9 9 2; 4 7: 1 0 1 9 – 1 0 2 4.
4 5.  R e vill S M, M or g a n M D L, Si n g h SJ, Willi a ms J, H ar d m a n A E. T h e e n d ur-
a nc e s h uttl e w al k: a n e w fi el d t est f or t h e ass ess m e nt of e n d ur a nc e c a p ac-
it y i n c hr o nic o bstr ucti v e p ul m o n ar y dis e as e. T h or a x  1 9 9 9; 5 4: 2 1 3 – 2 2 2.
4 6. Si n g h SJ, M or g a n M D L, H ar d m a n A E, R o w e C, B ar dsl e y P A. C o m p ar-
is o n of o x y g e n u pt a k e d uri n g a c o n v e nti o n al tr e a d mill t est a n d t h e
s h uttl e w al ki n g t est i n c hr o nic airfl o w li mit ati o n. E ur Res pir J  1 9 9 4; 7:
2 0 1 6 – 2 0 2 0.
4 7.  M or al es FJ, M arti n ez A, M e n d ez M, A g arr a d o A, Ort e g a F, F er n a n d ez-
G u err a J, M o nt e m a y or T, B ur g os J. A s h uttl e w al k t est f or ass ess m e nt of
f u ncti o n al c a p acit y i n c hr o nic h e art f ail ur e. A m He art J  1 9 9 9; 1 3 8: 2 9 2 – 2 9 8.
4 8.  E nri g ht P L, S h errill D L. R ef er e nc e e q u ati o ns f or t h e si x- mi n ut e w al k i n
h e alt h y a d ults. A m J Res pir Crit C are Me d  1 9 9 8; 1 5 8: 1 3 8 4 – 1 3 8 7.
4 9.  B arst RJ, R u bi n LJ, Mc G o o n M D, C al d w ell EJ. L o n g W A, L e v y P S.
S ur vi v al i n pri m ar y p ul m o n ar y h y p ert e nsi o n wit h l o n g-t er m c o nti n u-
o us i ntr a v e n o us pr ost ac ycli n. A n n I nter n Me d  1 9 9 4; 1 2 1: 4 0 9 – 4 1 5.
5 0. Mi y a m ot o S, N a g a y a N, S at o h T, K y ot a ni S, S a k a m a ki F, F ujit a M, N a-
k a nis hi N, Mi y at a k e K. Cli nic al c orr el at es a n d pr o g n ostic si g nific a nc e
of si x- mi n ut e w al k t est i n p ati e nts wit h pri m ar y p ul m o n ar y h y p ert e n-
si o n. A m J Res pir Crit C are Me d  2 0 0 0; 1 6 1: 4 8 7 – 4 9 2.
5 1.  G u y att G H, S ulli v a n MJ, T h o m ps o n PJ, F all e n E L, P u gsl e y S O, T a yl or
D W, B er m a n L B. T h e 6- mi n ut e w al k: a n e w m e as ur e of e x ercis e c a-
p acit y i n p ati e nts wit h c hr o nic h e art f ail ur e. C a n Me d Ass oc J  1 9 8 5;
1 3 2: 9 1 9 – 9 2 3.
5 2. Li p ki n D P, Scri vi n AJ, Cr a k e T, P o ol e- Wils o n P A. Si x mi n ut e w al ki n g
t est f or ass essi n g e x ercis e c a p acit y i n c hr o nic h e art f ail ur e. B MJ  1 9 8 6;
2 9 2: 6 5 3 – 6 5 5.
5 3. Tr o ost ers T, G oss eli n k R, D ecr a m er M. Si x mi n ut e w al ki n g dist a nc e i n
h e alt h y el d erl y s u bj ects. E ur Res pir J  1 9 9 9; 1 4: 2 7 0 – 2 7 4.
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
6 1


A m eri c a n T h or a ci c S o ci et y
1 1 7
5 4.  W eiss R A, et al. Si x mi n ut e w al k t est i n s e v er e C O P D: r eli a bilit y a n d ef-
f ect of w al ki n g c o urs e l a y o ut a n d l e n gt h. P a p er pr es e nt e d at A C C P
C o nf er e nc e; S e pt e m b er 2 0 0 0; S a n Fr a ncisc o.
5 5. St e v e ns D, El p er n E, S h ar m a K, Szi d o n P, A n ki n M, K est e n S. C o m p ar-
is o n of h all w a y a n d tr e a d mill si x- mi n ut e w al k t ests. A m J Res pir Crit
C are Me d  1 9 9 9; 1 6 0: 1 5 4 0 – 1 5 4 3.
