Clinical trial NCT04494646
Conditions: Covid19
Keywords: Bardoxolone Methyl
Sponsor: NYU Langone Health
Start date: 2020-09-08; Completion date: 2021-01-08
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multi-center, double-blind, placebo-controlled, randomized Phase 2 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in patients hospitalized with confirmed COVID-19. The trial will include approximately 40 patients and is designed to provide an early interim analysis of safety. Patients will be randomized using permuted block randomization in a 1:1 fashion to either once-daily administration of bardoxolone methyl (20 mg) or matching placebo and treatment will be administered for the duration of hospitalization (until recovery), with a maximum treatment duration of 29 days.

Detailed description:
Following randomization on Day 1, patients will be assessed while hospitalized on Days 3, 5, 8, 11, 15, 22, and 29. Assessments will include clinical status assessments, vital sign measurements, clinical chemistry collection, and adverse event collection. Patients that recover prior to Day 29 will complete an end-of-treatment visit. Patients will have an in-person follow-up on Day 29, regardless of treatment adherence and recovery status prior to Day 29, and a safety follow-up 60 days after randomization for clinical status assessments, vital sign measurements, clinical chemistry collection, and adverse event collection. Follow-up in-person visits are preferred but recognizing quarantine and other factors may limit the subject's ability to return to the site for the visit. In this case, the visit may be performed by phone. An independent Data and Safety Monitoring Board will advise the study leadership on safety aspects and overall progress of the study.

Arms: arm 1: Patients will be randomized using permuted block randomization in a 1:1 fashion to either once-daily administration of bardoxolone methyl (20 mg) or matching placebo arm 2: Patients will be randomized using permuted block randomization in a 1:1 fashion to either once-daily administration of bardoxolone methyl (20 mg) or matching placebo
Interventions: intervention 1: Bardoxolone Methyl intervention 2: Placebo
Intervention descriptions: intervention 1: Once-daily administration of bardoxolone methyl (20mg) intervention 2: Once-daily administration of matching placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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BARCONA Trial: A phase II/III, randomized, double-blind, placebo-
controlled, multi-center study of the effects of bardoxolone methyl in 
participants with SARS-Corona Virus-2 (COVID-19) 
 
Principal Investigator: 
 
Sripal Bangalore, MD, MHA 
Department of Medicine 
Division of Cardiology 
 
New York University Langone Health, 
530 First Avenue, SKI 9R-109 
New York, NY 10016 
Sripal.Bangalore@nyulangone.org 
212-263-3540 
 
NYULMC Study Number: 
S20-00591 
Funding Sponsor:  
Reata Pharmaceuticals, Inc.  
5320 Legacy Drive, Plano, TX 
(972) 865-2219 
 
IND Number: 
150943 
Regulatory Sponsor:  
Sripal Bangalore, MD, MHA 
Department of Medicine 
Division of Cardiology 
 
New York University Langone Health, 
530 First Avenue, SKI 9R-109 
New York, NY 10016 
Sripal.Bangalore@nyulangone.org 
212-263-3540 
 
Study Product: 
Bardoxolone methyl 
Study Product Provider:  
Reata Pharmaceuticals, Inc. 
ClinicalTrials.gov 
Number                 
NCT04494646 
 
Protocol Version: 1.1 
Version Date:  September 9, 2020
 


Study number: S20-00591 
 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study number: S20-00591 
 
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Interventional Template Version: 11 January 2019 
 
Protocol Signature Page 
 
BARCONA Trial: A phase II/III, randomized, double-blind, placebo-controlled, multi-center study 
of the effects of bardoxolone methyl in participants with SARS-Corona Virus-2 (COVID-19) 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 
 
Version Date:  September 9, 2020 
 
 
 
 
 
Signature of Principal Investigator 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 
 
Name of Facility 
 
 
 
 
 
 
Location of Facility (City, Country) 
 
 
 
 
 
 
 
 
 


Study number: S20-00591 
 
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Table of Contents 
 
STATEMENT OF COMPLIANCE .................................................................................................................. II 
PROTOCOL SIGNATURE PAGE ................................................................................................................. III 
LIST OF ABBREVIATIONS ....................................................................................................................... VII 
PROTOCOL SUMMARY ............................................................................................................................... 1 
SCHEMATIC OF STUDY DESIGN FOR PHASE II AND PHASE III ............................................................ 7 
1 
KEY ROLES .......................................................................................................................................... 8 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 9 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ................................................................ 9 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ............................................................. 10 
2.2.1 
Preclinical Data ...................................................................................................................... 10 
2.2.2 
Clinical Data to Date .............................................................................................................. 11 
2.2.3 
Dose Rationale (if applicable) ................................................................................................ 11 
2.3 
RATIONALE ................................................................................................................................... 11 
2.4 
POTENTIAL RISKS & BENEFITS ...................................................................................................... 12 
2.4.1 
Known Potential Risks ........................................................................................................... 12 
2.4.2 
Known Potential Benefits ....................................................................................................... 13 
3 
OBJECTIVES AND PURPOSE .......................................................................................................... 14 
3.1 
PHASE 2 ....................................................................................................................................... 14 
3.1.1 
Primary Objective ................................................................................................................... 14 
3.2 
PHASE 3 ....................................................................................................................................... 14 
3.2.1 
Primary Objectives ................................................................................................................. 14 
3.2.2 SECONDARY AND EXPLORATORY OBJECTIVES .................................................................................... 14 
3.2.3. SAFETY ENDPOINTS ......................................................................................................................... 14 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................. 15 
4.1 
DESCRIPTION OF STUDY DESIGN ................................................................................................... 15 
4.2 
STUDY ENDPOINTS ....................................................................................................................... 15 
4.2.1 
Phase 2 .................................................................................................................................. 15 
4.2.2 
Phase 3 .................................................................................................................................. 16 
5 
STUDY ENROLLMENT AND WITHDRAWAL ................................................................................... 16 
5.1 
INCLUSION CRITERIA ..................................................................................................................... 16 
5.2 
EXCLUSION CRITERIA .................................................................................................................... 17 
5.3 
VULNERABLE SUBJECTS ................................................................................................................ 17 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 18 
5.5 
DURATION OF STUDY PARTICIPATION ............................................................................................. 18 
5.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 18 
5.7 
PARTICIPANT TREATMENT DISCONTINUATION ................................................................................. 18 
5.7.1 
Reasons for Treatment Discontinuation ................................................................................ 18 
5.8 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 18 
5.8.1 
Reasons for Withdrawal or Termination ................................................................................ 18 
5.8.2 
Handling of Participant Withdrawals or Termination .............................................................. 19 
5.9 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 19 
6 
STUDY AGENT................................................................................................................................... 19 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 19 
6.1.1 
Acquisition .............................................................................................................................. 20 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................. 20 
6.1.3 
Product Storage and Stability ................................................................................................ 21 


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6.1.4 
Preparation ............................................................................................................................. 21 
6.1.5 
Dosing and Administration ..................................................................................................... 21 
6.1.6 
Route of Administration .......................................................................................................... 21 
6.1.7 
Starting Dose.......................................................................................................................... 21 
6.1.8 
Dose Adjustments/Modifications/Delays ................................................................................ 21 
6.1.9 
Duration of Therapy ............................................................................................................... 21 
6.1.10 
Tracking of Dose ................................................................................................................ 21 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES .............................................................................. 21 
7 
STUDY PROCEDURES AND SCHEDULE ........................................................................................ 22 
7.1 
STUDY PROCEDURES/EVALUATIONS .............................................................................................. 22 
7.1.1 
Study Specific Procedures ..................................................................................................... 22 
7.1.2 
Standard of Care Study Procedures ...................................................................................... 24 
7.2 
STUDY SCHEDULE ........................................................................................................................ 24 
7.2.1 
Screening/Enrollment ............................................................................................................. 24 
7.2.2 
Intermediate Visits .................................................................................................................. 24 
7.2.3 
Final Safety Follow-up............................................................................................................ 26 
7.2.4 
Withdrawal/Early Termination Visit ........................................................................................ 26 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................................. 27 
7.3 
JUSTIFICATION FOR SENSITIVE PROCEDURES ................................................................................. 27 
7.3.1 
Precautionary Medications, Treatments, and Procedures ..................................................... 27 
7.4 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ........................................................ 27 
8 
ASSESSMENT OF SAFETY .............................................................................................................. 27 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 27 
8.1.1 
Definition of Adverse Events (AE).......................................................................................... 27 
8.1.2 
Definition of Serious Adverse Events (SAE) .......................................................................... 28 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 28 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT........................................................................................ 28 
8.2.1 
Severity of Event .................................................................................................................... 28 
8.2.2 
Relationship to Study Agent ................................................................................................... 29 
8.2.3 
Expectedness ......................................................................................................................... 29 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 29 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB ........................................................................... 30 
8.4.1 
Serious Adverse Event Reporting .......................................................................................... 30 
8.4.2 
Unanticipated Problem Reporting .......................................................................................... 30 
8.4.3 
Reporting of Pregnancy ......................................................................................................... 30 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ....................................................... 31 
8.6 
REPORTING PROCEDURES – NOTIFYING THE FDA.......................................................................... 32 
8.7 
SAFETY OVERSIGHT ...................................................................................................................... 33 
9 
CLINICAL MONITORING ................................................................................................................... 33 
10 
STATISTICAL CONSIDERATIONS ................................................................................................... 33 
10.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) .................................................................................. 33 
10.2 
STATISTICAL HYPOTHESES ............................................................................................................ 34 
10.2.1 
Phase 2 .............................................................................................................................. 34 
10.2.2 
Phase 3 .............................................................................................................................. 34 
10.3 
ANALYSIS POPULATIONS ............................................................................................................... 34 
10.4 
DESCRIPTION OF STATISTICAL METHODS ....................................................................................... 34 
10.4.1 
General Approach .............................................................................................................. 34 
10.4.2 
Analysis of the Phase 3 Primary Efficacy Endpoint........................................................... 34 
10.4.3 
Analysis of the Secondary/Exploratory Endpoints............................................................. 35 
10.4.4 
Safety Analyses ................................................................................................................. 35 
10.4.5 
Adherence and Retention Analyses .................................................................................. 35 
10.4.6 
Baseline Descriptive Statistics ........................................................................................... 35 
10.4.7 
Planned Interim Analysis ................................................................................................... 35 


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10.4.8 
Additional Sub-Group Analyses ......................................................................................... 35 
10.4.9 
Multiple Comparison/Multiplicity ........................................................................................ 36 
10.4.10 
Tabulation of Individual Response Data ............................................................................ 36 
10.4.11 
Exploratory Analyses ......................................................................................................... 36 
10.5 
SAMPLE SIZE ................................................................................................................................ 36 
10.6 
MEASURES TO MINIMIZE BIAS ........................................................................................................ 37 
10.6.1 
Enrollment/Randomization/Masking Procedures .............................................................. 37 
10.6.2 
Breaking the Study Blind/Participant Code ....................................................................... 37 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 37 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................................................ 38 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 38 
13.1 
ETHICAL STANDARD ...................................................................................................................... 38 
13.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 38 
13.3 
INFORMED CONSENT PROCESS ..................................................................................................... 38 
13.3.1 
Consent and Other Informational Documents Provided to Participants ............................ 38 
13.3.2 
Consent Procedures and Documentation ......................................................................... 39 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY ..................................................................................... 39 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................... 40 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 40 
14.2 
STUDY RECORDS RETENTION........................................................................................................ 40 
14.3 
PROTOCOL DEVIATIONS ................................................................................................................ 41 
14.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 41 
15 
STUDY FINANCES ............................................................................................................................. 41 
15.1 
FUNDING SOURCE ........................................................................................................................ 41 
15.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 41 
15.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................. 41 
16 
STUDY ADMINISTRATION ................................................................................................................ 41 
16.1 
STUDY LEADERSHIP ...................................................................................................................... 41 
17 
CONFLICT OF INTEREST POLICY ................................................................................................... 41 
18 
REFERENCES .................................................................................................................................... 43 
19 
SCHEDULE OF EVENTS ................................................................................................................... 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study number: S20-00591 
 
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List of Abbreviations 
 
Abbreviation or Specialist Term 
Explanation 
ADPKD 
Autosomal dominant polycystic kidney disease 
AE 
Adverse event 
AKI 
Acute kidney injury 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BNP 
B-type natriuretic peptide 
BUN 
Blood urea nitrogen 
CCC 
Clinical Coordination Center 
CFR 
Code of Federal Regulations (US) 
CGI-I 
Clinical Global Impression - Improvement 
CK 
Creatine kinase 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
Coronavirus disease 2019 
CrCl 
Creatinine clearance 
CRO 
Clinical research organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
DCC 
Data Coordinating Center 
EC 
Ethics Committee 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
ERA 
Endothelin receptor antagonist 
FDA 
Food and Drug Administration (US) 


