Conditions: Breast Cancer
Keywords: RTA 408 RTA 408 Lotion Breast cancer Radiation therapy Radiation dermatitis Oxidative stress Inflammation omaveloxolone
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 187
Healthy volunteers: no

Brief summary:
Radiation dermatitis is experienced by almost all patients (up to 95%) receiving radiation therapy for cancer. Radiation dermatitis can be a serious condition because, in addition to its direct physical complications and the resulting impact on overall quality of life, it can also be a dose-limiting toxicity requiring changes to the prescribed course of radiation therapy. The most common strategy employed in an attempt to prevent or minimize radiation dermatitis involves moisturization of the irradiated area, use of a mild soap to keep the area clean, and minimizing exposure to potential mechanical irritants, such as scratching and rough clothing. However, this strategy has been shown to lack clinically significant efficacy. Consequently, there is a clinical need for new treatments that are effective in protecting against radiotherapy-induced oxidative stress and the subsequent development of radiation dermatitis.

Based on data from previous studies in animals and humans, Reata believes that omaveloxolone (RTA 408) Lotion may effectively prevent and mitigate radiation dermatitis in oncology patients undergoing radiation therapy.

This randomized, double-blind, vehicle-controlled, parallel-group trial will study the efficacy, tolerability and safety of two concentrations of omaveloxolone (RTA 408) Lotion (3% and 0.5%) versus vehicle in patients with breast cancer for whom radiation therapy is recommended.

Detailed description:

Arms:
arm 1: Omaveloxolone Lotion at a fixed dose of 0.5% administered topically to the radiation area, twice daily for approximately 9 weeks (up to a maximum of 16 weeks) arm 2: Omaveloxolone Lotion at a fixed dose of 3% administered topically to the radiation area, twice daily for approximately 9 weeks (up to a maximum of 19 weeks) arm 3: Vehicle Lotion administered topically to the radiation area, twice daily for approximately 9 weeks (up to a maximum of 16 weeks)

Interventions: intervention 1: Omaveloxolone Lotion 0.5% intervention 2: Omaveloxolone Lotion 3% intervention 3: Vehicle Lotion intervention 4: 3D conformal radiation therapy
Intervention descriptions: intervention 1: Omaveloxolone lotion 0.5% will be applied topically twice-daily, for up to 13 weeks, during the course of radiation therapy intervention 2: Omaveloxolone lotion 3% will be applied topically twice-daily, for up to 13 weeks, during the course of radiation therapy intervention 3: Lotion vehicle manufactured to mimic RTA 408 lotion will be applied topically twice-daily, for up to 13 weeks, during the course of radiation therapy intervention 4: 45 50.4 Gy in 1.8 Gy per day, in addition to 10 - 16 Gy boost or 46 - 50 Gy in 2 Gy per day, in addition to 10 - 16 Gy boost, at the physician's discretion

Protocol document:
Prot_000.pdf: 
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RTA 408 
 
408-C-1306 
 
A RANDOMIZED, DOUBLE-BLIND, VEHICLE-
CONTROLLED, PARALLEL-GROUP PHASE 2 STUDY 
OF THE EFFICACY, SAFETY, PHARMACOKINETICS 
AND PHARMACODYNAMICS OF RTA 408 LOTION IN 
THE TREATMENT OF PATIENTS AT RISK FOR 
RADIATION DERMATITIS 
 
VERSION 4.0 
 
The information contained herein is confidential and the proprietary property of 
Reata Pharmaceuticals, Inc. and any unauthorized use or disclosure of such 
information without the prior written authorization of Reata Pharmaceuticals, 
Inc. is expressly prohibited. 
 
 
 




