A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients With Alport Syndrome
Phase: PHASE2
Conditions: Alport Syndrome
Sponsor: Biogen

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
1 
 
 
 
 
 
 
 
 
 
 
 
BARDOXOLONE METHYL (RTA 402) 
 
 
402-C-1603 
 
EUDRACT NUMBER: 2016-004395-22 
 
 
A PHASE 2/3 TRIAL OF THE EFFICACY AND SAFETY 
OF BARDOXOLONE METHYL IN PATIENTS WITH 
ALPORT SYNDROME 
 
 
US/AUS ADDENDUM 1.0 
DATED 05 JUNE 2020 
TO 
PROTOCOL VERSION 4.0 – 22 APR 2019 
 
The information contained herein is confidential and the proprietary property of Reata 
Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information without the 
prior written authorization of Reata Pharmaceuticals, Inc. is expressly prohibited. 
 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
3 
 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the addendum to the protocol v4 dated 22 Apr 2019 aimed at managing 
the study during the COVID-19 emergency and agree to conduct the study according the 
mitigation measures put in place. I agree to maintain the confidentiality of all information 
received or developed in connection with this addendum. 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
Date 
 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
4 
2.
TABLE OF CONTENTS
1.
TITLE PAGE ................................................................................................................1 
2.
TABLE OF CONTENTS .............................................................................................4 
3.
JUSTIFICATION FOR THE ADDENDUM ...............................................................5 
4.
CHANGES TO THE CURRENT APPROVED PROTOCOL ....................................6 
5.
CHANGES IN OTHER STUDY-RELATED DOCUMENTS ..................................11 
5.1. 
Informed Consent .......................................................................................................11 
6.
APPENDICES ............................................................................................................12 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
5 
 
 
3. 
JUSTIFICATION FOR THE ADDENDUM 
Since the WHO declared the COVID-19 pandemic, various challenges exist which result in 
restrictions of visits to healthcare facilities, increased demands on the health services and 
changes to trial staff availability and resources. Study participants may also be required to 
self-isolate, which introduces difficulties for Investigators to maintain medical oversight.  
These challenges could have an impact on the conduct of trials and data integrity, such as the 
completion of trial assessments, completion of trial visits, continued patient safety oversight and 
the provision of Investigational Products (IPs). 
As a sponsor, Reata Pharmaceuticals is committed to ensuring the safety of trial participants, 
maintaining compliance with good clinical practice (GCP), and minimizing risks to trial 
integrity. 
To face this evolving situation, Reata Pharmaceuticals has put in place some pragmatic actions to 
address the challenges of conducting research, while ensuring the rights, safety and wellbeing of 
participants. 
This addendum outlines Reata Pharmaceuticals’ strategies to be implemented during the 
COVID-19 pandemic, to maintain ongoing safety reporting, access to study drug, continuity of 
patient care, and oversight of clinical site performance and quality. 
This document is being presented in an effort to make available information regarding the 
mitigation strategies that have been implemented for the CARDINAL study as a result of 
COVID-19.  Since the nature and scope of this outbreak is rapidly evolving, Reata continues to 
monitor the situation and adjust its response as appropriate. 
The main activities this addendum addresses are: 
• ongoing safety monitoring of the trial participants 
• continuity of IP supply for subjects 
• preservation of trial integrity through the collection of critical data 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
6 
 
 
4. 
CHANGES TO THE CURRENT APPROVED PROTOCOL 
THE FOLLOWING CHANGES ARE IMPLEMENTED DURING THE COVID-19 
PANDEMIC. AS THE IMPACTS OF COVID RESOLVE, THE CURRENTLY APPROVED 
VERSION OF THE PROTOCOL WILL BE FULLY REIMPLEMENTED FOR STUDY 
CONDUCT.  AS SUCH, THESE CHANGES ARE PRESENTED AS AN ADDENDUM TO BE 
FOLLOWED, AS NEEDED, AND DURING THIS GIVEN PERIOD ONLY. 
 