Study number: S20-00591 
 
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Abbreviation or Specialist Term 
Explanation 
FSGS 
Focal segmental glomerular sclerosis 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transpeptidase 
hCG-Qual 
Human chorionic gonadotropin-qualitative  
HDPE 
High-density polyethylene 
HO-1 
Heme oxygenase-1 
ICH 
International Conference on Harmonization 
IgAN 
IgA nephropathy 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
Keap1 
Kelch-like ECH associated protein-1 
LAR 
Legally Authorized Representative 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MRI 
Magnetic resonance imaging 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B-cells 
Nrf2 
Nuclear factor (erythroid-derived 2)-related factor 2 
PBO 
Placebo  
PH 
Pulmonary hypertension 
RRT 
Renal replacement therapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
T2D 
Type 2 diabetes  
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
UP 
Unanticipated Problem 
US 
United States 
WHO 
World Health Organization 
WOCBP 
Women of child bearing potential 
 
 


Study number: S20-00591 
 
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Protocol Summary 
Title 
BARCONA Trial: A phase II/III, randomized, double-blind, placebo-
controlled, multi-center study of the effects of bardoxolone methyl in 
participants with SARS-Corona Virus-2 (COVID-19) 
Short Title 
BARCONA Trial: A Randomized Trial of Bardoxolone Methyl in Patients 
Infected with SARS-Corona Virus-2 (COVID-19) 
Brief Summary 
This multi-center, double-blind, placebo-controlled, randomized Phase 
2/3 trial will study the safety, tolerability, and efficacy of bardoxolone 
methyl in approximately 400-440 patients hospitalized with confirmed 
COVID-19.  The Phase 2 portion of the trial will include approximately 
40 patients and is designed to provide an early interim analysis of 
safety. The Phase 3 portion of the trial will include approximately 360-
400 additional patients, and is designed to determine whether 
bardoxolone methyl increases the probability of recovery at Day 29 
when compared with matching placebo.  Patients will be randomized 
using permuted block randomization in a 1:1 fashion to either once-daily 
administration of bardoxolone methyl (20 mg) or matching placebo and 
treatment will be administered for the duration of hospitalization (until 
recovery), with a maximum treatment duration of 29 days. 
Phase 
Phases 2/3 
Objectives 
Phase 2 
Primary: To provide an initial assessment of the safety of bardoxolone 
methyl in COVID-19 patients when compared with matching placebo 
Phase 3 
Primary: To determine whether bardoxolone methyl in COVID-19 
patients increases the probability of recovery at Day 29 when compared 
with matching placebo. To assess the safety of bardoxolone methyl in 
COVID-19 patients when compared with matching placebo 
Secondary and Exploratory: To assess the effect of bardoxolone 
methyl on other endpoints including renal function when compared with 
matching placebo. 


Study number: S20-00591 
 
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Methodology 
This multi-center, double-blind, placebo-controlled, randomized Phase 
2/3 trial will study the safety, tolerability, and efficacy of bardoxolone 
methyl in approximately 400-440 patients hospitalized with confirmed 
COVID-19.  Phase 2 has safety as the primary endpoint and 
approximately 40 patients will be enrolled.  A pause in enrollment will 
occur until the DSMB performs an initial safety assessment of Phase 2.  
Phase 3 is designed to determine whether bardoxolone methyl 
increases the probability of recovery at Day 29 compared with matching 
placebo. In phase 3, approximately additional 360-400 patients will be 
enrolled. Patients will be randomized using permuted block 
randomization in a 1:1 fashion to either once-daily administration of 
bardoxolone methyl (20 mg) or matching placebo.  Patients will be 
stratified by study center and invasive mechanical ventilation (i.e., 
mechanical ventilation with endotracheal intubation) use at baseline 
(yes or no).  Enrollment of patients ≥70 years of age may be limited 
(e.g., comprise no more than 10% of all randomized patients), pending 
safety review by the DSMB and executive committee.  Treatment will 
be administered for the duration of hospitalization (until recovery), with 
an expected duration of 10 days. For patients who are hospitalized for 
more than 10 days, treatment can be continued for a maximum 
treatment duration of 29 days.  Dose de-escalation (down to 10 mg) is 
permitted during the study if indicated clinically, and subsequent dose 
re-escalation is also permitted.   
 
Patients in the Phase 2 and Phase 3 portions of the study will follow the 
same schedule of dosing and study assessments.  Following 
randomization on Day 1, patients will be assessed while hospitalized on 
Days 3, 5, 8, 11, 15, 22, and 29.  Assessments will include clinical status 
assessments, vital sign measurements, clinical chemistry collection, 
and adverse event collection.  Patients that recover prior to Day 29 will 
complete an end-of-treatment visit. Patients will have an in-person 
follow-up on Day 29, regardless of treatment adherence and recovery 
status prior to Day 29, and a safety follow-up 60 days after 
randomization for clinical status assessments, vital sign measurements, 
clinical chemistry collection, and adverse event collection. Follow-up in-
person visits are preferred but recognizing quarantine and other factors 
may limit the subject’s ability to return to the site for the visit. In this 
case, the visit may be performed by phone. An independent Data and 
Safety Monitoring Board will advise the study leadership on safety 
aspects and overall progress of the study. 


Study number: S20-00591 
 
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Endpoints 
Phase 2 
Primary: 
• 
Safety (e.g., frequency, intensity, and relationship to study drug 
of serious adverse events [including unexpected deaths], 
change from baseline in vital sign and laboratory assessments) 
at Day 29 
Phase 3 
Primary: 
• 
Proportion of subjects recovered (defined as alive, free of 
respiratory failure [e.g., need for non-invasive or invasive 
mechanical ventilation, high flow oxygen, or ECMO], and free of 
renal replacement therapy [RRT]) at Day 29 
Secondary (assessed at Day 29 unless stated otherwise): 
 
• 
Number of renal replacement therapy (RRT)-free days 
• 
Number of mechanical ventilation-free days  
• 
All-cause mortality 
• 
Proportion of subjects experiencing a deterioration from 
baseline (as defined by a 1-point worsening) to end of treatment 
or Day 29 (whichever comes first) in clinical status using an 11-
category ordinal scale:  
o 0 – Uninfected; no viral RNA detected 
o 1 – Asymptomatic; viral RNA detected 
o 2 – Symptomatic; Independent 
o 3 – Symptomatic; assistance needed 
o 4 – Hospitalized; no oxygen therapy 
o 5 – Hospitalized; oxygen by mask or nasal prongs 
o 6 – Hospitalized; oxygen by NIV or High flow 
o 7 – Intubation & Mechanical ventilation; pO2/FIO2 >/= 
150 or SpO2/FIO2 >/=200 
o 8 
– 
Mechanical 
ventilation 
SpO2/FIO2 
< 
150  
(SpO2/FIO2 <200) or vasopressors 
o 9 – Mechanical ventilation pO2/FIO2 < 150 and 
vasopressors, dialysis or ECMO 
o 10 – Death 
Exploratory (assessed at Day 29 unless stated otherwise): 
• 
Change from baseline in eGFR 
• 
Time to recovery  
• 
Recovery at Day 60 
• 
Change from baseline in PaO2/ FiO2 (while hospitalized on Day 
5, 8, 15, and end of treatment) 


Study number: S20-00591 
 
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• 
Change from baseline in D-dimer, CRP, LDH, troponin and 
cytokine levels (while hospitalized on Day 5, 8, 15, and end of 
treatment) 
Study Duration 
Approximately 12 months  
Participant 
Duration 
Approximately 2 months (including follow-up) 
Duration 
of 
IP 
administration 
Bardoxolone methyl or placebo will be administered for the duration of 
hospitalization (until recovery), with an expected duration of 10 days. 
For patients who are still hospitalized for more than 10 days, treatment 
can be continued for a maximum treatment duration of 29 days. 


Study number: S20-00591 
 
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Population 
Diagnosis and main criteria for inclusion: 
1. Laboratory-confirmed COVID-19 infection as determined by 
polymerase chain reaction (PCR) 
2. Hospitalized patients who meet one of the following conditions:   
(i) 
Radiographic infiltrates by imaging (chest x-ray, CT scan, 
etc.); OR  
(ii) At rest, blood oxygen saturation ≤ 94%; OR   
(iii) Require supplemental oxygen; OR  
(iv) Requiring non-invasive ventilation; OR  
(v) Requiring invasive mechanical ventilation for up to 2 days.  
3.  Age ≥ 18 years.  Enrollment of patients ≥70 years of age may 
be limited (e.g., comprise no more than 10% of all randomized 
patients), pending safety review by the DSMB and executive 
committee 
4. Participant or legally authorized representative is willing to give 
informed consent  
Exclusion criteria: 
1. Intubated and on invasive mechanical ventilation for three or 
more days at the time of randomization   
2. Known left ventricular ejection fraction (LVEF) <40% or prior 
hospitalization for heart failure  
3. Cardiac arrest   
4. Shock  
5. Known uncontrolled bacterial, fungal, or non-COVID viral 
infection  
6. eGFR <30 ml/min/1.73 m2 or requiring dialysis  
7. ALT or AST > 5X ULN  
8. History of cirrhosis, chronic active hepatitis or severe hepatic 
disease  
9. Pregnant or lactating women  
10. Enrolled in other trial of unapproved therapies, unless approved 
by trial Principal Investigator. In general, co-enrollment will be 
permitted unless there are safety concerns, mechanistic 
incompatibility or inability to adjudicate serious adverse events 
and will be decided on a case by case basis.  
11. If in the opinion of the clinical team, progression to death is 
imminent and inevitable within the next 24 hours, irrespective of 
the provision of treatments   
Study Sites 
Approximately 20 sites 
Number 
of 
participants 
Approximately 400-440 participants across approximately 20 sites 
Description 
of 
Study 
Agent/Procedure 
Bardoxolone methyl will be administered orally at 20 mg once daily. 
Patients unable to receive oral dosing will receive study drug via a 
nasogastric or orogastric tube. 


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Reference Therapy 
Placebo 
Statistical Analysis 
A total sample size of approximately 400 participants (Phase 2 
combined with Phase 3, or Phase 3 alone) randomized 1:1 using 
permuted block randomization (~200 bardoxolone methyl; ~200 
placebo) is expected to provide approximately 80% power at a two-
sided 0.05 significance level using a generalized linear model analysis 
to detect a risk difference of +14%, assuming the following: 
• 
Follow-up for events for 28 days after randomization 
(through Day 29) 
• 
2% of patients in each group drop-out prior to recovery 
• 
Recovery for 50% patients randomized to placebo relative to 
64% of patients randomized to bardoxolone methyl. 
At a designated time during the trial (~40% and ~70% of projected 
sample size has accrued) interim analysis will be performed for safety, 
harm, and futility.  
The analysis will be based on intention to treat using a generalized 
linear model analysis to compare the probability of recovery at Day 
29.  The phase 2 analysis for safety will not assess the primary endpoint 
and will not impact the overall type I error rate of the trial. If the DSMB 
concludes the trial should continue to the Phase 3 part, then the phase 
2 patients will be included in the phase 3 portion of the study (unless 
Phase 2 is unblinded as discussed in Section 8.6).  
 
 
 


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Schematic of Study Design for Phase II and Phase III 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 Key Roles 
 
Role in Study 
Name 
Address and Email 
Principal Investigator 
Sripal Bangalore, MD, MHA 
New York University Langone Health, 
530 First Avenue, SKI 9R-109 
New York, NY 10016 
 
Sripal.Bangalore@nyulangone.org 
Sub-Investigator 
Atul Sharma, MD 
 
NYU Langone Hospital-Brooklyn 
150 55th St,  
Brooklyn, NY 11220 
 
Atul.Sharma@nyulangone.org 
Sub-Investigator 
Alexander Slotwiner, MD 
NYU Langone Hospital-Brooklyn 
150 55th St,  
Brooklyn, NY 11220 
 
Alexander.Slotwiner@nyulangone.org 
Sub-Investigator 
Juan Gaztanaga, MD 
 
New York University Winthrop 
259 First Street 
Mineola, NY 11501 
 
Juan.Gaztanaga@nyulangone.org 
Sub-Investigator 
Kevin Marzo, MD 
 
New York University Winthrop 
259 First Street 
Mineola, NY 11501 
 
Kevin.Marzo@nyulangone.org 
Sub-Investigator 
Eugene Yuriditsky, MD 
 
New York University Langone Health, 
530 First Avenue 
New York, NY 10016 
 
Eugene.Yuriditsky@nyulangone.org 
Sub-Investigator 
James Horowitz, MD 
New York University Langone Health, 
530 First Avenue 
New York, NY 10016 
 
James.Horowitz@nyulangone.org 
Sub-Investigator 
Norma Keller, MD 
New York University Langone Health, 
530 First Avenue 
New York, NY 10016 
 
Norma.Keller@nyulangone.org  


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Role in Study 
Name 
Address and Email 
Sub-Investigator 
Carlos Alviar, MD 
New York University Langone Health, 
530 First Avenue 
New York, NY 10016 
 
Carlos.Alviar@nyulangone.org 
Clinical Coordinating 
Center 
NYU Clinical Coordinating 
Center 
Translational Research Building 
227 East 30th Street, 8th Floor 
New York, NY 10016 
 
BARCONA@nyulangone.org 
Data Coordinating 
Center 
NYU Clinical Research 
DataCore 
360 Park Avenue South  
New York, NY 10010 
 
BARCONA@nyulangone.org  
Statistician 
Charles Cleland, PhD 
180 Madison Avenue, 2-53 
New York, NY 10016 
  