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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for RTA 408.  I have read the 408-C-1306 
clinical study protocol and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Reata Pharmaceuticals 
Name of Investigational Product: 
RTA 408 Lotion 
Name of Active Ingredient: 
RTA 408 
Title of Study:  
A Randomized, Double-blind, Vehicle-controlled, Parallel-group Phase 2 Study of the Efficacy, Safety, 
Pharmacokinetics and Pharmacodynamics of RTA 408 Lotion in the Treatment of Patients at Risk for 
Radiation Dermatitis 
Study center(s): Up to 35 study centers in the US 
Studied period (years): < 1 
Estimated date first patient enrolled: June 2014 
Estimated date last patient completed: May 2015 
Phase of development:  
2 
Objectives:  
Primary: 
• 
To determine the time-averaged effect on radiation dermatitis grade measured with Common 
Terminology Criteria for Adverse Events (CTCAE, Version 4.03) following 3D conformal radiation 
therapy to the breast and concomitant administration of RTA 408 Lotion (0.5% and 3%) compared to 
administration of vehicle 
• 
To evaluate the safety of RTA 408 Lotion  
Secondary: 
• 
To determine the mean maximum radiation dermatitis grade measured with CTCAE of RTA 408 
Lotion (0.5% and 3%) compared to administration of vehicle 
• 
To determine the proportion of patients with treatment success, defined as post-baseline maximum 
dermatitis grade < 2 using the CTCAE criteria following administration of RTA 408 Lotion compared 
to administration of vehicle 
• 
To determine the mean duration of grade ≥ 2 radiation dermatitis using the CTCAE criteria 
following administration of RTA 408 Lotion compared to administration of vehicle 
• 
To determine the extent of systemic exposure to RTA 408 following administration of RTA 408 
Lotion following radiation therapy 
• 
To evaluate patient-reported outcomes (Skindex-16) 
Methodology:  
This double-blind, randomized, vehicle-controlled, parallel-group study will assess the safety, 
tolerability, and efficacy of RTA 408 Lotion (0.5% or 3%) versus vehicle in the treatment of patients at 
risk for radiation dermatitis.  Eligible patients will be randomized using a 1:1:1 assignment ratio to 
receive RTA 408 Lotion 0.5%, RTA 408 Lotion 3%, or vehicle and will be stratified by smoking status 
(smoker or ex-smoker versus non-smoker) and breast cancer treatment prior to radiation therapy (full 
mastectomy versus partial mastectomy or lumpectomy).  Study drug application will start 


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approximately 1 week prior to scheduled initiation of radiation therapy with twice daily applications 
continuing throughout the duration of radiation therapy (i.e., 5-6 weeks) and two weeks following 
completion of radiation therapy, for an expected total of up to 9 weeks of study drug application.  In 
cases where radiation treatment is delayed (e.g., delayed radiation treatment initiation or radiation 
treatment interruptions), the total study drug application period may be extended from the expected 
8-9 weeks up to a maximum of 13 weeks.  Study drug is to be applied twice daily.  On days of morning 
radiation treatments, the patient will apply the study drug at the radiation treatment center immediately 
after the radiation therapy concludes and at night before bed.  On days of afternoon radiation 
treatments, the patient will apply the study drug in the morning at least 4 hours before radiation 
treatment and at night before bed.  Any residual lotion from a prior application should be removed 
prior to radiation treatment.  Following randomization, patients will be assessed in person at weekly 
visits during administration of study drug.  A follow-up visit will occur 4 weeks after the last 
application of study drug.   
Number of patients (planned):  
Approximately 177 patients will be enrolled in this study with 59 patients in each of the three groups 
Diagnosis and main criteria for inclusion:  
Key inclusion criteria: 
1. Adult female patients (18 to 80 years of age, inclusive); 
2. Patients diagnosed with ductal carcinoma in situ or non-inflammatory breast adenocarcinoma 
who have been referred for post-operative radiotherapy to one breast and have had no prior 
radiation treatment to that breast; 
3. Patients planning to undergo 3D conformal radiation therapy to the whole breast (as part of 
breast-conservation therapy / lumpectomy) or chest wall (as part of post-mastectomy 
irradiation), with or without treatment of regional lymph nodes (i.e., axillary, supraclavicular, 
or internal mammary), using one of the following treatment schedules: 
a. 45 – 50.4 Gy in 1.8 Gy per day, in addition to a mandatory 10-16 Gy boost 
b. 46 – 50  Gy in 2 Gy per day, in addition to a mandatory 10-16 Gy boost; 
4. Patients who received breast-conservation therapy / lumpectomy must be receiving ≥ 107% of 
the total radiation dose (calculated from the total radiation dose including boost) to any portion 
of the breast, based on radiation inhomogeneity, and/or have a breast volume ≥ 1200 cc; 
5. Female patients of childbearing potential who are willing to practice methods of birth control 
from screening through 1 month after applying the final dose of study drug; 
6. Female patients of childbearing potential who are non-pregnant, non-lactating and have a 
negative pregnancy test result prior to enrollment in the study; 
7. Patients willing and able to give written informed consent for study participation; 
8. Patients willing and able to cooperate with all aspects of the protocol. 
9. Patients for whom at least 14 days have elapsed since breast conservation surgery, mastectomy 
surgery and/or chemotherapy prior to randomization; 
10. Have adequate hematologic and organ function at screening as follows:  
• 
Hematologic: Absolute neutrophil count ≥ 1.5 x 103 /μL, platelets > 100 x 109/L, 
hemoglobin ≥ 9 g/dL; 
• 
 Hepatic: total bilirubin ≤ 2 times (X) upper limit of normal (ULN), ALT and AST  
≤ 2X ULN; 
• 
Renal: serum creatinine ≤1.5 mg/dL  
 