5 6. J e ns e n L A, O n ys ki w J E, Pr as a d N G N. M et a- a n al ysis of art eri al o x y g e n
s at ur ati o n m o nit ori n g b y p uls e o xi m etr y i n a d ults. He art L u n g  1 9 9 8;
2 7: 3 8 7 – 4 0 8.
5 7.  B art h el e m y J C, G e yss a nt A, Riff at J, A nt o ni a dis A, B err u y er J, L a C o ur
J R. Acc ur ac y of p uls e o xi m etr y d uri n g m o d er at e e x ercis e: a c o m p ar a-
ti v e st u d y. Sc a n d J Cli n L a b I n vest  1 9 9 0; 5 0: 5 3 3 – 5 3 9.
5 8.  B or g G A V. Ps yc h o- p h ysic al b as es of p erc ei v e d e x erti o n. Me d Sci S p orts
E xerc  1 9 8 2; 1 4: 3 7 7 – 3 8 1.
5 9. L e ac h R M, D a vi ds o n A C, C hi n n S, T w ort C H C, C a m er o n I R, B at e m e n
N T. P ort a bl e li q ui d o x y g e n a n d e x ercis e a bilit y i n s e v er e r es pir at or y
dis a bilit y. T h or a x  1 9 9 2; 4 7: 7 8 1 – 7 8 9.
6 0.  M u n g all I P F, H ai ns w ort h R. Ass ess m e nt of r es pir at or y f u ncti o n i n p a-
ti e nts wit h c hr o nic o bstr ucti v e air w a ys dis e as e. T h or a x  1 9 7 9; 3 4: 2 5 4 – 2 5 8.
6 1.  R o b erts C M, B ell J, W e dzic h a J A. C o m p aris o n of t h e effic ac y of a d e-
m a n d o x y g e n d eli v er y s yst e m wit h c o nti n u o us l o w fl o w o x y g e n i n s u b-
j ects wit h st a bl e C O P D a n d s e v er e o x y g e n d es at ur ati o n o n w al ki n g.
T h or a x  1 9 9 6; 5 1: 8 3 1 – 8 3 4.
6 2.  H a y  J G,  St o n e  P,  C art er  J,  C h urc h  S,  E yr e- Br o o k  A,  P e ars o n  M G,
W o o dc oc k A A, C al v erl e y P M. Br o nc h o dil at or r e v ersi bilit y, e x ercis e
p erf or m a nc e a n d br e at hl ess n ess i n st a bl e c hr o nic o bstr ucti v e p ul m o-
n ar y dis e as e. E ur Res pir J  1 9 9 2; 5: 6 5 9 – 6 6 4.
6 3.  Gr o v e A, Li p w ort h BJ, R ei d P, S mit h R P, L a m a g e L, I n gr a m C G, J e n ki ns
RJ, Wi nt er J H, D hill o n D P. Eff ects of r e g ul ar s al m et er ol o n l u n g f u ncti o n
a n d e x ercis e c a p acit y i n p ati e nts wit h C O P D. T h or a x  1 9 9 6; 5 1: 6 8 9 – 6 9 3.
6 4.  R e d el m ei er D A, B a y o u mi A M, G ol dst ei n R S, G u y att G H. I nt er pr eti n g
s m all diff er e nc es i n f u ncti o n al st at us: T h e si x mi n ut e w al k t est i n c hr o nic
l u n g dis e as e p ati e nts. A m J Res pir Crit C are Me d  1 9 9 7; 1 5 5: 1 2 7 8 – 1 2 8 2.
6 5.  W ei n er P, M a g a dl e R, B er ar- Y a n a y N, D a vi d o vic h A, W ei n er M. T h e
c u m ul ati v e  eff ect  of  l o n g- acti n g  br o nc h o dil at ors,  e x ercis e,  a n d  i n-
s pir at or y  m uscl e  tr ai ni n g  o n  t h e  p erc e pti o n  of  d ys p n e a  i n  p ati e nts
wit h a d v a nc e d C O P D. C hest  2 0 0 0; 1 1 8: 6 7 2 – 6 7 8.
6 6.  Bitt n er V, S a n d ers o n B, Br el a n d J, A d a ms C, Sc h u m a n C. Ass essi n g
f u ncti o n al c a p acit y as a n o utc o m e i n c ar di ac r e h a bilit ati o n: r ol e of t h e
6 mi n ut e w al k t est. Cli nic al E xercise P h ysi ol o g y 2 0 0 0.