Charles.Cleland@nyulangone.org 
Reata Medical Contact 
Medical Monitor Team 
 
Reata Pharmaceuticals, Inc. 
5320 Legacy Drive, Plano, TX  
 
Phone: 469-262-6622 
Email: MedMon@Reatapharma.com 
Sub-Investigator 
Sudhakar Prabhu, MD 
NYC Health + Hospitals/Coney Island 
2601 Ocean Parkway 
Brooklyn, New York 11235 
 
Email: sudhakar.prabhu@nychhc.org 
Sub-Investigator 
Mazullah Kamran, MD 
NYC Health + Hospitals/Elmhurst 
79-01 Broadway 
Elmhurst, New York 11373 
 
Email: kamranma@nychcc.org 
 
2 Introduction, Background Information and Scientific Rationale 
2.1 
Background Information and Relevant Literature 
Infection with the recently identified SARS-CoV-2 virus leads to an illness known as COVID-19. Mild cases 
of COVID-19 generally resolve quickly; however, some patients with moderate-to-severe COVID-19 rapidly 
develop symptoms that lead to serious complications such as acute respiratory distress syndrome (ARDS), 


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acute kidney injury (AKI), and multiple organ failure (Sarzi-Puttini, 2020; Huang, 2020; Chen, 2020; 
Guan,2020). The severity of COVID-19, as well as the development of serious complications, is associated 
with an imbalance in the response of the immune system to the infection with excessive production of pro-
inflammatory cytokines and chemokines (Liu, 2020). The Keap1-Nrf2 system rapidly responds to cellular 
stress by orchestrating an elaborate genetic program that enhances cellular cytoprotective functions, 
including detoxification, antioxidant, and anti-inflammatory networks (Dinkova-Kostova, 2015).  
The potent anti-inflammatory effects of bardoxolone methyl in cultured cells has translated into broad 
protective activity in animal models of acute lung injury and inflammation (Nichols, 2009, Chen 2015, Pei, 
2019; Reddy, 2009; Zhang, 2019; Nagashima, 2019; Kulkarni, 2013). Bardoxolone methyl and analogs 
significantly reduce neutrophil and macrophage infiltration and suppress proinflammatory cytokine and 
chemokine levels in the lungs of mice treated with inflammatory stimuli (Nichols, 2009; Chen 2015, Reddy, 
2009). In these models, bardoxolone methyl and analogs also reduced pulmonary edema, decreased lung 
injury scores, prevented fibrosis, and improved lung function (Chen 2015; Pei, 2019; Kulkarni, 2013).  
Bardoxolone methyl and analogues also reduce proinflammatory cytokines and chemokines, prevent organ 
damage (lung, liver, and pancreas), and increase survival in models of systemic inflammation 
(Thimmulappa, 2006; Auletta, 2010, Osburn, 2008; Keleku-Lukwete, 2015; Robles, 2016).  
In addition to their anti-inflammatory and tissue protective activity, bardoxolone methyl and analogs have 
been shown to inhibit viral replication, suppress viral infection, inhibit transcription of viral genes, and 
prevent latent viral reactivation in vitro (Vázquez, 2005; Shao, 2016; Chandra, 2018; Patra, 2019; Nio, 2019; 
Wyler, 2019; Rothan, 2019). Consistent with the mechanism of action of these compounds, the Nrf2 target 
heme oxygenase-1 (HO-1) has been shown to exhibit significant antiviral activity (Espinoza, 2017). 
In patients with COVID-19, AKI has been reported to occur in up to 28% of all patients and up to 72% of 
non-survivors (Fanelli, 2020; Yang, 2020; Zhou, 2020; Naicker, 2020). Bardoxolone methyl and analogues 
protect kidney tissue, reduce inflammation, prevent fibrosis, and increase kidney function in animal models 
of chronic kidney disease and AKI (Chin, 2013; Tanaka, 2008; Wu, 2011; Aminzadeh, 2013).  Moreover, 
bardoxolone methyl has been shown to improve kidney function—assessed using a variety of measures 
including measured inulin clearance, creatinine clearance, and estimated glomerular filtration rate—in 
patients with diabetes, Alport syndrome, autosomal dominant polycystic kidney disease (ADPKD), IgA 
nephropathy (IgAN), and focal segmental glomerular sclerosis (FSGS) (Pergola, 2011; de Zeeuw, 2013). 
The profile of eGFR increases with bardoxolone methyl reflects its multiple protective and anti-inflammatory 
effects.  Early improvements in eGFR evident within the first 4 weeks of bardoxolone methyl treatment are 
likely attributed to the reversal of acute, dynamic inflammation-mediated processes such as endothelial 
dysfunction and mesangial cell contraction resulting in glomerular filtration surface area increases 
(Aminzadeh, 2013; Chin, 2018; Ding, 2013; Ferguson, 2010).   
Taken together, the broad anti-inflammatory, antiviral, and tissue protective activities of bardoxolone methyl 
suggest that it may reduce the excessive production of cytokines and chemokines and prevent ARDS and 
AKI in patients with COVID-19. 
2.2 
Name and Description of the Investigational Agent  
Bardoxolone methyl, an investigational drug, has been shown to activate the Keap1-Nrf2 system, which 
allows Nrf2 to increase expression of antioxidant and cytoprotective genes and decrease expression of pro-
inflammatory NF-κB target genes (Lee, 2009; Dinkova-Kostova, 2005; Rojas-Rivera, 2012; Osburn & 
Kensler, 2008).  Consistent with this activity, bardoxolone methyl and analogues suppress proinflammatory 
cytokines and chemokines and reduce oxidative stress in many cell types in response to a variety of 
inflammatory triggers (Chen 2015; Thimmulappa, 2007; Pei, 2019, Nichols, 2009).  Approximately 3200 
individuals have been exposed to bardoxolone methyl in clinical trials, including studies in patients with 
cancer, chronic kidney disease (CKD), and pulmonary hypertension (PH).  
2.2.1 Preclinical Data 
The potent anti-inflammatory effects of bardoxolone methyl in cultured cells has translated into broad 
protective activity in animal models of acute lung injury and inflammation (Nichols, 2009, Chen 2015, Pei, 
2019; Reddy, 2009; Zhang, 2019; Nagashima, 2019; Kulkarni, 2013). Bardoxolone methyl and analogs 


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significantly reduce neutrophil and macrophage infiltration and suppress proinflammatory cytokine and 
chemokine levels in the lungs of mice treated with inflammatory stimuli (Nichols, 2009; Chen 2015, Reddy, 
2009). In these models, bardoxolone methyl and analogs also reduced pulmonary edema, decreased lung 
injury scores, prevented fibrosis, and improved lung function (Chen 2015; Pei, 2019; Kulkarni, 2013).  
Bardoxolone methyl and analogues also reduce proinflammatory cytokines and chemokines, prevent organ 
damage (lung, liver, and pancreas), and increase survival in models of systemic inflammation 
(Thimmulappa, 2006; Auletta, 2010, Osburn, 2008; Keleku-Lukwete, 2015; Robles, 2016).  
In addition to their anti-inflammatory and tissue protective activity, bardoxolone methyl and analogs have 
been shown to inhibit viral replication, suppress viral infection, inhibit transcription of viral genes, and 
prevent latent viral reactivation in vitro (Vázquez, 2005; Shao, 2016; Chandra, 2018; Patra, 2019; Nio, 2019; 
Wyler, 2019; Rothan, 2019). Consistent with the mechanism of action of these compounds, the Nrf2 target 
heme oxygenase-1 (HO-1) has been shown to exhibit significant antiviral activity (Espinoza, 2017). 
Lastly, preclinical studies have demonstrated that bardoxolone methyl and analogues protect kidney tissue, 
reduce inflammation, prevent fibrosis, and increase kidney function in many different animal models of 
kidney disease, including: ischemia-reperfusion-induced acute kidney injury (AKI) (Liu, 2014), chemically 
induced acute kidney injury (AKI) (Tanaka, 2008; Aleksunes, 2010; Wu, 2014), CKD associated with 
diabetes and/or obesity (Chin, 2013; Tan, 2014; Camer, 2016), CKD caused by nephron loss (Aminzadeh, 
2013; Aminzadeh, 2014; Son, 2015), CKD caused by glomerulonephritis (Nagasu, 2019), autoimmune-
associated kidney disease (Wu, 2014), and hypertension-associated kidney disease (Hisamichi, 2018). 
2.2.2 Clinical Data to Date 
Approximately 3200 individuals have been exposed to bardoxolone methyl in clinical trials, including studies 
in healthy subjects, patients with cancer, pulmonary hypertension (PH), and various forms of chronic kidney 
disease (CKD). As described in Section Error! Reference source not found., bardoxolone methyl has 
been shown to improve kidney function—assessed using a variety of measures including measured inulin 
clearance, creatinine clearance, and estimated glomerular filtration rate—in patients with CKD due to 
diabetes, Alport syndrome, autosomal dominant polycystic kidney disease (ADPKD), IgA nephropathy 
(IgAN), and focal segmental glomerular sclerosis (FSGS) (Pergola, 2011; de Zeeuw, 2013). 
The profile of eGFR increases with bardoxolone methyl reflects its multiple protective and anti-inflammatory 
effects.  Early improvements in eGFR evident within the first 4 weeks of bardoxolone methyl treatment are 
likely attributed to the reversal of acute, dynamic inflammation-mediated processes such as endothelial 
dysfunction and mesangial cell contraction resulting in glomerular filtration surface area increases 
(Aminzadeh, 2013; Chin, 2018; Ding, 2013; Ferguson, 2010).   
Please refer to the Investigator’s Brochure for a detailed discussion of safety findings for studies in healthy 
subjects, cancer, CKD, and PH patients with bardoxolone methyl. 
2.2.3 Dose Rationale (if applicable)  
Several dose-ranging studies which have been conducted with bardoxolone methyl demonstrated that 
changes in eGFR are dose-dependent.  The 20 mg bardoxolone methyl dose used in the present study 
provides near-optimal pharmacological activity and efficacy while also minimizing potential tolerability 
issues.  Furthermore, most of the available clinical safety and efficacy data for bardoxolone methyl has 
been collected with the 20 mg dose.   
2.3 
Rationale 
Some patients with moderate-to-severe COVID-19 rapidly develop symptoms that lead to serious 
complications such as ARDS, AKI, and multiple organ failure. The severity of COVID-19, as well as the 
development of serious complications, is associated with an imbalance in the response of the immune 
system to the infection with excessive production of pro-inflammatory cytokines and chemokines. 
Bardoxolone methyl and analogues exhibit potent anti-inflammatory activity in vitro. Moreover, bardoxolone 
and analogues suppress inflammation and tissue damage in animal models of acute lung injury and reduce 
mortality in models of systemic inflammation. In addition to the anti-inflammatory and tissue protective 


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effects, bardoxolone methyl and analogues have been shown to possess potent antiviral activity. AKI is a 
serious complication of COVID-19 and frequently occurs in patients with severe symptoms. Bardoxolone 
methyl protects the kidney in several animal models of CKD and AKI and improves kidney function in 
patients with diabetes, Alport syndrome, ADPKD, IgAN, and FSGS. Thus, the collective data suggest 
bardoxolone methyl may reduce the excessive production of cytokines and chemokines and prevent ARDS 
and AKI in patients with COVID-19. 
2.4 
Potential Risks & Benefits 
2.4.1 Known Potential Risks 
Please refer to the Investigator’s Brochure for a detailed discussion of safety findings for studies conducted 
with bardoxolone methyl in healthy subjects or patients with cancer, CKD, or PH. 
2.4.1.1 
Fluid Overload 
Similar to endothelin receptor antagonists (ERAs) in certain patient populations, including bosentan in 
advanced congestive heart failure and avosentan in advanced CKD, bardoxolone methyl treatment was 
found to be associated with an increased risk for fluid overload and heart failure hospitalizations in the 
BEACON trial, which enrolled patients with Stage 4 CKD (eGFR 15 to 29 mL/min/1.73 m2) and type 2 
diabetes (Chin, 2014).  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.  
Patients with fluid overload events who were treated with intravenous diuretics generally resolved their 
symptoms.  Elevated BNP and prior hospitalization for heart failure were identified as risk factors that 
contributed to increased risk for these events.  For patients without these baseline characteristics, the risk 
for heart failure events among bardoxolone methyl- and placebo- treated patients was similar (2%) (Chin, 
2014).  The increased risk for these events from bardoxolone methyl treatment had also not been observed 
in six previous CKD studies, which were conducted mostly in patients with Stage 3b CKD (eGFR of 30 to 
44 mL/min/1.73 m2), patients with hepatic dysfunction or cancer, or healthy volunteers.  
Subsequent studies, enrolling over 1500 patients, have employed risk mitigation procedures 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.  
Since these exclusions have been applied, no increased risk for acute fluid overload AEs with bardoxolone 
methyl has been observed.  As such, BARCONA will exclude patients with known left ventricular ejection 
fraction (LVEF) <40% or prior hospitalization for heart failure to mitigate this risk. 
2.4.1.2 
Transaminase and Gamma-glutamyl Transpeptidase (GGT) Elevations  
In clinical studies of bardoxolone methyl, almost all patients had increases of transaminase enzymes above 
baseline upon initiation of treatment, which followed a consistent pattern.  These increases were not 
associated with elevations in bilirubin or other signs of liver toxicity.  In BEACON, fewer hepatobiliary SAEs 
were observed in the bardoxolone methyl arm than in the placebo arm.  The elevations begin immediately 
after initiation of treatment or an increase in dose; they peak approximately two to four weeks later.  In most 
patients, transaminase elevations were mild, but approximately 4% to 11% of patients experienced an 
elevation greater than 3X the ULN.  The elevations resolved to levels less than the ULN in most all patients 
with elevations, within two weeks after peak values while patients continued taking study drug.  Patients 
who experienced elevations to greater than 3X the ULN sometimes required additional time to resolve.  
While some patients have had elevations to above 3X the ULN, persistent elevations to above 3X the ULN 
have not been observed, and the elevations did not recur once resolved, unless caused by other factors. 
Bardoxolone methyl regulates GGT, a known Nrf2 target gene.  In clinical studies, low level GGT elevations 
during treatment were common, mild, and typically lasted longer than ALT/AST elevations.  Bilirubin levels 
in patients experiencing transaminase or GGT elevations due to treatment with bardoxolone methyl either 
remained at baseline levels or decreased.  The ALT, AST, and GGT elevations were generally self-limiting 
in patients who continued treatment with study drug.  