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Key exclusion criteria: 
1. Patients with TNM Classification T4 or Stage IV breast cancer; 
2. Patients with prior radiation therapy to the breast treated in this study; 
3. Patients with type V or VI skin according to the Fitzpatrick scale; 
4. Patients with current bilateral breast cancer who are receiving radiation treatment in both 
breasts; 
5. Patients receiving partial breast irradiation therapy;    
6.  Patients with uncontrolled diabetes (HbA1c > 11.0%, historical values within 6 months of 
screening are acceptable); 
7. Patients with collagen vascular disease or vasculitis; 
8. Patients with concurrent active malignancy other than adequately treated basal cell carcinoma 
of the skin or carcinoma in situ of the cervix; 
9. Patients with active and not adequately treated bacterial, fungal, or viral skin infections, at the 
investigator’s discretion; 
10.  Patients with known active hepatitis B or hepatitis C infection; 
11. Patients who intend to use any other topical cream, lotion or preparation applied to the 
radiation treatment area; 
12. Patients with known or suspected active drug or alcohol abuse; 
13. Patients with any abnormal laboratory test value which, in the opinion of the investigator, 
would put the patient at risk by trial enrollment; 
14. Participation in other interventional clinical studies within 30 days prior to consent; 
15. Patients with known hypersensitivity to excipients in the drug product; 
16. Patients receiving concomitant chemotherapy during the course of the planned radiation 
treatment regimen.  Patients are eligible if they are receiving sequential, neoadjuvant or 
adjuvant chemotherapy that is not anticipated to be delivered during the time course of the 
radiation treatment regimen; 
17. Patients unable to comply with the requirements of the study protocol or are unsuitable for the 
study for any reason in the opinion of the investigator; 
18. Patients receiving any form of brachytherapy radiation treatment including a brachytherapy 
boost; 
19. Patients receiving reverse-planned intensity modulated radiation treatment (IMRT). 
Investigational product, dosage and mode of administration:  
RTA 408 Lotion (0.5% and 3%) will be applied topically twice daily.  On days of morning radiation 
treatments, the patient will apply the study drug at the radiation treatment center immediately after the 
radiation therapy concludes and at night before bed.  On days of afternoon radiation treatments, the 
patient will apply the study drug in the morning at least 4 hours before radiation treatment and at night 
before bed.  A thin layer of lotion will be applied to the irradiated area.  RTA 408 Lotion or vehicle 
lotion should never be applied immediately before radiation treatment, and any residual lotion from a 
prior application should be removed prior to radiation treatment.  If patients develop grade 2 or higher 
radiation dermatitis and the radiation dermatitis is believed to be inadequately controlled in the opinion 
of the Investigator, additional topical creams, lotions, hydrocortisone or other escape medications may 
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with vehicle utilizing a hierarchical testing strategy to control the overall type I error.  The primary 
efficacy analyses will first test the difference between RTA 408 Lotion pooled and vehicle lotion.  If 
the first comparison is statistically significant, RTA 408 Lotion 3.0% will be compared to vehicle 
lotion.  Otherwise, the second comparison will not be performed or the p-value will be considered 
nonsignificant.  Similarly, only if the second comparison is statistically significant, RTA 408 lotion 
0.5% will be compared to vehicle lotion. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Background on RTA 408 ............................................................................................17 
5.2. 
Background on Radiation-Induced Dermatitis ...........................................................19 
5.3. 
Rationale .....................................................................................................................19 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................20 
6.1. 
Primary Study Objectives ...........................................................................................20 
6.2. 
Secondary Study Objectives .......................................................................................20 
7. 
INVESTIGATIONAL PLAN .....................................................................................21 
7.1. 
Overall Study Design ..................................................................................................21 
7.2. 
Number of Patients .....................................................................................................21 
7.3. 
Treatment Assignment ................................................................................................21 
7.4. 
Criteria for Study Termination ...................................................................................22 
7.5. 
Schedules of Assessments ..........................................................................................22 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................25 
8.1. 
Patient Inclusion Criteria ............................................................................................25 
8.2. 
Patient Exclusion Criteria ...........................................................................................26 
8.3. 
Patient Re-screening ...................................................................................................27 
8.4. 
Patient Withdrawal and Discontinuation ....................................................................27 
9. 
TREATMENT OF PATIENTS ..................................................................................29 
9.1. 
Description of Study Drug ..........................................................................................29 
9.2. 
Concomitant Medications ...........................................................................................29 
9.2.1. 
Excluded Medications ................................................................................................29 
9.2.2. 
Permitted Medications ................................................................................................29 
9.3. 
Treatment Compliance ................................................................................................30 