VERSION NUMBER 
VERSION DATE 
CURRENT APPROVED 
PROTOCOL: 
4.0 
22 Apr 2019 
CHANGES TO THE CURRENT APPROVED PROTOCOL 
1. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
7. INVESTIGATIONAL PLAN page 34 
OLD TEXT: 
No changes 
NEW TEXT: 
Added subparagraph 7.6. Home Health Provider Use 
Due to the COVID-19 outbreak and the resulting restrictive measures put 
in place by the different national and regional governments that, in many 
cases, resulted in travel restrictions, limited availability of site access and 
personnel, and local limitation on the movement of delegated individuals, 
the use of  home health services has been implemented to assist with the 
collection of study required visits and laboratory assessments while also 
guaranteeing the rights, safety and wellbeing of participants and of the trial 
sites’ staff. The use of a company specialized in home health services 
ensures the ongoing safety monitoring of trial participants and maintaining 
trial integrity through the collection of critical data, in accordance with 
FDA and local guidelines about the COVID-19 pandemic management.  
For each hired home health nurse/professional, the site will be provided 
with the following documentation: signed and dated CV, current Nursing 
Licensure, GCP training certificate, and protocol training certificate.  The 
home health nurse/professional will also be included in the Delegation of 
Activities log of the site. 
The tasks delegated to the home health nurse/professional at the patient’s 
home will be: collection of vital signs and weight measurements, 
collection of information about adverse events and concomitant 
medications, collection of laboratory samples (blood and urine), supply 
urine pregnancy test for self-reading, drug accountability, and diary 
collection. The laboratory samples are collected using the laboratory kit 
provided by the centralized laboratory, normally used for the study visit 
conduct, and are processed and shipped according to the laboratory manual 
of the study. All costs relevant to these additional services will be covered 
by Reata Pharmaceuticals. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the sponsor to ensure safety of subjects 
and trial’s integrity during the COVID outbreak. 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
7 
 
 
2. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
8.5 Patient Discontinuation and Termination page 42 
OLD TEXT: 
No changes 
NEW TEXT: 
Added sub-paragraph 8.5.3 SARS-COV-2 Testing and 
Investigational Product Use 
If a patient tests positive for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, the 
investigational product (IP) RTA-402 (bardoxolone methyl) must be 
temporarily discontinued until the patient no longer presents an active 
infection, as assessed by the Investigator and/or the patient’s 
physician(s).  The Sponsor must be notified immediately for 
additional guidance.  
When the investigator deems that the patient can safely return to the 
site for an in-person visit, the investigator should conduct an 
unscheduled visit and perform a full clinical assessment with labs: 
• 
Safety labs  
o Clinical chemistry (including eGFR) 
o BNP and NT-proBNP 
o Hematology 
o Urinalysis and microscopy / Urine collection for ACR 
o Urine pregnancy test for WOCBP  
• 
Vital signs  
• 
Weight  
• 
Adverse event assessment  
• 
Prior and concomitant medication assessment  
IP may be resumed if there are no changes in clinical status that 
would preclude restarting IP. A follow-up telephone call should be 
conducted 2 weeks after the unscheduled visit to collect adverse 
events and concomitant medications. Four weeks after the 
unscheduled visit, the patient should return to the clinic for repeat 
assessments as outlined in the Week 1 visit. The patient’s visit 
schedule, as outlined in the protocol, may resume thereafter. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the Sponsor to ensure safety of subjects 
and trial’s integrity during the COVID outbreak. 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
8 
 
 
3. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
9.10.12. Pregnancy Test page 55 
OLD TEXT: 
No changes 
NEW TEXT: 
Added new sub-paragraph 9.10.12.1 Self Reading Pregnancy Test  
Urinary pregnancy tests for self-reading will be provided by the home 
health nurse/professional coming to the patient’s home. Results will 
be documented and provided to the site investigators. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the Sponsor to ensure safety of subjects 
during the COVID outbreak. 
 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
9 
 