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2.4.1.3 
Muscle Spasms 
Muscle spasm was the most frequently reported adverse event in clinical trials of bardoxolone methyl in 
patients with CKD who also had type 2 diabetes.  The muscle spasms most often manifested in the first 
two months of treatment and resolved spontaneously or with empirical treatment.  They occurred mostly at 
night, in the lower extremities, and were generally mild to moderate in severity.  Muscle spasms 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.  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, creatine kinase, lactate 
dehydrogenase (LDH), BUN, uric acid, phosphorus, and potassium. 
2.4.2 Known Potential Benefits 
As seen in Table 1, improvements in kidney function, including eGFR, creatinine clearance, and inulin 
clearance, have been observed with bardoxolone methyl treatment in multiple clinical studies, including 
patients with CKD, cancer, and pulmonary hypertension (PH).  Bardoxolone methyl was originally 
considered for development in cancer patients, and in two Phase 1 studies, bardoxolone methyl was 
observed to reduce serum creatinine levels, corresponding to an increase in eGFR (Hong, 2012).  The 
reductions of serum creatinine concentrations and resultant increases in eGFR were time-dependent and 
manifested in a majority (82%) of the patients studied.  In subsequent studies that enrolled over 2600 
patients with type 2 diabetes and CKD, bardoxolone methyl has been shown to consistently produce 
clinically and statistically significant improvements in eGFR that are durable for at least one year in treated 
patients (Chin, 2018; Pergola, 2011).  The change in serum creatinine was not related to a reduction in 
creatinine generation (Chertow, 2018); improved kidney function was confirmed in a study of Japanese 
patients with type 2 diabetes wherein GFR was measured using inulin clearance, as well as estimated, 
using conventional GFR estimating equations (Nangaku, 2020). 
Most recently, bardoxolone methyl was shown to significantly increase eGFR in patients with CKD due to 
Alport syndrome, ADPKD, IgAN, T1D CKD, or FSGS (Pergola, 2019). The clinical activity of bardoxolone 
methyl in various forms of CKD with distinct etiologies suggests that the anti-inflammatory and anti-fibrotic 
effects of bardoxolone methyl target the common final pathway contributing to GFR loss in multiple forms 
of CKDs. 
Table 1: 
Cross-Study Comparison of Increases in eGFR, Inulin Clearance, and 
Creatinine Clearance with Bardoxolone Methyl Treatment 
Study 
Phase/ 
Country 
Study 
Population 
# of 
Patients 
Treatment 
Duration 
∆eGFR 
(mL/min/1.73m2)(1) 
CKD Studies 
402-C-0801  
(Stratum 1) 
(open label) 
2a/ 
US 
Age 
≥ 
18, 
Diabetic nephropathy 
60 
28 days 
6.7 
(p<0.001) 
402-C-0801  
(Stratum 2) 
(open label) 
2b/ 
US 
Age 
≥ 
18, 
Diabetic nephropathy 
20 
56 days 
7.2 
(p<0.001) 
CrCl 
also 
sig. 
increased 
402-C-0804 
(BEAM) 
2/ 
US 
Age 
≥ 
18, 
T2D and CKD 
227 
52 weeks 
8.6 at WK52 
(p<0.001 vs PBO) 
402-C-0902 
2/ 
US 
Age ≥ 18, T2D and CKD 
131 
85 days 
6.5 
(p<0.001) 
402-C-0903 
(BEACON) 
3/ 
Global 
Age 
≥ 
18, 
T2D and Stage 4 CKD 
2185 
Median: 
7 months with 522 
patients 
through 
Week 48 
6.4 
(p<0.001 vs PBO) 
CrCl also significantly 
increased 


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402-C-1102 
1/US 
Age 
≥ 
18, 
T2D and Stage 3b and Stage 
4 CKD 
24 
56 days 
9.0 
(p<0.05) 
RTA402-005 
(TSUBAKI) 
2/ 
Japan 
Age 
≥ 
20,  
T2D and Stage 3 and 4 CKD 
108 
16 weeks 
6.6 (inulin GFR) 
(p=0.008 vs PBO) 
402-C-1603 
2/US 
Age 
12 
to 
65, 
Alport Syndrome 
30 
48 weeks 
10.4 (p<0.001) 
402-C-1603 
3/Global 
Age 
12 
to 
70, 
Alport Syndrome 
157 
48 weeks 
9.5  
(p<0.001 vs PBO) 
402-C-1702 
2/US 
Age 
18 
to 
70, 
ADPKD 
31 
12 weeks 
9.3 (p<0.001) 
402-C-1702 
2/US 
Age 
18 
to 
70, 
IgA Nephropathy 
 
26 
12 weeks 
8.0 (p<0.001) 
402-C-1702 
2/US 
Age 
18 
to 
70, 
T1D CKD 
28 
12 weeks 
5.5 (p=0.02) 
Non-CKD Studies 
402-C-0501 
1/ 
US 
Age ≥ 18, 
Advanced Solid Tumors or 
Lymphoid Malignancies 
47 
Median:  
56 days 
18.2 
(p<0.0001) 
402-C-0702 
1/2/ 
US 
Pancreatic Cancer 
34 
Median:  
56 days 
32.2 
(p=0.001) 
402-C-1302 
(LARIAT) 
2/ 
US 
Age 18 to 75 
PH 
(Baseline 
eGFR  
82 mL/min/1.73 m2) 
54(2) 
16 weeks 
14.7 
(p<0.001 vs PBO) 
a Unless noted, data are mean eGFR changes from baseline for bardoxolone methyl patients and p-values are 
calculated from two-sided paired t-tests comparing eGFR change to 0. 
b Number of patients enrolled in Cohorts 1 and 2. 
 
 
3 Objectives and Purpose 
3.1 
Phase 2 
3.1.1 Primary Objective 
• 
To provide an initial assessment of the safety of bardoxolone methyl in COVID-19 patients when 
compared with matching placebo 
3.2 
Phase 3 
3.2.1 Primary Objectives 
• 
To determine whether bardoxolone methyl in COVID-19 patients increases the probability of 
recovery at Day 29 when compared with matching placebo 
• 
To assess the safety of bardoxolone methyl in COVID-19 patients when compared with matching 
placebo 
3.2.2 Secondary and Exploratory Objectives 
• 
To assess the effect of bardoxolone methyl on other endpoints including renal function when 
compared with matching placebo 
3.2.3. Safety Endpoints 
The following safety endpoints will be assessed during the study: 


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• 
All adverse events that are serious, unexpected, and have a reasonable possibility of having been 
related to the study drug  
• 
All unexpected deaths 
4 Study Design and Endpoints 
4.1 
Description of Study Design 
This multi-center, double-blind, placebo-controlled, randomized Phase 2/3 trial will study the safety, 
tolerability, and efficacy of bardoxolone methyl in patients hospitalized with confirmed COVID-19.  Phase 2 
is designed to provide an early interim analysis for safety and will enroll approximately 40 patients. Phase 
3 is designed to determine whether bardoxolone methyl increases the probability of recovery at Day 29 
compared with matching placebo. In phase 3, approximately 360-400 additional patients will be enrolled.  
 
Patients will be randomized using permuted block randomization in a 1:1 fashion to either once-daily 
administration of bardoxolone methyl (20 mg) or matching placebo.  Randomization will be stratified by 
study center and invasive mechanical ventilation (i.e., mechanical ventilation with endotracheal intubation) 
use at baseline (yes or no).   
 
Enrollment of patients ≥70 years of age may be limited (e.g., comprise no more than 10% of all randomized 
patients), pending safety review by the DSMB and executive committee.  Treatment will be administered 
for the duration of hospitalization (until recovery), with an expected duration of 10 days. For patients who 
are still hospitalized for more than 10 days, treatment can be continued for a maximum treatment duration 
of 29 days. Dose de-escalation (down to 10 mg) is permitted during the study if indicated clinically, and 
subsequent dose re-escalation is also permitted.  Once a patient’s dose has been reduced, dose re-
escalation back to a higher dose is permitted. 
 
Randomization will be performed using an interactive web response system (IWRS).   Following 
randomization on Day 1, patients will be assessed while hospitalized on Days 3, 5, 8, 11, 15, 22, and 29.  
Assessments will include clinical status assessments, vital sign measurements, clinical chemistry 
collection, and adverse event collection.  Patients that recover prior to Day 29 will complete an end-of-
treatment visit. Patients will have an in-person follow-up on Day 29, regardless of treatment adherence and 
recovery status prior to Day 29, and a safety follow-up 60 days after randomization for clinical status 
assessments, vital sign measurements, clinical chemistry collection, and adverse event collection. Follow-
up in-person visits are preferred but recognizing quarantine and other factors may limit the subject’s ability 
to return to the site for the visit. In this case, the visit may be performed by phone.  An independent Data 
and Safety Monitoring Board (DSMB) will advise the study leadership on safety aspects and overall 
progress of the study. 
 
The phase 2 primary endpoint will be assessed during the treatment phase, defined as while hospitalized 
and up to Day 15. The phase 3 primary endpoint will be assessed during the treatment phase, defined as 
while hospitalized and up to Day 29. Enrollment of the phase 3 cohort will initiate after safety and proof of 
concept has been confirmed in the Phase 2 cohort.  
4.2 
Study Endpoints 
4.2.1 Phase 2 
4.2.1.1 
Primary Endpoint 
• 
Safety (e.g., frequency, intensity, and relationship to study drug of serious adverse events 
[including unexpected deaths], change from baseline in vital sign and laboratory assessments) at 
Day 29 


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4.2.2 Phase 3 
4.2.2.1 
Primary Efficacy Endpoint 
• 
Proportion of subjects recovered (defined as alive, free of respiratory failure [e.g., need for non-
invasive or invasive mechanical ventilation, high flow oxygen, or ECMO], and free of renal 
replacement therapy [RRT]) at Day 29.  
4.2.2.2 
Seconday Efficacy Endpoint (assessed at Day 29 unless stated otherwise) 
• 
Number of renal replacement therapy (RRT)-free days 
• 
Number of mechanical ventilation-free days  
• 
All-cause mortality 
• 
Proportion of subjects experiencing a deterioration from baseline (as defined by a 1-point 
worsening) to end of treatment or Day 29 (whichever comes first) in clinical status using an 11-
category ordinal scale: 
o 
0 – Uninfected; no viral RNA detected 
o 
1 – Asymptomatic; viral RNA detected 
o 
2 – Symptomatic; Independent 
o 
3 – Symptomatic; assistance needed 
o 
4 – Hospitalized; no oxygen therapy 
o 
5 – Hospitalized; oxygen by mask or nasal prongs 
o 
6 – Hospitalized; oxygen by NIV or High flow 
o 
7 – Intubation & Mechanical ventilation; pO2/FIO2 >/= 150 or SpO2/FIO2 >/=200 
o 
8 – Mechanical ventilation pO2/FIO2 < 150  (SpO2/FIO2 <200) or vasopressors 
o 
9 – Mechanical ventilation pO2/FIO2 < 150 and vasopressors, dialysis or ECMO 
o 
10 – Death 
4.2.2.3 
Exploratory Efficacy Endpoint (assessed at Day 29 unless stated otherwise) 
• 
Change from baseline in eGFR 
• 
Time to recovery  
• 
Recovery at Day 60  
• 
Change from baseline in PaO2/ FiO2 (while hospitalized on Day 5, 8, 15, and end of treatment) 
• 
Change from baseline in D-dimer, C-reactive protein (CRP), LDH, troponin and cytokine levels 
(while hospitalized on Day 5, 8, 15, and end of treatment) 
5 Study Enrollment and Withdrawal 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Laboratory-confirmed COVID-19 infection as determined by polymerase chain reaction (PCR) 
2. Hospitalized patients that meets one of the following conditions:   
a. Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.); OR  


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b. At rest, blood oxygen saturation ≤ 94%; OR   
c. Require supplemental oxygen; OR  
d. Requiring non-invasive ventilation; OR  
e. Requiring invasive mechanical ventilation for up to 2 days.  
3.  Age ≥ 18 years. Enrollment of patients ≥70 years of age may be limited (e.g., comprise no more 
than 10% of all randomized patients), pending safety review by the DSMB and executive committee 
4. Participant or legally authorized representative is willing to give informed consent  
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Intubated and on invasive mechanical ventilation for three or more days at the time of 
randomization   
2. Known left ventricular ejection fraction (LVEF) <40% or prior hospitalization for heart failure  
3. Cardiac arrest   
4. Shock  
5. Known uncontrolled bacterial, fungal, or non-COVID viral infection  
6. eGFR <30 ml/min/1.73 m2 or requiring dialysis  
7. ALT or AST > 5X ULN  
8. History of cirrhosis, chronic active hepatitis or severe hepatic disease  
9. Pregnant or lactating women  
10. Enrolled in other trial of unapproved therapies, unless approved by trial Principal Investigator. In 
general, co-enrollment will be permitted unless there are safety concerns, mechanistic 
incompatibility or inability to adjudicate serious adverse events and will be decided on a case by 
case basis.  
11. If in the opinion of the clinical team, progression to death is imminent and inevitable within the next 
24 hours, irrespective of the provision of treatments   
5.3 
Vulnerable Subjects 
The study will include subjects with diminished or lack of capacity to provide consent if their Legally 
Authorized Representative (LAR) is able to provide consent on their behalf. Due to the known progression 
of the COVID-19 disease, there is the possibility that a patient may be sedated, under mechanical 
ventilation, or under the effects of hypoxia, etc. that may contribute to an altered mental status before the 
study team is able to obtain written consent. We believe that this group of patients will have a potential for 
direct benefit by participating in the trial. In addition to the standard of care monitoring by their treatment 
team, there will be additional monitoring for the study. Overall, we believe that participation in this trial will 
facilitate close monitoring of their clinical status which may improve their clinical care. 
  