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9.4. 
Randomization ............................................................................................................30 
9.5. 
Blinding ......................................................................................................................30 
9.5.1. 
Patient Unblinding ......................................................................................................31 
9.5.2. 
Unblinding for Regulatory Submission ......................................................................31 
9.6. 
Unscheduled Visits .....................................................................................................31 
9.7. 
Pregnancy ...................................................................................................................31 
9.7.1. 
Women of Childbearing Potential ..............................................................................31 
9.7.2. 
Methods of Birth Control............................................................................................32 
9.7.3. 
Suspected Pregnancy ..................................................................................................32 
9.8. 
Study Procedures ........................................................................................................33 
9.8.1. 
Informed Consent .......................................................................................................33 
9.8.2. 
Inclusion/Exclusion ....................................................................................................33 
9.8.3. 
Demographics and Baseline Disease Characteristics .................................................33 
9.8.4. 
Concomitant Medications ...........................................................................................33 
9.8.5. 
Medical History ..........................................................................................................33 
9.8.6. 
Height .........................................................................................................................33 
9.8.7. 
Weight and Body Mass Index (BMI) .........................................................................33 
9.8.8. 
Vital Signs ..................................................................................................................33 
9.8.9. 
Physical Exam ............................................................................................................34 
9.8.10. 
Fitzpatrick Skin Score .................................................................................................34 
9.8.11. 
Pregnancy Test ............................................................................................................34 
9.8.12. 
Smoking Status ...........................................................................................................34 
9.8.13. 
Study Drug Administration.........................................................................................34 
9.8.14. 
Study Drug Dispensation ............................................................................................35 
9.8.15. 
Adverse Event Collection ...........................................................................................35 
9.8.16. 
Clinical Chemistry ......................................................................................................35 
9.8.17. 
Hematology .................................................................................................................35 
9.8.18. 
Urinalysis and Microscopy .........................................................................................35 
9.8.19. 
Chest Wall Separation ................................................................................................36 
9.8.20. 
Breast Volume ............................................................................................................36 
9.8.21. 
Radiation Treatment ...................................................................................................36 
9.8.22. 
Radiation Treatment Area ...........................................................................................36 
9.8.23. 
Weigh Study Drug ......................................................................................................36 