A P P E N DI X
T h e f oll o wi n g el e m e nts s h o ul d b e pr es e nt o n t h e 6 M W T w or ks h e et a n d r e p ort:
L a p c o u nt er: 
_ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _
P ati e nt n a m e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
P ati e nt I D # _ _ _ _ _ _ _ _ _ _ _
W al k # _ _ _ _ _ _ 
T ec h I D: _ _ _ _ _ _ _ _ _  D at e: _ _ _ _ _ _ _ _ _ _
G e n d er:  M F  
A g e: _ _ _ _  
R ac e: _ _ _ _  
H ei g ht: _ _ _ft _ _ _ _i n, _ _ _ _ m et ers
W ei g ht: _ _ _ _ _ _ l bs, _ _ _ _ _ k g  
Bl o o d pr ess ur e: _ _ _ _ _ / _ _ _ _ _
M e dic ati o ns t a k e n b ef or e t h e t est ( d os e a n d ti m e): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
S u p pl e m e nt al o x y g e n d uri n g t h e t est:  N o  
Y es, fl o w _ _ _ _ _ _ L/ mi n, t y p e _ _ _ _ _
B as eli n e  
E n d of T est
Ti m e 
_ _ _: _ _ _
_ _ _: _ _ _
H e art R at e _ _ _ _ _
_ _ _ _ _
D ys p n e a 
_ _ _ _
_ _ _ _ ( B or g sc al e)
F ati g u e 
_ _ _ _
_ _ _ _ ( B or g sc al e)
S p O 2
_ _ _ _ %
_ _ _ _ %
St o p p e d or p a us e d b ef or e 6 mi n ut es ?  N o  
Y es, r e as o n: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Ot h er s y m pt o ms at e n d of e x ercis e: a n gi n a 
dizzi n ess 
hi p, l e g, or c alf p ai n
N u m b er of l a ps: _ _ _ _ (
6 0 m et ers) 
 fi n al p arti al l a p: _ _ _ _ _ m et ers
T ot al dist a nc e w al k e d i n 6 mi n ut es: _ _ _ _ _ _ m et ers
Pr e dict e d dist a nc e: _ _ _ _ _ m et ers 
P erc e nt pr e dict e d: _ _ _ _ _ %
T ec h c o m m e nts:
I nt er pr et ati o n (i ncl u di n g c o m p aris o n wit h a pr ei nt er v e nti o n 6 M W D):
Pr ot oc ol 4 0 2- C- 1 6 0 2
Reata P har mace uticals, I nc.
C o nfi de ntial
Versi o n 3. 0
6 2


Pr ot oc ol 4 0 2- C- 1 6 0 2 
Reata P har mace uticals, I nc. 
C o nfi de ntial 
Versi o n 3. 0 
6 3   
2 0.  
A P P E N DI X 2: F U N C TI O N A L C L A S SI FI C A TI O N O F 
P U L M O N A R Y H Y P E R T E N SI O N M O DI FI E D A F T E R T H E N E W 
Y O R K H E A R T A S S O CI A TI O N F U N C TI O N A L 
C L A S SI FI C A TI O N A C C O R DI N G T O T H E W H O 1 9 9 8 
(G A LI E, 2 0 0 9 ) 
W orl d He alt h Or g a niz ati o n f u ncti o n al assess me nt cl assific ati o n   
Cl ass 
I:  
Patie nts wit h p ul m o nar y h y perte nsi o n ( P H)  b ut wit h o ut res ulti n g li mitati o n of p h ysic al 
acti vit y. Or di n ar y p h ysic al acti vit y d oes n ot ca use u n d ue d ys p n ea or fati g u e, c hes t pai n, 
or near s y n c o pe.  
Cl ass 
II:  
Patie nts  wit h P H res ulti n g i n sli g ht li mitati o n of p h ysical acti vit y. T h e y are c o mf orta ble 
at rest. Or di nar y p h ysical acti vit y ca uses u n d ue d ys p nea or fati g u e, c hest p ai n, or near 
s y nc o p e. 
Cl ass 
III:  
Patie nts  wit h P H res ulti n g i n mar ke d li mitati o n of p h ysical acti vit y. T h e y are 
c o mf orta ble at rest. Less t ha n or di nar y acti vit y ca uses u n d ue d ys p nea or fati g ue, c h est 
pai n, or near s y nc o pe.  
Cl ass 
I V:  
Patie nts  wit h P H wit h i na bilit y t o carr y o ut a n y p h ysical acti vit y wit h o ut s y m pt o ms. 
T hese patie nts  ma nifest si g ns of ri g ht -h eart fail ure. D ys p n ea a n d/ or fati g ue ma y e ve n be 
prese nt at rest. Disc o mf ort is i ncrease d b y a n y p h ysical acti vit y.  


Pr ot oc ol 4 0 2- C- 1 6 0 2 
Reata P har mace uticals, I nc. 
C o nfi de ntial 
Versi o n 3. 0 
6 4   
2 1.  
A P P E N DI X 3:  B O R G C R 1 0 S C A L E