As usual, assessment of a subject’s capacity will be conducted by the treating physician based on the 
standard clinical assessment of capacity, which includes assessment of patients understanding of the facts 
presented, assessment of their appreciation and reasoning about the choice, etc. and communicated to the 
study team. If it is determined that the subject is unable to provide consent, consent will be obtained from 
subject’s LAR before study-related procedures can begin. The study will be explained to the LAR by the 
study team using the IRB-approved Informed Consent Form. The hierarchy of identifying the LAR will be in 
the following order: health care agent, spouse (if not legally separated), domestic partner, adult child, 
parent, adult sibling, and close friend. The hierarchy may vary from state to state and the local site should 
refer to their local regulatrions. Identification and verification of the LAR will follow the standard policies and 
procedures in place at each study site. 
 


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Subjects’ capacity will be re-assessed at each study visit with the treatment team. Once the participant 
regains capacity to consent, they will be informed of their participation in the study and will have an 
opportunity to withdraw from further participation in the study. Subjects who regain the capacity to consent 
and decline to continue participation will be asked if previously collected data can still be used. If they 
decline to allow use of previously collected data, their data will be discarded. If a subject provides consent 
with capacity, and subsequently loses capacity, their participation in the study is expected to continue 
unless the LAR notifies the study team of study withdrawal.  
5.4 
Strategies for Recruitment and Retention 
Participants will be screened by designated qualified clinical staff in an electronic medical records system, 
such as EPIC or similar, using the inclusion and exclusion criteria specified for the study. When a potential 
participant is identified, the Investigator will contact the participant’s treating physician (TP), or equivalent, 
to further verify eligibility for the study. The Investigator and TP will determine the best way to approach the 
potential participant to introduce the study. The consenting process will occur in an in-patient setting. In 
addition to screening by the study team, the Principal Investigator and Investigators at participating sites 
may publicize this study internally to clinical colleagues. Referrals from clinical colleagues will be reviewed 
to verify eligibility before proceeding to the consenting process. 
5.5 
Duration of Study Participation 
Bardoxolone methyl or placebo will be administered for the duration of hospitalization (until recovery), for 
up to a maximum of 29 days. A final follow-up visit will occur 60 days after randomization. Total duration of 
study participation is estimated to be approximately 2 months.  
5.6 
Total Number of Participants and Sites  
Recruitment will end when approximately 400-440 participants are enrolled.  Recruitment is planned to 
occur at approximately 20 sites. 
5.7 
Participant Treatment Discontinuation 
5.7.1 Reasons for Treatment Discontinuation 
Study drug discontinuation refers to a patient’s stopping administration of study drug.  Participants are free 
to discontinue study treatment at any time for any reason without prejudice to their medical care.  
Furthermore, the investigator may disconintue a patient from study drug.  The reason for a patient’s 
discontinuation from stu drug will be rcorded in the electronic case report form (eCRF).  
Reasons for study drug discontinuation may include the following: 
• 
Adverse event;  
• 
Death; 
• 
Lost to follow-up; 
• 
Physician decision; 
• 
Protocol specified criterion met; 
• 
Withdrawal by subject 
 
Patients who are discontinued from study drug should still continue in the study, complete all study visits, 
and undergo all scheduled study assessments, if possible.   
5.8 
Participant Withdrawal or Termination 
5.8.1 Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request, without prejudice 
to their medical care. The reason for a patient’s withdrawal or termination will be recorded in an electronic 
case report form (eCRF). The potential reasons could be: 


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• 
Withdrawal of Consent by Participant 
• 
Lost to Follow-up 
 
Discontinuation of treatment is not a withdrawal of participation from the study. If treatment is discontinued, 
the participant should remain in the study and continue to be assessed at the scheduled study 
assessments. 
5.8.2 Handling of Participant Withdrawals or Termination 
If a participant (or legally authorized representative who provided consent) notifies the study team about 
withdrawing participation from the study, the study team will make all efforts to collect data related to the 
primary and secondary endpoints. 
 
The investigator will make reasonable efforts to obtain, at a minimum, survival data on all participants lost 
to follow-up.  Before a participant is considered lost to follow-up, study team will use any combination of the 
following methods to ascertain vital status: 
• 
Multiple phone calls to participant and/or their next-of-kin 
• 
Send certified letters to known addresses 
• 
Search medical records system for recent routine visits 
 
The overall clinical care of this patient will not change as a result of participation in this study nor will it 
change should the patient be withdrawn for any reason.  
5.9 
Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to the Principal Investigator, funding agency, the IND sponsor and 
regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly inform the 
IRB and will provide the reason(s) for the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy 
the sponsor, IRB and/or FDA. 
 
Although Reata intends to complete the study, Reata reserves the right to discontinue the study at any time 
for clinical or administrative reasons, or if required by regulatory agencies.  If Reata discontinues the study, 
all study drug will be discontinued and the investigator will be responsible for securing any alternative 
therapy to be administered, as appropriate. 
6 Study Agent 
6.1 
Study Agent(s) and Control Description 
Bardoxolone methyl (RTA 402) drug product information is shown in Table 2.  Information about the placebo 
is shown in Table 3. 
Table 2: 
Bardoxolone Methyl Drug Product Information 
Description 
Bardoxolone methyl capsule (5 mg, 15 mg) 


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Ingredients 
Bardoxolone methyl 
Methacrylic Acid – Ethyl Acrylate Copolymer (1:1), 
Type A  
Silicified Microcrystalline Cellulose  
Hydroxypropyl Methylcellulose  
Lactose Monohydrate 
Sodium Lauryl Sulfate 
Colloidal Silicon Dioxide 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide (capsule pigment) 
Route of Administration 
Oral 
Table 3: 
Placebo Information 
Description 
Placebo for bardoxolone methyl capsule 
(size #4 and size #1) 
Ingredients 
Silicified Microcrystalline Cellulose  
Lactose monohydrate 
Magnesium Stearate  
Gelatin capsules 
Titanium Dioxide (capsule pigment) 
Route of Administration 
Oral 
 
6.1.1 Acquisition 
Study drug will be shipped directly to each site prior to the start of the study.  Blinded ordering of supplies 
will be maintained via the IWRS.  Shipping contact information will be managed within the IWRS.  All 
requests will require client approval prior to shipment.    
6.1.2 Formulation, Appearance, Packaging, and Labeling 
The study drug will be supplied in tamper-evident sealed kits containing two high-density polyethylene 
(HDPE) bottles. The 20mg kit contains two (HDPE) bottles (1) 30ct 15mg bottle and (1) 30ct 5mg bottle. 
The 20mg dose is attained by taking 1 capsule from each bottle as directed. The 10mg kit contains two 
(HDPE) bottles (2) 30ct 5mg bottles.  The 10mg dose is attained by taking 1 capsule from each bottle as 
directed. Each bottle will utilize foil induction-seal liners and a child-resistant closure.  Each bottle of study 
drug will contain 30 capsules of 5 mg or 15 mg strength bardoxolone methyl or the matching placebo 
capsules.  Each bottle will also contain a desiccant insert that must not be ingested.  Labeling on each 
bottle will contain at minimum the following information: 
• 
Protocol: s20-00591 
• 
Product name and strength 
• 
Caution: New Drug – Limited by Federal Law to Investigational Use 
• 
Keep out of reach of children 
• 
Control or lot number 
• 
Store at 15° – 25°C (59° – 77°F) 


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• 
Reata Pharmaceuticals, Inc., Irving, TX 
6.1.3 Product Storage and Stability 
The stability of the drug product has been and is currently being evaluated in ongoing studies. Investigative 
sites must store the investigational product in a secure location with room temperature conditions of 15° - 
25°C (59° - 77°F). 
6.1.4 Preparation 
Patients will be administered one capsule from each bottle included in the study drug kit orally once a day 
beginning on Day 1 while the patient remains hospitalized. Patients unable to receive oral medications 
(e.g., due to intubation and/or mechanical ventilation) may receive the contents of the capsule through a 
nasogastric or orogastric tube flushed with water.  Each dose of study drug should be administered at 
approximately the same time each day, preferably in the morning. 
6.1.5 Dosing and Administration 
Please refer to Section 7.1.1.7 for details on study drug administration, which will be administered at the 
time points listed in Table 1.  Patients must be instructed to continue taking study drug once daily while 
hospitalized (until recovery) with an expected duration of 10 days. For patients who are still hospitalized for 
more than 10 days, treatment can be continued for a maximum treatment duration of 29 days.    
6.1.6 Route of Administration 
Bardoxolone methyl will be administered orally. Patients unable to receive oral dosing will receive study 
drug via a nasogastric or orogastric tube. 
6.1.7 Starting Dose  
Patients will be randomized 1:1 to either 20 mg of bardoxolone methyl or placebo.   
6.1.8 Dose Adjustments/Modifications/Delays 
The investigator may choose to decrease the patient’s dose to a lower dose (e.g., 20 mg to 10 mg), if 
clinically indicated.  Reasons for dose de-escalation should be documented.  Once a patient’s dose has 
been reduced, dose re-escalation back to a higher dose is permitted. 
6.1.9 Duration of Therapy 
Patients will receive study drug while hospitalized (until recovery) with an expected duration of 10 days. For 
patients who are still hospitalized for more than 10 days, treatment can be continued for a maximum 
treatment duration of 29 days.    
6.1.10 Tracking of Dose 
Study drug administration should be recorded in patient source record.  
6.2 
Study Agent Accountability Procedures 
The investigator, or designee, will maintain a record of all study drug received, dispensed, and returned.  
Study drug bottles and any unused capsules from dispensed kits should be disposed as biohazardous 
waste.  At the conclusion of the study or in an instance of planned study drug replacement, Reata or its 
designee will direct the site regarding the final disposition of study drug. 


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7 Study Procedures and Schedule 
7.1 
Study Procedures/Evaluations 
7.1.1 Study Specific Procedures 
7.1.1.1 
Informed Consent 
Informed consent (see Section Error! Reference source not found.) must be obtained from the patient or 
the legally authorized representative (for patients who cannot consent, for example, those who are 
intubated) 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. 
7.1.1.2 
Inclusion/Exclusion 
Inclusion and exclusion criteria must be reviewed as indicated in Table 1.  Patients must meet all of the 
inclusion and none of the exclusion criteria for entry in the study.  Investigators should contact the Reata 
Medical Monitor or the Clinical Coordinating Center with any questions regarding eligibility prior to 
randomizing the patient on Day 1. 
7.1.1.3 
Demographics and Baseline Disease Characteristics 
Demographic data including sex, age, race, and ethnicity, will be collected as indicated in  
Table 1.  Baseline disease characteristics will be collected as indicated in Table 1.   
7.1.1.4 
Prior and Current Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking.  Trade or 
generic drug names should be used where possible.  Concomitant medications will be reviewed as 
indicated in Table 1 and all changes will be recorded. 
7.1.1.5 
Medical History 
A complete medical history that includes all available medical history must be collected.  Medical history 
will be recorded as indicated in Table 1.   
7.1.1.6 
Pregnancy Test 
WOCBP will complete a pregnancy test as indicated in Table 1, or at any time if pregnancy is suspected.  
Any patient who becomes pregnant during the study must discontinue taking study drug immediately.  See 
Section 8.4.4 for a description of procedures to be followed in case of pregnancy. 
7.1.1.7 
Study Drug Administration 
Patients will be administered one capsule from each bottle included in the study drug kit orally once a day 
beginning on Day 1 while the patient remains hospitalized, as indicated in Table 1.  Each dose of study 
drug should be administered at approximately the same time each day, preferably in the morning.  Patients 
unable to receive oral medications (e.g., due to intubation and/or mechanical ventilation) may receive the 
contents of the capsule through a nasogastric or orogastric tube flushed with water.  A vomited dose must 
not be replaced.  A double dose (e.g., missed dose from previous day and dose for current day) must not 
be taken. 