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9.8.24. 
Pharmacokinetic (PK) Blood Samples .......................................................................36 
9.8.25. 
Dermatitis Assessment ................................................................................................37 
9.8.26. 
Photographs of Radiation Treatment Area .................................................................37 
9.8.27. 
Skindex-16 Assessment ..............................................................................................37 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
10.1. 
Study Drug ..................................................................................................................38 
10.2. 
Study Drug Packaging and Labeling ..........................................................................38 
10.3. 
Study Drug Storage .....................................................................................................38 
10.4. 
Study Drug Administration.........................................................................................38 
10.5. 
Study Drug Accountability .........................................................................................38 
10.6. 
Study Drug Handling and Disposal ............................................................................39 
11. 
PHARMACOKINETIC, PHARMACODYNAMIC, AND EFFICACY 
ASSESSMENTS.........................................................................................................40 
11.1. 
Pharmacokinetic Samples ...........................................................................................40 
12. 
SAFETY ASSESSMENTS ........................................................................................41 
12.1. 
Safety Parameters .......................................................................................................41 
12.2. 
Adverse and Serious Adverse Events .........................................................................41 
12.2.1. 
Definition of Adverse Events .....................................................................................41 
12.2.1.1. 
Adverse Event .............................................................................................................41 
12.2.1.2. 
Serious Adverse Event ................................................................................................41 
12.3. 
Eliciting Adverse Event Information ..........................................................................42 
12.4. 
Assessment of Causality .............................................................................................42 
12.5. 
Assessment of Severity ...............................................................................................43 
12.6. 
Recording Adverse Events .........................................................................................43 
12.7. 
Reporting Serious Adverse Events .............................................................................44 
13. 
STATISTICS ..............................................................................................................46 
13.1. 
Sample Size ................................................................................................................46 
13.2. 
Study Variables ...........................................................................................................46 
13.2.1. 
Pharmacokinetic Variables .........................................................................................46 
13.2.2. 
Efficacy Variables ......................................................................................................46 
13.2.2.1. 
Dermatitis assessment .................................................................................................46 
13.2.2.2. 
Skindex-16 assessment ...............................................................................................46 
13.2.3. 
Safety Variables ..........................................................................................................47 


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13.3. 
Statistical Analyses .....................................................................................................47 
13.3.1. 
Primary Efficacy Analysis ..........................................................................................47 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................48 
14.1. 
Study Monitoring ........................................................................................................48 
14.2. 
Audits and Inspections ................................................................................................48 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................49 
15.1. 
Quality Assurance .......................................................................................................49 
15.2. 
Financial Disclosure ...................................................................................................49 
15.3. 
Sponsor Obligations....................................................................................................49 
15.4. 
Investigator Documentation ........................................................................................49 
15.5. 
Clinical Study Insurance .............................................................................................50 
15.6. 
Use of Information ......................................................................................................50 
16. 
ETHICS ......................................................................................................................51 
16.1. 
Institutional Review Board (IRB) Review .................................................................51 
16.2. 
Ethical Conduct of the Study ......................................................................................51 
16.3. 
Written Informed Consent ..........................................................................................51 
16.4. 
Confidentiality ............................................................................................................52 
16.5. 
Modification of the Protocol .......................................................................................52 
16.6. 
Protocol Deviations ....................................................................................................52 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................54 
17.1. 
Retention of Records ..................................................................................................54 
17.2. 
Case Report Forms .....................................................................................................54 
18. 
PUBLICATION POLICY ..........................................................................................55 
19. 
LIST OF REFERENCES ............................................................................................56 
20. 
APPENDICES ............................................................................................................58 
APPENDIX A. FITZPATRICK SKIN TYPE ASSESSMENT ..................................................59 
APPENDIX B. SKINDEX-16 ASSESSMENT ..........................................................................60 
 
 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 3: 
Overall Schedule of Assessments ...............................................................................23 
Table 4: 
AE Severity Grades ....................................................................................................43 
Table 5: 
SAE Reporting Contact Information ..........................................................................44 
Table 6: 
CTCAE Radiation Dermatitis Grade ..........................................................................46 
 
  


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
3D 
Three-dimensional 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
cc 
Cubic centimeters 
CFR 
Code of Federal Regulations (US) 
cm 
Centimeter 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ET 
End of treatment 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
Gy 
Gray 
HbA1c 
Hemoglobin A1c 
HDPE 
High-density polyethylene 
HIV 
Human immunodeficiency virus 
hr 
Hour 
ICH 
International Conference on Harmonization 
IFNγ 
Interferon-gamma 
IMRT 
Intensity modulated radiation treatment 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
LLOQ 
Lower limit of quantitation 


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Abbreviation or Specialist Term 
Explanation 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
μg 
Microgram 
mL 
Milliliter 
μM 
Micromolar 
mm Hg 
Millimeters of mercury 
n 
Number of patients 
NCI 
National Cancer Institute 
NF-κB 
Nuclear factor kappa-light-chain-enhancer of activated B-cells 
ng 
Nanogram 
Nrf2 
Nuclear factor erythroid-derived 2-related factor 2 
NO 
Nitric oxide 
NOAEL 
No observed adverse effect level 
NQO1 
NAD(P)H:quinone oxidoreductase 1 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
RBC 
Red blood cell 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOP 
Standard operating procedure 
STAT 
Skin toxicity assessment tool 
TBL 
Total bilirubin 
TNM 
Cancer classification system based on assessment of the 
Tumor, lymph Nodes, and Metastases 
US 
United States 
WBC 
White blood cell 
WK 
Week 
WOCBP 
Women of child bearing potential 
 