 
4. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
9.10.14. Study Drug Dispensation and Collection page 56 
OLD TEXT: 
No changes 
NEW TEXT: 
Added subparagraph 9.10.14.1 Study drug distribution during the 
COVID-19 pandemic 
Prior to the COVID-19 pandemic, trial participants were assigned and 
dispensed IP during study site visits. During the study site visits, trial 
participants are sent home with IP and instructed to self-administer 
the IP each day until their next onsite study visit, at which they would 
return any unused IP. As the trial participants have been responsible 
for IP storage within their homes, as well as self-administration of the 
IP throughout the study, they are properly acquainted with these 
facets of the study. For those trial participants who discontinue 
physical site visits during COVID-19, distribution of IP may be made 
directly to the trial participants’ homes by shipment from investigator, 
through the Hospital pharmacy. IP distributed in this manner will be 
shipped via traceable courier as an expedited shipment. Given the 
stability profile of bardoxolone methyl capsules under multiple 
temperatures and relative humidity conditions, short term temperature 
excursions above 30°C and as low as 15℃ during storage are 
acceptable. For IP shipments to trial participants’ homes, 
investigators will monitor the time from shipment to receipt of the IP 
by the trial participant. In the absence of temperature monitoring, and 
if shipping time exceeds 48 hours, the investigator will immediately 
instruct the patient not to use the IP until further guidance is provided. 
The investigator site will then contact Reata (the sponsor) to 
determine whether the shipment may be used or must be replaced. 
The investigator site will contact the patient as to the disposition of 
the IP. Investigators will remain in close contact with trial participants 
receiving IP at their home and, if necessary, will provide any 
instructions needed on the use of the IP. Accountability of the IP for 
these trial participants will be conducted by home health nurses 
during home visits. After accountability is complete, the home health 
nurse will secure the kits in a bag that will be returned to the site 
when the trial participant is able to return to the site for their next 
visit. The trial participant will be instructed not to take any additional 
IP from the kits that have been placed in the plastic bag. 
REASON FOR 
CHANGE: 
Mitigation measures taken by the sponsor to ensure safety of subjects 
during the COVID outbreak. 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
10 
 
 
5. 
SECTION NO., 
SECTION TITLE, 
PAGE NO.(S): 
10.4 Study Drug Administration page 60 
OLD TEXT: 
No changes 
NEW TEXT: 
Added subparagraph 10.4.1. Intake of IP Beyond Week 100 During 
the COVID-19 Outbreak 
The Week 100 visit (Day 700 +/- 3 days) serves to collect the final 
“on treatment” lab values from patients. To minimize any days off 
drug prior to the Week 100 visit, and given the evolving situation of 
COVID-19, sites may extend dosing by 1 week beyond the protocol 
window for the Week 100 visit. The maximum extension in dosing is 
to study Day 710 (Day 707 +/- 3 days), unless otherwise approved by 
Reata and the IRB. The Week 104 visit must be adjusted accordingly 
to ensure the Week 104 labs are collected 4 weeks after completing 
the end of treatment (last dose). 
REASON FOR 
CHANGE: 
Mitigation measures taken by the sponsor to ensure safety of subjects. 
6. 
SECTION NO., 
SECTION 
TITLE, PAGE 
NO.(S): 
15.6. Protocol Deviations page 65 
OLD TEXT: 
No changes 
NEW TEXT: 
Added new subparagraph 15.6.1. Deviation during the COVID-19 
Outbreak 
Any data that cannot be assessed remotely will be noted as missing. 
All deviations due to the impacts of COVID-19 will be identified and 
documented accordingly by the site and the Sponsor. The failure to 
complete an in-clinic protocol visit will not be considered as a reason 
for study discontinuation and, beyond the necessary documentation 
(e.g., duly documented in patient’s note by the Investigator), will not 
be considered as a major deviation. Deviations will be reported, 
evaluated, and discussed according to the study plan and in the final 
study report. Sites will continue to document and report protocol 
deviations according to their usual procedure and institutional 
requirements. 
REASON FOR 
CHANGE: 
As allowed by FDA and local guidelines for management of clinical 
trials during the COVID-19 outbreak. 
 