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7.1.1.8 
SARS CoV-2 PCR Test 
A sample will be collected from the patient to test for presence of viral load as indicated in Table 1. At the 
screening visit, study team is required to confirm there is a positive SARS CoV-2 PCR test to satisfy the 
study’s inclusion criteria. If feasible per local clinical care, SARS CoV-2 PCR test is requested to be 
collected at Day 15 or End of Treatment, whichever is earlier. 
7.1.1.9 
In-person/Telephone Contact 
Patients will have a follow-up on Day 29, regardless of treatment adherence and recovery status prior to 
Day 29, and a safety follow-up 60 days after randomization, which may be conducted by in-person visit 
(preferable) or telephone call (if there are quarantine and other restrictions).  The call will include questions 
on health status including new adverse events, continuing adverse events, hospital visits, continued care, 
reinfection or death following exposure to bardoxolone methyl or placebo in the trial.  
7.1.1.10 Adverse Event Collection 
All adverse events will be recorded as indicated in Table 1.   
7.1.1.11 Clinical Status Assessment 
Clinical status of the patient will be assessed as indicated in Table 1. The assessment will include collection 
of data related to critical events and other data to support the safety reporting criteria set by the DSMB. An 
11-category ordinal scale defined in Section 4.2.2.3 will be used to support data collection for the 
exploratory endpoint. 
7.1.1.12 Recovery Assessment 
Each of the following patient recovery components will be assessed as indicated in Table 4:   
• 
Alive (yes/no) 
• 
Free of respiratory failure (yes/no) 
• 
Free of RRT (yes/no) 
7.1.1.13 eGFR 
The eGFR value will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) equation: 
eGFR (mL/min/1.73 m2) = 141 × min (Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age ×  
1.018 [if female] × 1.159 [if black] 
Where the patient’s age on the date of consent is used, Scr is serum creatinine (mg/dL), κ is 0.7 for females 
or 0.9 for males, and α is -0.329 for females or -0.411 for males.  Min indicates the minimum of Scr/κ or 1 
and max indicates the maximum of Scr/κ or 1.   
7.1.1.14 PaO2/FiO2 Ratio 
PaO2/FiO2 ratio will be collected as indicated in Table 1 and calculated by using the PaO2 from the arterial 
blood gas and then dividing by the estimated FiO2 for that oxygen delivery method (0.21 for room air, 0.21 
+ (oxygen flow rate * 0.03) for nasal cannula, 0.80 for non-rebreather mask or the recorded FiO2 for non-
invasive or invasive ventilation) (Brown SM et al. Chest 2016;150:307-13). 


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7.1.2 Standard of Care Study Procedures 
7.1.2.1 
Vital Sign Measurements 
Vital sign measurements include the patient’s heart rate, respiration rate, and body temperature.  Vital sign 
measurements should be taken as indicated in Table 1. Data related to vitals signs will be used to calculate 
a National Early Warning Score (NEWS) at each assessment. If feasible, vital sign measurements will be 
taken during outpatient study visits. 
7.1.2.2 
Laboratory Assessments 
Samples will be collected for specified clinical chemistry and hemoatology analyses as indicated in Table 
1. If feasible, available laboratory assessments will be reviewed during outpatient visits. The analyses will 
include the following: 
• 
Clinical Chemistry and biomarkers 
o 
Comprehensive metabolic panel 
o 
Lipid panel 
o 
Cytokines (if feasible per local clinical care) 
o 
Ferritin 
o 
Lactate dehydrogenase 
o 
C-reactive protein 
o 
Cardiac markers (Troponin) 
o 
B-type natriuretic peptide (BNP) 
• 
Hematology 
o 
Complete blood count (CBC) 
o 
CBC differential 
o 
Coagulation testing (including PT, INR, fibrinogen, D-dimer, etc.) 
7.1.2.3 
Chest Imaging 
Chest imaging test performed as part of standard of care will be reviewed for eligibility. . 
7.2 
Study Schedule 
All patients enrolled in the Phase 2 and Phase 3 portions of the trial will follow the same study schedule. 
7.2.1 Screening/Enrollment  
 
Screening/Enrollment Visit (Day -3 to 1) 
• 
Obtain informed consent of potential participant, or legally authorized representative verified by 
signature on study informed consent form. Written and/or electronic signature are acceptable. 
• 
Review medical history and medications history to determine eligibility based on inclusion/exclusion 
criteria. 
• 
Perform medical examinations needed to determine eligibility based on inclusion/exclusion criteria. 
• 
Verify inclusion/exclusion criteria. 
• 
Obtain blood or urine for pregnancy test if subject is WOCBP. 
• 
Obtain demographic information, medical history, medication history, alcohol and tobacco use 
history. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
7.2.2 Intermediate Visits 
7.2.2.1 
Visit 1 (Day 1) 
• 
Verify inclusion/exclusion criteria. 


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• 
Administer first dose of the study treatment in accordance with Section 6 of protocol. 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status.  
• 
Record adverse events as reported by participant or observed by investigator following first dose 
of study treatment.  
7.2.2.2 
Visit 2 (Day 3) 
• 
Verify study drug was administered in accordance with Section 6 of protocol since the last visit. 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Record adverse events as reported by participant or observed by investigator.  
7.2.2.3 
Visit 3 (Day 5) 
• 
Verify study drug was administered in accordance with Section 6 of protocol since the last visit 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Record adverse events as reported by participant or observed by investigator.  
7.2.2.4 
Visit 4 (Day 8) 
• 
Verify study drug was administered in accordance with Section 6 of protocol since the last visit. 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Record adverse events as reported by participant or observed by investigator.  
7.2.2.5 
Visit 5 (Day 11) 
• 
Verify study drug was administered in accordance with Section 6 of protocol since the last visit. 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Record adverse events as reported by participant or observed by investigator.  
7.2.2.6 
Visit 6 (Day 15) 
• 
Verify study drug was administered in accordance with Section 6 of protocol since the last visit. 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 


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• 
Record adverse events as reported by participant or observed by investigator.  
7.2.2.7 
Visit 7 (Day 22) 
• 
Verify study drug was administered in accordance with Section 6 of protocol since the last visit. 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Record adverse events as reported by participant or observed by investigator.  
7.2.2.8 
Visit 8 (Day 29) 
• 
If patient is receiving treatment on Day 29, verify study drug was administered in accordance with 
Section 6 of protocol since the last visit. 
• 
If patient was discharged prior to Day 29, make arrangements for outpatient follow-up visit. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Assess recovery status. 
• 
Record adverse events as reported by participant or observed by investigator. 
7.2.2.9 
End of Treatment Visit (or Day of Recovery if prior to Day 29) 
• 
Due to the nature of this visit (end of treatment or day of recovery), study drug will not be 
administered at this visit. 
• 
Verify study drug was administered in accordance with Section 6 of protocol since the last visit. 
• 
Review and record concurrent medications. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Assess recovery status. 
• 
Record adverse events as reported by participant or observed by investigator. 
7.2.3 Final Safety Follow-up 
Final Safety Follow-up (Visit 10, Day 60) 
• 
Safety follow-up with participant 60 days after randomization. 
• 
Review and record available laboratory assessments as indicated in Table 1. 
• 
Review and record vital signs, results of medical examinations, results of laboratory assessment, 
and other assessments as indicated in Table 1.   
• 
Assess clinical status. 
• 
Assess recovery status. 
• 
Record adverse events as reported by participant or observed by investigator.  
7.2.4 Withdrawal/Early Termination Visit 
 
Withdrawal/Early Termination Visit 
• 
Review and record concurrent medications. 
• 
Record adverse events as reported by participant or observed by investigator.  
• 
Assess clinical status. 
• 
If study treatment is ongoing at time of withdrawal: 


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o 
Verify study drug was administered in accordance with Section 6 of protocol since the last 
visit. 
o 
Review and record available laboratory assessments as indicated in Table 1. 
o 
Review and record vital signs, results of medical examinations, results of laboratory 
assessment, and other assessments as indicated in Table 1.   
Concomitant Medications, Treatments, and Procedures 
All concomitant prescription medications taken during study participation will be recorded on the case report 
forms (CRFs). For this protocol, a prescription medication is defined as a medication that can be prescribed 
only by a properly authorized/licensed clinician. Medications to be reported in the CRF are concomitant 
prescription medications, over-the-counter medications and non-prescription medications. 
7.3 
Justification for Sensitive Procedures 
The use of placebo as the comparator will provide an objective assessment of bardoxolone methyl’s 
treatment effect on proportion recovered in patients with COVID-19.   
7.3.1 Precautionary Medications, Treatments, and Procedures 
The investigator may choose to decrease the patient’s dose to a lower dose (e.g., 20 mg to 10 mg), if 
clinically indicated.  Reasons for dose de-escalation should be documented.  Once a patient’s dose has 
been reduced, dose re-escalation back to a higher dose is permitted. 
7.4 
Prohibited Medications, Treatments, and Procedures 
Patient enrolled in other trials of unapproved therapies will ineligble for enrollment unless approved by trial 
Principal Investigator.  Given the nature of the clinical situation in patients with COVID-19 and the evolving 
status of therapies for the illness, this study will permit simultaneous enrollment (co-enrollment) in other 
studies.  Permission to co-enroll will be decided on a case by case basis weighing in any additional safety 
concerns, mechanistic incompatibility and ability to adjudicate serious adverse events. Data on co-
enrollment will be captured in the EDC and SAE/AE in this subset will be tracked through the length of the 
trial (see section 8.4.1).  Moreover, subgroup analysis will be performed in the cohort of patients co-enrolled 
in other trials (see section 10.4.8).  In general, co-enrollment will be permitted unless there are safety 
concerns, mechanistic incompatibility or inability to adjudicate serious adverse events and will be decided 
on a case by case basis.   
 
Concomitant use with strong CYP3A4 inhibitors is prohibited.  If a strong CYP3A4 inhibitor is medically 
necessary, study drug should be temporarily discontinued.  Concomitant study drug use with moderate 
CYP3A4 inhibitors should be avoided whenever possible, and switching to an alternative agent should be 
considered.   
8 Assessment of Safety 
8.1 
Specification of Safety Parameters  
The following safety endpoints will be assessed during the study: 
• 
All adverse events that are serious, unexpected, and have a reasonable possibility of having 
been related to the study drug  
• 
All unexpected deaths 
8.1.1 Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse 
events.  Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 


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• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
8.1.2 Definition of Serious Adverse Events (SAE) 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in 
in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
8.1.3 Definition of Unanticipated Problems (UP) 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
8.2 
Classification of an Adverse Event 
8.2.1 Severity of Event 
Severity for each adverse event will be graded using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) system. All adverse events will be recorded:  
 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living. 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
 


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8.2.2 Relationship to Study Agent 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. The degree of certainty about 
causality will be graded using the categories below. 
• Definitely Related – The event follows: (a) a reasonable, temporal sequence from study drug or a 
study procedure; and (b) cannot be explained by the known characteristics of the participant’s 
clinical state or other therapies; and (c) evaluation of the participant’s clinical state indicates to the 
investigator that the experience is definitely related to study procedures. 
• Probably Related – The event should be assessed following the same criteria for “Definitely 
Related”. If in the investigator’s opinion at least one or more of the criteria are not present, then is 
can be assessed as “probably” related. 
• Possibly Related – The event should be assessed following the same criteria for “Definitely 
Related”. If in the investigator’s opinion at least one or more of the criteria are not present, then it 
can be assessed as “possibly” related. 
• Probably Not Related – The event occurred while the participant was receiving study 
drug/intervention or undergoing study procedures but can reasonably be explained by the known 
characteristics of the participant’s clinical state or other therapies. 
• Definitely Not Related – The event is definitely produced by the participant’s clinical state or by 
other therapies administered to the participant. 
• Uncertain Relationship: The event does not meet any of the criteria previously outlined. 
8.2.3 Expectedness 
The investigator responsible at each local site will be responsible for determining whether an AE is expected 
or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. 
 
There are a plethora of adverse events expected that will be related to COVID-19 infection and not the use 
of the drug, including death. Some examples of expected COVID-19 related AE include (but not limited to) 
death, intubation, need for pressors, mechanical circulatory support, resuscitated cardiac arrest, acute 
kidney injury, infection (non COVID-19), LFTs >5x ULN, disseminated intravascular coagulation, and 
symptomatic venous thromboembolism.  
8.3 
Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. All adverse 
events will be captured on the appropriate eCRF. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs will 
be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. UPs will be recorded in the data collection system throughout 
the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of onset 
and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is obtained 
until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study 
visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed 
for outcome information until resolution or stabilization.  
 