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5. 
INTRODUCTION 
5.1. 
Background on RTA 408 
Natural triterpenoids, such as oleanolic acid and ursolic acid, are derived from plant extracts and 
have been used extensively in Asian medicine for their anti-inflammatory and anticancer 
properties (Liu 1995).  A series of semi-synthetic triterpenoids was prepared based on the 
structure of oleanolic acid and tested to identify compounds optimized for their ability to inhibit 
the induction of nitric oxide in primary mouse macrophages treated with interferon-gamma 
(IFN-γ) (Honda 1999).  RTA 408 is a novel oleanane triterpenoid and part of this class of 
compounds.  Mechanistic studies have revealed that RTA 408 and the semi-synthetic 
triterpenoids are potent activators of nuclear factor erythroid derived 2-related factor 2 (Nrf2) 
and inhibitors of nuclear factor kappa light-chain-enhancer of activated B-cells (NF-κB), and 
thus induce an antioxidant and anti-inflammatory phenotype. 
The transcription factor Nrf2 regulates the expression of numerous antioxidant and anti-
inflammatory genes.  Activation of Nrf2 induces the expression of a battery of cytoprotective 
genes, which results in a coordinated cellular effort to protect against oxidative insult, 
highlighted by increased anti-oxidative capacity, induction of glutathione synthesis, and 
conjugation and efflux of potentially harmful molecules.  RTA 408 and the semi-synthetic 
oleanane triterpenoids are among the most potent activators of Nrf2 identified to date 
(Sporn 2011, Dinkova-Kostova 2005).  The structure and activity profile of this class resembles 
that of the cyclopentenone prostaglandins, the endogenous regulators of Nrf2, which also inhibit 
NF-κB and play an important role in the resolution of inflammation (Levonen 2004, 
Cernuda Morollon 2001, Cuzzocrea 2003, Kawamoto 2000, Rossi 2000, Straus 2000).  RTA 408 
exhibits efficacy in a broad range of animal models of diseases involving inflammation and 
oxidative stress, including models of radiation-induced skin and organ damage, cancer, 
idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, rheumatoid arthritis, 
multiple sclerosis, asthma, and sepsis. 
Reata has demonstrated that topical dermal administration of RTA 408 activates the Nrf2 
pathway and increases expression of Nrf2 target genes in both the dermis and epidermis of 
various nonclinical species (Reisman 2013), as well as in human skin explants ex vivo.  RTA 408 
is highly effective in rodent models of radiation-induced dermatitis and also protects against 
organ damage from whole-body irradiation and radiation-induced oral mucositis.  
Dermal application of RTA 408 Lotion was well-tolerated in a variety of nonclinical studies.  In 
dermal Good Laboratory Practice (GLP) toxicity studies with up to 13 weeks of twice-daily 
dosing, no evidence of skin toxicity related to RTA 408 Lotion was observed in either rats or 
minipigs with doses as high as 8% RTA 408 Lotion.  Further, in marked contrast to the 
negligible systemic exposure that has been observed in the Phase 1 clinical study with dermal 
dosing of RTA 408 Lotion to healthy volunteers, meaningful systemic exposure was observed in 
rats and minipigs.  In the 14-day dermal GLP toxicity studies, systemic exposures, based on the 
area under the curve (AUC(0-24hr)), of up to 5.3 hr*μg/mL in rats and 4.9 hr*μg/mL in minipigs at 
the maximum feasible dose of 8% RTA 408 Lotion were not associated with any adverse effects 
and consequently, the no-observed-adverse-effect-level (NOAEL) was 8% for both species.  In 
the 13-week minipig dermal GLP toxicity study, systemic exposures (AUC(0-24hr)) up to 