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
11 
 
 
5. 
CHANGES IN OTHER STUDY-RELATED DOCUMENTS 
5.1. 
Informed Consent 
A home health service provider has been appointed by the Sponsor to support visit conduct and 
patient safety management during this period. To further ensure and maintain the protection of 
patients’ rights, the master ICF document will be revised to incorporate this mitigation strategy 
as an alternate option to support continuity in care and participation.  

Protocol Addendum 402-C-1603 
Reata Pharmaceuticals, Inc. 
Confidential 
 
Addendum 1 (USA and AUS only) to 
Protocol Version 4.0 – 22 Apr 2019 
12 
 
 
6. 
APPENDICES 
List of memos provided to study sites: 
1. Initial COVID-19 Guidance dated 10 March 2020 
2. IP shipping instructions dated 17 March 2020 
3. Lab Kit Shipping Instructions dated 19 March 2020 
4. Guidance for Direct-to-Patient Shipping of RTA-402 Drug Product Capsules During the 
Coronavirus (COVID-19) Pandemic dated 25 March 2020 
5. COVID-19 Update Memo- Q&A dated 26 March 2020 
6. IP Kits Round Two dated 06 April 2020 

 
 
March 25, 2020 
 
 
To:     Clinical Program Operations 
           Reata Pharmaceuticals, Inc. 
 
From: Chemistry, Manufacturing & Controls / Quality Assurance 
           Reata Pharmaceuticals, Inc. 
 
Via E-mail Transmission 
 
RE: Guidance for Direct-to-Patient Shipping of RTA 402 Drug Product Capsules during the 
Coronavirus (COVID-19) Pandemic  
 
 
As a result of the coronavirus (COVID-19), certain adjustments have been made to 
ensure study patients receive their investigational product, on time, and consistently. 
 
For clinical investigators, where patients are unable to travel outside of their home to the 
site, one adjustment being implemented is the shipping of investigational product directly 
to the patient, from the clinical investigator site. 
 
As background, RTA 402 drug product capsule kits (30ct, 1g desiccant, 60 mL bottle) 
have been assessed for stability following ICH guidelines for long term and accelerated 
conditions. The results support the current labeled storage conditions of controlled room 
temperature, which is defined as 20°C to 25°C (68°F to 77°F), with brief excursions 
allowed to 15°C to 30°C (59°F to 86°F).  
 
The stability results also provide supporting data to assess potential impact of short-term 
temperature excursions outside the labeled storage conditions. More specifically, for drug 
product capsule stored as a 30ct supply in 60 ml bottle with 1g desiccant, no significant 
changes in drug product quality were observed for 6 months for accelerated (40°C/75% 
RH) and 36 months for long term (25℃/60%RH) conditions.   
 
Given the stability of the product under multiple temperatures and relative humidity 
conditions, it can be concluded that short term temperature excursions above 30°C and 
low as 15℃ during storage are acceptable.  For those excursions to non-freezing 
temperatures below 15°C but at or above 1°C, no additional risk to drug product quality 
is presented based on the well-established principal of Arrhenius degradation kinetics 
(i.e., degradation reaction rates are temperature-dependent and occur faster at higher 
temperatures and slower at lower temperatures).  
 
20

In consideration of the product stability information, the following direct-to-patient guidance is 
provided during this coronavirus (COVID-19) pandemic period: 
 
1. To mitigate any unforeseen issues impacting the shipment (i.e., lengthy delays, extreme 
temperatures, etc.), shipping only the minimum number of product required for patient dosing 
administration and priority overnight shipment is advised.  
 
2. While the data provides assurance that RTA 402 Drug Product Capsules are stable, additional 
shipping and storage studies are either planned or currently being conducted. As such, certain 
limitations have been placed on the product until these results are reported. Accordingly, 
shipment durations during this period lasting longer than 48 hours, without a temperature 
monitor, are not advised. If shipment exceeds this duration due to unforeseen shipping delays, 
the site should contact Reata for further guidance. 
 
 Additional guidance will be provided when data is available. 
 
Best regards, 
 
 
 
 
 
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