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All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.  The investigator 
should notify the study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study.  The sponsor 
should also be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study 
that may reasonably be related to this study.    
8.4 
Reporting Procedures – Notifying the IRB  
8.4.1 Serious Adverse Event Reporting 
The cumulative incidence of adverse events that are serious, unexpected, and have a reasonable possibility 
of having been related to a study drug (from time of administration of the first dose at the Day 1 visit until 
the final visit indicated in Table 4) must be reported. 
The investigator is responsible for reporting all 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 
1, as appropriate).  Additional information from the investigator may be requested to ensure the timely 
completion of accurate safety reports.  Serious adverse events related to COVID-19 infections will not be 
reported. 
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.  The investigator may be contacted for additional 
information on any SAE which has not resolved at the time the patient completes the study.  
 
A summary of SAEs and AEs experienced by subjects co-enrolled in other clinical trials will be reported to 
the IRB on a monthly basis. The report will include a statement from the PI regarding whether or not there 
are any safety concerns to the co-enrolled group as compared to the not co-enrolled group. 
8.4.2 Unanticipated Problem Reporting 
Incidents or events that meet the criteria for UPs in Section 8.1.3 require the creation and completion of an 
UP report form. It is the site investigator’s responsibility to report UPs to their IRB and to the DCC/study 
sponsor. The UP report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
 
• UPs that are SAEs will be reported to the IRB and to the DCC/study sponsor within 24 hours of the 
investigator becoming aware of the event. 
• Any other UP will be reported to the IRB and to the DCC/study sponsor within 72 hours of the 
investigator becoming aware of the problem. 
8.4.3 Reporting of Pregnancy 
During the study, and for 30 days following administration of the final dose of study medication, all WOCBP 
must practice one of the following acceptable methods of birth control: 


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• 
Use double barrier contraception method defined as male use of a condom and female use of 
a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, diaphragm [always 
use with spermicidal jelly/cream]); 
• 
Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal); 
• 
Use of an intrauterine device; 
• 
Abstain from sexual intercourse completely.     
Males who have female partners of childbearing potential must practice one of the following methods of 
birth control during the study, and for 30 days following administration of the final dose of study medication: 
• 
Have had a vasectomy; 
• 
Use double barrier contraception method, defined as male use of a condom and female use of 
a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, diaphragm [always 
use with spermicidal jelly/cream]); 
• 
Partner use of an intrauterine device; 
• 
Partner use of hormonal contraceptives (oral, parenteral, vaginal or transdermal); 
• 
Abstain from sexual intercourse completely.     
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 Reata Medical Monitor a pregnancy associated with study drug exposure.  The early discontinuation 
protocol-required procedures outlined for End-of-treatment and Follow-up visits must be performed on the 
patient.  
Pregnancy is not considered an AE; however, the investigator must follow a pregnant patient, or the 
pregnant female partner of a male patient (if consenting), and report follow-up information regarding the 
course of the pregnancy, including perinatal and neonatal outcome.  Infants resulting from such 
pregnancies should be followed for a minimum of 8 weeks.  Reata or designee may contact the investigator 
to request additional information throughout the course of the pregnancy. 
The following pregnancy outcomes must be considered SAEs and will require additional reporting in the 
eCRF and reported as a serious AE: 
• 
Congenital anomaly/birth defect; 
• 
Stillbirth; 
• 
Spontaneous miscarriage. 
8.5 
Reporting Procedures – Notifying the Study Sponsor 
The study clinician will complete a SAE Form within the following timelines: 
 
• All unexpected deaths and immediately life-threatening events, will be recorded on the SAE Form 
and submitted to the DCC/study sponsor within 24 hours of site awareness. See Section 1, Key 
Roles for contact information. 
• Other SAEs regardless of relationship will be submitted to the DCC/study sponsor within 72 hours 
of site awareness. 
 


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All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
the DCC/study sponsor and should be provided as soon as possible.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated event or the unanticipated problem in 
the form of a written narrative.  Significant new information on ongoing unanticipated adverse effects shall 
be provided promptly to the study sponsor. 
8.6 
Reporting Procedures – Notifying the FDA  
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  These 
mandatory written notifications of adverse events are referred to as IND safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and associated type 
of event: 
 
• As soon as possible but no later than 7 calendar days  
Any adverse experience that is: 
– suspected, and 
– unexpected, and 
– fatal or life-threatening 
 
• As soon as possible but no later than 15 calendar days 
Any adverse experience that is: 
– suspected, and 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit the 
criteria for reporting (reporting within 15 calendar days from when event was deemed 
reportable). 
 
Definitions: 
• Suspected: there is reasonable possibility that the drug caused the adverse event. For the purposes 
of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  
• Unexpected: refers to an event or reaction that is not listed in the investigator’s brochure or is not 
listed at the specificity or severity that has not been observed / is not consistent with the risk 
information described in the IND application. 
• Life-threatening: the sponsor determines that adverse event or suspected adverse reaction is 
considered life-threatening if its occurrence places the participant at immediate risk of death. 
 
Note: Serious adverse events related to COVID-19 infections will not be reported to the FDA unless it 
meets the criteria above. There is a plethora of adverse events expected in the patient population being 
evaluated that will be related to the COVID-19 infection and not associated with the use of bardoxolone 
methyl. These adverse events include death, which is expected in severe cases of COVID-19. 
 
Follow-up Safety Reporting 
Sponsors are also required to identify in IND safety reports all previous reports concerning similar adverse 
events and to analyze the significance of the current event in light of the previous reports. 
 
Reporting Process 
Adverse 
events 
may 
be 
submitted 
on 
FDA 
Form 
3500A 
(MEDWATCH 
Form: 
https://www.fda.gov/media/76299/download), or in a narrative format. If supplied as in a narrative format, 
the minimum information to be supplied is noted above at the beginning of section 8.3.  


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Study Halting Rules 
At a designated time during Phase 3 of the trial (~40% and ~70% of projected sample size has accrued) 
interim analysis will be performed for safety, harm and futility. Safety and harm stopping rules will be based 
on one-tailed group sequential Z-testing with three stages and boundaries calculated from an O’Brien-
Fleming spending function. Futility stopping rules will be based on symmetric, two-tailed group sequential 
Z-testing with three stages and boundaries calculated from an O’Brien-Fleming spending function. The 
Executive Committee can request to be unblinded after receiving the recommendation from the DSMB after 
the Phase 2 portion of the trial. If the Phase 2 portion is unblinded, participants enrolled during Phase 2 
portion will not be included in the total for the Phase 3 portion of the trial, which will require an additional 
400 patients to be enrolled.  If Phase 2 portion remains blinded, an additional 360 patients will be enrolled. 
Detailed plans for interim monitoring will be documented in a separate DSMB analysis plan. 
8.7 
Safety Oversight 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan.  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. All study 
information will be communicated between the PI and study sites on an as-needed basis via emails, phone 
calls, teleconferences, webinars, and in-person meetings. All attempts will be made to ensure 
communications are timely with respect to the topic of the communication. 
 
Safety oversight will be under the direction of the NYU Langone Health COVID-19 DSMB. This DSMB 
committee will be comprised of individuals with expertise across a broad range of disciplines. The DSMB 
will operate under the rules of an approved charter.  The DSMB charter will specify the meeting frequency 
when safety data on each arm of the study will be assessed. 
 
9 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial 
is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). 
 
• Monitoring for this study will be performed by designated staff at the Coordinating Center at NYU 
Langone Health. 
• Monitoring will be performed centrally at specified time points throughout the study. For-cause on-
site monitoring will be performed when needed.  A random review of certain data points related to 
endpoint, safety, and other key data variables will be performed. Monitoring related to protocol 
adherence will be performed on an ongoing basis.  
• Details of clinical site monitoring will be documented in a CMP.  The CMP will describe the frequency 
of monitoring, which data points will be monitored, and the distribution of monitoring reports. 
10 Statistical Considerations 
10.1 Statistical and Analytical Plans (SAP) 
A formal SAP detailing the analyses will be developed and finalized prior to database lock and unblinding 
of the study.  All statistical analyses and data summaries will be performed using SAS® (Version 9.4 or 
higher) or other validated software.  The SAP will serve as the final arbiter of all statistical analyses.   


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10.2 Statistical Hypotheses 
10.2.1 Phase 2 
In a given group of 20 subjects the probability of not observing an adverse event when the underlying rate 
is 10%, 20%, 30%, 40%, and 50% is 0.12, 0.01, 0.001, 0, and 0, respectively. This indicates that in a sample 
of 20 subjects, the study is sufficiently sized to observe AEs that occur at a rate of 10% or greater. 
10.2.2 Phase 3 
All statistical hypotheses will be tested using a two-sided significance level of 0.05.  The Phase 3 primary 
outcome is recovery at Day 29.  The key parameter of interest is the “risk difference,” which quantifies the 
shift in probability of recovery resulting from treatment.  A positive risk difference 1 indicates a higher 
proportion of patients recovering in the bardoxolone methyl group relative to placebo.  The null hypothesis 
to be tested is that the risk difference is the same for the placebo and bardoxolone methyl arms and is 
stated as H0: RD = 0, where RD denotes the risk difference.      
10.3 Analysis Populations 
The following analysis populations will be defined: 
• 
The intention-to-treat (ITT) population includes all randomized patients categorized by their 
assigned treatment group (whether or not they received study drug).  Efficacy analyses of the 
primary and secondary outcomes will be performed using the ITT population. 
• 
The safety population includes all patients who received at least one dose of randomized study 
drug. Patients who receive at least one dose of bardoxolone methyl will be classified in the 
bardoxolone methyl group, and patients who receive at least one dose of placebo and no dose of 
bardoxolone methyl will be classified in the placebo group. 
• 
Additional analysis populations may be defined in the SAP as appropriate. 
10.4 Description of Statistical Methods 
The following subsections include brief descriptions of the planned statistical methods.  Full detail of the 
planned analyses will be described in the formal SAP. 
10.4.1 General Approach 
This is a double-blind placebo controlled randomized trial testing a superiority hypothesis with a two-sided 
significance level of 0.05. Data for this placebo-controlled trial will be summarized by treatment group 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. 
Handling of missing data will be described in the SAP.  
10.4.2 Analysis of the Phase 3 Primary Efficacy Endpoint 
The primary efficacy endpoint is recovery, where recovery is defined as meeting all of the following criteria 
at Day 29: 
• Alive,  
• Free of respiratory failure, and 
• Free of renal replacement therapy (RRT). 
Analysis of the Phase 3 primary endpoint will occur after the last patient enrolled has been followed up to 
Day 29 and the study is complete.  The analysis will be based on the test of treatment effect estimated from 
a generalized linear model analysis accounting for the stratification factors of study center and mechanical 
ventilation status as covariates.  The primary efficacy endpoint will be a covariate-adjusted estimate as 
specified in the Statistical Analysis Plan.  Events will be analyzed and presented as summary tables of 
proportion recovered with risk differences and 95% confidence intervals (CIs) for the comparison of 


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bardoxolone methyl to placebo.  The SAP will include additional detail of the planned analyses and 
definitions of sensitivity analyses.   
10.4.3 Analysis of the Secondary/Exploratory Endpoints 
The secondary endpoints include the following: 
• Change in eGFR (mL/min/1.73 m2) during treatment as calculated using the CKD-EPI formula. 
• Number of mechanical ventilation-free days. 
The two treatment groups will be compared with respect to the secondary endpoints. The treatment of 
missing data, and the strategy to preserve the overall Type I error will be described in the SAP.  
10.4.4 Safety Analyses 
Safety and tolerability are evaluated by AEs, SAEs, clinical laboratory test results, vital sign measurements, 
and PaO2/FiO2 ratio.  All analyses of the safety data will be performed using the safety analysis set.  
Descriptive statistics are presented by treatment group assignment in the safety analysis set.   
10.4.4.1 Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be used to classify all AEs 
reported during the study by system organ class (SOC) and preferred term (PT).  All summary tables will 
include counts of patients with treatment-emergent adverse events (TEAEs).  TEAEs are defined as those 
AEs that have an onset time either at or after the start of study drug administration and no more than 30 
days after the last dose of study drug is administered.  An overall summary of TEAEs will be presented with 
the number and percentage of patients having a TEAE, a serious TEAE, a TEAE leading to study 
discontinuation, a TEAE with an outcome of death, a TEAE related to study drug (definitely, probably, or 
possibly related), or a severe TEAE.  The overall incidence of TEAEs will be summarized by SOC and by 
SOC and PT using the number and percentage of patients reporting an event and the number of events 
reported.  The incidence of serious TEAEs and TEAEs leading to premature study discontinuation will be 
summarized in a similar manner.  TEAEs will also be summarized by maximum severity (mild, moderate, 
or severe), and assessed relationship to study drug with the percentage of patients in each category. TEAEs 
leading to premature study discontinuation, and TEAEs with an outcome of death will also be presented in 
separate listings. 
10.4.5 Adherence and Retention Analyses 
The number of patients enrolled and completed or discontinued will be summarized by treatment group and 
overall.  Duration of treatment will be summarized by treatment group as the number of days the patient 
received randomized treatment and as a percent of the expected number of doses.  
10.4.6 Baseline Descriptive Statistics 
Summaries of demographic and other baseline characteristic data will be presented by treatment arm for 
all analysis populations. For continuous measures, the mean, standard deviation, and interquartile range 
will be summarized. Categorical variables will be described by the proportion in each category, with the 
corresponding sample sizes. 
10.4.7 Planned Interim Analysis 
10.4.7.1 Safety Review 
A DSMB will be reviewing unblinded data from the study to ensure patient safety.  The DSMB charter will 
describe the scope and frequency for regularly occurring interim safety reviews.   
10.4.8 Additional Sub-Group Analyses 
The efficacy outcomes will be analyzed for subgroups of interest, including in the subgroup of patients co-
enrolled in other trials, as specified in the SAP.   