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1.7 hr*μg/mL were also not associated with any adverse findings, and thus, the NOAEL was also 
8% RTA 408 Lotion.  In the 13-week rat dermal GLP toxicity study, systemic exposures 
exceeded those associated with adverse effects in chronic oral toxicity studies in rats 
(i.e., 4.6 hr*μg/mL in the 13-week dermal study vs. 2.3 hr*μg/mL in the 6-month oral dosing 
study).  The liver and kidney were identified as target organs in the 13-week rat dermal GLP 
toxicity study, consistent with findings from the oral toxicity studies, and the resulting NOAELs 
were 0.3% RTA 408 Lotion in females and < 0.3% RTA 408 Lotion in males.  Furthermore, the 
systemic toxicity potential of RTA 408 has been extensively studied in rats and monkeys, with 
daily oral administration for up to six months in rats and nine months in monkeys.  Overall, 
based on an integrated assessment of the nonclinical data, and based on the demonstrated low 
systemic exposure to RTA 408 in healthy human volunteers after topical administration, it is 
concluded that RTA 408 Lotion has an acceptable safety profile for topical use as indicated in 
this Phase 2 study in female patients at risk for radiation dermatitis. 
A Phase 1 study (408-C-1305) was completed to evaluate the safety, local pharmacodynamics 
(PD), and systemic pharmacokinetics (PK) of RTA 408 following topical application of 
RTA 408 Lotion to healthy volunteers.  The Phase 1 study was conducted in three parts.  In 
Part A of the study, RTA 408 Lotion Vehicle and RTA 408 Lotion (0.5%, 1%, and 3%) were 
each concurrently applied to a small skin surface area (four individual 4-cm2 sites; 16 cm2 total 
area) twice daily for 14 days.  The maximum tolerated drug concentration in Part A was 3% 
RTA 408 Lotion.  In Part B, RTA 408 Lotion (3%) was applied topically twice daily for 14 days 
to a larger skin surface area (~100 cm2).  In Part C, 3% RTA 408 Lotion was applied topically 
twice daily for 28 days to an even larger skin surface area (~500 cm2).  Approximately 
32 healthy adult volunteers were enrolled in the Phase 1 study with 12 volunteers in Part A, 
10 volunteers in Part B, and 10 volunteers in Part C. 
Overall, RTA 408 Lotion, at doses as high as 3%, was well tolerated and elicited a significant 
pharmacodynamic response in the skin.  No drug-related SAEs were observed in the study.  Two 
drug-related AEs were reported from a single healthy volunteer enrolled in Part C of the study.  
In this subject, mild erythema at the dose site and mild, intermittent pruritus at the dose site were 
observed within the first 2 weeks of dosing and both resolved spontaneously with continued 
application of RTA 408 Lotion.  No drug-related systemic AEs were observed in any subject.  
The local pharmacodynamic response was assessed in skin biopsy samples collected during each 
part of the study.  Administration of RTA 408 Lotion significantly increased protein levels of 
NAD(P)H:quinone oxidoreductase 1 (NQO1, a prototypical Nrf2 target gene) in skin, consistent 
with the known pharmacology of RTA 408. 
RTA 408 Lotion produced very low systemic exposures to RTA 408.  The highest dose 
evaluated in the Phase 1 study was 3% RTA 408 Lotion applied to a 500-cm2 skin area twice 
daily for 28 days.  Plasma concentrations of RTA 408 were near or below the lower limit of 
quantitation (LLOQ; 0.075 ng/mL) for all healthy volunteers.  Only 1 volunteer demonstrated 
measurable RTA 408 concentrations in plasma samples collected in the study; the subject was 
enrolled in the Part C cohort that received the highest dose evaluated, and had measurable 
plasma RTA 408 concentrations only on Day 28.  The maximal plasma RTA 408 concentration 
observed in the healthy volunteer with RTA 408 plasma concentrations was 0.0943 ng/mL 
(0.00017 μM), and the total AUC(0-24hr) was 0.0019 hr*μg/mL. 