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10.4.9 Multiple Comparison/Multiplicity 
This study includes a single primary endpoint.  The two secondary efficacy endpoints will be tested using a 
strategy that preserves the overall Type I error rate. 
10.4.10 Tabulation of Individual Response Data 
Individual patient data will be listed by endpoint and time point. 
10.4.11 Exploratory Analyses 
The SAP will describe exploratory efficacy analyses. 
10.5 Sample Size 
A total sample size of approximately 400 participants (Phase 2 combined with Phase 3, or Phase 3 alone, 
depending on unblinding of Phase 2) randomized 1:1 using block randomization (~200 bardoxolone methyl; 
~200 placebo) is expected to provide approximately 80% power at a two-sided 0.05 significance level using 
a generalized linear model analysis to detect a risk difference of +.14, assuming the following: 
• 
Follow-up for events for 28 days after randomization (at Day 29) 
• 
2% of patients in each group drop-out prior to Day 29 
• 
Increase in the probability of recovery from 50% for patients randomized to placebo relative to 
64% of patients randomized to bardoxolone methyl. 
Under these assumptions, approximately 228 (57% of the 400 enrolled) will have recovered at Day 29.  The 
primary analysis will be based on the ITT population.  The secondary endpoints will be tested using a 
strategy that preserves the overall Type I error rate.  Analysis of the primary endpoint will occur after the 
last patient enrolled has been followed to Day 29.  The phase 2 analysis for safety will not assess the 
primary endpoint and will not impact the overall type I error rate of the trial. If the DSMB concludes the trial 
should continue to the Phase 3 part, then the phase 2 patients will be included in the phase 3 portion of the 
study. 
  
Table 5 shows effects detectable with 80% power for a total sample size of 400 and a range of proportion 
of placebo patients recovered at Day 29.  
 
Table 5. Effects detectable with 80% power for a sample size of n=400 
and a range of proportion of placebo patients recovered 
Placebo Proportion 
Recovered at Day 29 
Bardoxolone Proportion 
Recovered at Day 29 
Risk 
Difference 
0.350 
0.488 
0.14 
0.400 
0.539 
0.14 
0.450 
0.590 
0.14 
0.500 
0.638 
0.14 
0.550 
0.686 
0.14 
0.600 
0.732 
0.13 
0.650 
0.776 
0.13 
0.700 
0.819 
0.12 
0.750 
0.861 
0.11 
0.800 
0.900 
0.10 
0.850 
0.936 
0.09 
0.900 
0.969 
0.07 
    


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10.6 Measures to Minimize Bias 
10.6.1 Enrollment/Randomization/Masking Procedures 
An IWRS will be utilized to randomize patients 1:1 to once daily administration of bardoxolone methyl or 
placebo.  Randomization will be performed using block randomization with the following strata: center and 
invasive mechanical ventilation (i.e., mechanical ventilation with endotracheal intubation) at baseline (yes 
or no).  Enrollment of patients ≥70 years of age may be limited (e.g., comprise no more than 10% of all 
randomized patients), pending safety review by the DSMB and executive committee 
 
All patients, investigators, site personnel, laboratories, and study personnel with direct involvement in the 
conduct of the study or their designees will be blinded to treatment assignments.  To prevent potential bias, 
appropriate measures will be taken to ensure the blind is maintained for the patients and personnel 
mentioned previously.  To maintain the blind, investigators will distribute blinded study drug treatment to 
patients as directed by the IWRS system.  Investigators and patients will not be blinded to dose level, but 
will be blinded to treatment assignment (i.e., bardoxolone methyl vs. placebo).  
 
An IWRS will manage treatment assignments and study drug dispensing.  The only people with direct 
access to treatment assignments prior to database lock will be those individuals who develop and maintain 
the randomization code and the DSMB.   
 
Following database lock after completion of each phase the study, randomization codes will be released to 
the statistical team for analysis. 
10.6.2 Breaking the Study Blind/Participant Code 
Although bardoxolone methyl has no known antidote, under rare circumstances unblinding may be 
considered medically necessary. 
 
The investigator is encouraged to contact the medical monitor to discuss situations in which he or she 
believes that the blind should be broken, but the investigator has the right to break the blind (e.g., in the 
event of a serious or life-threatening medical situation).  If unblinding is required, the investigator will utilize 
the IWRS to perform the unblinding.  If a study drug assignment is unblinded, the investigator must describe 
the event that required unblinding in the patient’s source documents.  
 
Patients must permanently discontinue taking study drug if their treatment assignment has been unblinded 
to the investigator (or designee).  Such patients must undergo the same study drug discontinuation 
procedures as those patients who discontinue taking study drug for other reasons.  Following permanent 
study drug discontinuation due to patient unblinding, patients should continue with study follow-up through 
their scheduled study assessments. 
 
Patient treatment assignments must not be unblinded in the case of an AE or SAE, except as described 
above. 
11 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. It is acceptable to use CRFs as source documents. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded, unless otherwise noted in the CRF instructions.  


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Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government regulatory 
bodies, and University compliance and quality assurance groups of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.).  The investigator will 
ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
12 Quality Assurance and Quality Control 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be 
run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP). 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
13 Ethics/Protection of Human Subjects 
13.1 Ethical Standard 
This clinical study was designed and shall be implemented and reported in accordance with the ICH 
Harmonised Tripartite Guidelines for Good Clinical Practice, with applicable local regulations (e.g., US Code 
of Federal Regulations Title 21, European Directive 2001/20/EC), and with the ethical principles laid down 
in the Declaration of Helsinki.  
The principal investigator agrees to conduct the study in accordance with the International Conference on 
Harmonization 
(ICH) 
for 
Guidance 
for 
Industry 
on 
Good 
Clinical 
Practice 
(GCP) 
ICH E6(R2) [https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/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. 
13.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted 
to the IRB for review and approval. Approval of both the protocol and the consent form must be obtained 
before any participant is enrolled. Any amendment to the protocol will require review and approval by the 
IRB before the changes are implemented to the study. All changes to the consent form will be IRB approved; 
a determination will be made regarding whether previously consented participants need to be re-consented. 
13.3 Informed Consent Process 
13.3.1 Consent and Other Informational Documents Provided to Participants 
Because the study will be conducted under a United States Investigational New Drug Application, a signed 
informed consent form, in compliance with Title 21 of US CFR Part 50, will be obtained from each patient 
before the patient enters the study.  In the event that the participant is not able to provide consent due to 


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temporary loss of capacity during critical illness, the legally authorized representative will provide consent.  
A study team member may conduct the informed consent process via telephone or video (webex) with use 
of e-consent through REDCap to obtain and document informed consent from the subject or legally 
authorized representative. 
 
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 or legally authorized representative 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 or legally authorized representative understands the 
implications of participating in the study, the patient will be asked to give consent to participate in the study.   
 
Eligible patients may only be included in the study after providing 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.  
 
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 or legally authorized representative.  The original form will be 
maintained in the patient’s medical records at the site. 
13.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IRB-
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential risks 
of the study and of their rights as research participants. Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done specifically for the 
study. The participants may withdraw consent at any time throughout the course of the trial. A copy of the 
signed informed consent document will be given to the participants for their records. The rights and welfare 
of the participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. The 
consent process, including the name of the individual obtaining consent, will be thoroughly documented in 
the subject’s research record. Any alteration to the standard consent process (e.g. use of a translator, 
consent from a legally authorized representative, consent document presented orally, etc.) and the 
justification for such alteration will likewise be documented.  
13.4 Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  


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In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples in addition 
to the clinical information relating to participants. Therefore, the study protocol, documentation, data, and 
all other information generated will be held in strict confidence. No information concerning the study or the 
data will be released to any unauthorized third party without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at NYU Langone Medical Center. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by clinical sites 
and by NYU Langone Medical Center research staff will be secured and password protected. At the end of 
the study, all study databases will be de-identified and archived at the NYU Langone Medical Center. 
 
14 Data Handling and Record Keeping 
14.1 Data Collection and Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Data reported in the eCRF derived from source documents should be consistent with the source 
documents or the discrepancies should be explained and captured in a progress note and maintained in 
the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into a 21 CFR Part 11-compliant data capture system, Medidata RAVE, 
maintained by Reata Pharmaceuticals Inc. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
14.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for the drug 
for the indication for which it is being investigated or 2 years after the investigation is discontinued and FDA 
is notified if no application is to be filed or if the application has not been approved for such indication. No 


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records will be destroyed without the written consent of the sponsor, if applicable. It is the responsibility of 
the sponsor to inform the investigator when these documents no longer need to be retained. 
14.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the scheduled 
protocol-required activity. 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements. Further details about the handling of 
protocol deviations will be included in the MOP. 
14.4 Publication and Data Sharing 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. 
15 Study Finances 
15.1 Funding Source 
This study is financed by Reata Pharmaceuticals, Inc. 
15.2 Costs to the Participant 
The patient will not incur costs associated with participation in this study. 
15.3 Participant Reimbursements or Payments 
No payments or reimbursements will be disbursed to participants in exchange for participation in this study. 
16 Study Administration 
16.1 Study Leadership 
The Steering Committee will govern the conduct of the study. The Steering Committee will be composed 
of the study PI, representatives of Reata Pharmaceuticals, Inc., and the PIs of the participating clinical sites. 
The Steering Committee will meet via teleconference at least monthly or as guided by the need. 
17 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 


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persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the trial. 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU 
Langone Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. All 
NYULMC investigators will follow the applicable conflict of interest policies. 
 


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Interventional Template Version: 11 January 2019 
19 Schedule of Events 


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Table 1: Schedule of Assessments  
Assessment 
Screening 
Day 1a 
Day 3 
Day 5 
Day 8 
Day 11 
Day 15 
Day 22 
Day 29k 
End of 
Treatment j 
Day 60 
Safety 
Follow-upb 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and baseline 
disease characteristics 
X 
 
 
 
 
 
 
 
 
 
 
Chest imaging 
Xh 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test for WOCBPe 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
Xb,c 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital sign measurements 
X 
Xd,e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
 
-----------------------------------------------------------------------X------------------------------------------------------------------------  
 
Adverse event collection 
 
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Recovery status assessment  
 
 
 
 
 
 
 
X 
X 
X 
Clinical status assessment 
X 
Xf,g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
metabolic 
panel 
X 
X c 
 
X 
X 
 
 
X 
X 
X 
X 
Lipid panel 
 
X c 
 
X 
X 
 
 
X 
 
X 
 
Cytokinesl 
 
X c 
 
X 
X 
 
 
X 
 
X 
 
Ferritin 
 
X c 
 
X 
X 
 
 
X 
 
X 
 
Lacate dehydrogenase (LDH)  
X c 
 
X 
X 
 
 
X 
 
X 
 
C-reactive protein (CRP) 
 
X c 
 
X 
X 
 
 
X 
 
X 
 
Cardiac markers (Troponin I, 
CK) 
 
X c 
 
X 
X 
 
 
X 
 
X 
 
BNP 
 
Xh,i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood count (CBC)  
Xj,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC differential 
 
Xl,m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT & INR 
 
Xn,o 
X 
X 
X 
X 
X 
X 
 
X 
 
Fibrinogen 
 
Xp,q 
X 
X 
X 
X 
X 
X 
 
X 
 
D-dimer 
 
Xr,s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PaO2/FiO2 
 
X c 
X 
X 
X 
X 
X 
X 
 
X 
 
SARS CoV-2 PCR Test 
Xi 
 
 
 
 
 
Xg 
 
 
X g 
 
a Day 1 is the day of administration of the first dose.   
Error! Reference source not found. Patients who discontinue from study drug prior to recovery or prior to Day 29 will have a safety assessment 60 days after randomization.  
This will be in-person visit when possible or telephone follow-up.  


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b Screening assessments conducted on the same day as randomization (Day 1) do not have to be repeated.   
c Performed pre-dose on Day 1. 
e A serum pregnancy test will be performed at the Screening visit for WOCBP or at any point in time if a pregnancy is suspected.  Additional pregnancy assessments 
will be performed more frequently if required by local law or requested by local regulatory authorities or IRBs/ECs.   
Error! Reference source not found. AE assessments on Day 1 should be performed following study drug administration.  Only AEs that are serious and have a reasonable 
possibility of having been related to a study drug  will be collected.  
g If feasible per clinical care at local site, to be performed on Day 15 or End of Treatment, whichever is earlier. 
h Results available from test performed as per standard of care can be reviewed for eligibility. If not available or not done, it is not required to be performed. 
i At screening, this test does not need to be performed. Only need to confirm a positive test is available to meet the study’s inclusion criteria. 
j End of Treatment visit can occur on Day 29 or earlier. If the End of Treatment visit is on Day 29, follow schedule of assessments for End of Treatment visit.  
k All patients, regardless of treatment adherence and recovery status prior to Day 29, will have a follow-up visit at Day 29. This will be in-person visit when possible 
or telephone follow-up. 
l Cytokines are to be reported if feasible per clinical care at local site.