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5.2. 
Background on Radiation-Induced Dermatitis 
Radiation dermatitis is experienced by almost all patients (up to 95%) receiving radiation therapy 
for cancer (Ryan 2012).  Radiation dermatitis can be a serious condition because, in addition to 
its direct physical complications and the resulting impact on overall quality of life, it can also be 
a dose-limiting toxicity requiring changes to the prescribed course of radiation therapy.  The 
most common strategy employed in an attempt to prevent or minimize radiation dermatitis 
involves moisturization of the irradiated area, use of a mild soap to keep the area clean, and 
minimizing exposure to potential mechanical irritants, such as scratching and rough clothing.  
However, this strategy has been shown to lack clinically significant efficacy (Salvo 2010).  
Consequently, there is a clinical need for new treatments that are effective in protecting against 
radiotherapy-induced oxidative stress and the subsequent development of radiation dermatitis. 
RTA 408 Lotion has shown significant efficacy in mouse models of radiation dermatitis with 
both fractionated and acute radiation regimens.  In these models, disease severity was evaluated 
using a 5-point clinical scoring scale, similar to the CTCAE scale used in clinical practice.  In the 
fractionated radiation dermatitis model, RTA 408 Lotion was effective in decreasing the severity 
of dermatitis in mice that received a cumulative radiation dose of 60 Gray (Reisman 2014).  
Specifically, RTA 408 Lotion treatment was associated with a lower incidence of animals that 
developed severe dermatitis and improved histology scores compared with vehicle controls.  
Further, RTA 408 Lotion is unlikely to interfere with radiation therapy, as RTA 408 has 
demonstrated enhanced therapeutic efficacy when orally administered concomitantly with 
radiation therapy in a mouse xenograft cancer model, and an oral dosage form of RTA 408 is 
currently being studied in a Phase 1 study in patients with advanced cancers.  Based on these 
data, Reata believes that RTA 408 Lotion may effectively prevent and mitigate radiation 
dermatitis in oncology patients undergoing radiation therapy. 
5.3. 
Rationale 
This randomized, double-blind, vehicle-controlled, parallel-group trial will study the efficacy, 
tolerability and safety of two concentrations of RTA 408 Lotion (3% and 0.5%) versus vehicle in 
patients with breast cancer for whom radiation therapy is recommended.  The primary outcome 
will be the change in dermatitis grade measured with Common Terminology Criteria for Adverse 
Events (CTCAE, Version 4.03) following administration of RTA 408 Lotion compared to 
administration of vehicle.   


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Study Objectives 
The primary objectives of this study are the following: 
1. To determine the time-averaged effect on radiation dermatitis grade measured with 
Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03) following 3D 
conformal radiation therapy to the breast and concomitant administration of RTA 408 
Lotion (0.5% and 3%) compared to administration of vehicle. 
2. To evaluate the safety of RTA 408 Lotion  
6.2. 
Secondary Study Objectives 
The secondary objectives of this study are the following: 
1. To determine the mean maximum radiation dermatitis grade measured with CTCAE of 
RTA 408 Lotion (0.5% and 3%) compared to administration of vehicle 
2. To determine the proportion of patients with treatment success, defined as post-baseline 
maximum dermatitis grade < 2 using the CTCAE criteria following administration of 
RTA 408 Lotion compared to administration of vehicle 
3. To determine the mean duration of grade ≥ 2 radiation dermatitis using the CTCAE 
criteria following administration of RTA 408 Lotion compared to administration of 
vehicle 
4. To determine the extent of systemic exposure to RTA 408 following administration of 
RTA 408 Lotion following radiation therapy 
5. To evaluate patient-reported outcomes (Skindex-16) 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This randomized, double-blind, vehicle-controlled, parallel-group study will assess the safety, 
tolerability and efficacy of RTA 408 Lotion (0.5% or 3%) versus vehicle in the treatment of 
patients at risk for radiation dermatitis.  Eligible patients will be randomized using a 1:1:1 
assignment ratio to receive RTA 408 Lotion 0.5%, RTA 408 Lotion 3%, or vehicle 1 week 
(± 2 days) prior to initiation of radiation therapy.  Randomization will be stratified by smoking 
status (smoker or ex-smoker versus non-smoker) and breast cancer treatment prior to radiation 
therapy (mastectomy versus lumpectomy/partial mastectomy).   
Study drug application will start approximately 1 week prior to scheduled initiation of radiation 
therapy with twice daily applications continuing throughout the duration of radiation therapy 
(i.e., 5-6 weeks) and two weeks following completion of radiation therapy, for an expected total 
of up to 9 weeks of study drug application.  In cases where radiation treatment is delayed 
(e.g., delayed start of radiation treatment or radiation treatment interruptions), the total study 
drug application period may be extended from the expected 8-9 weeks up to a maximum of 
13 weeks. Study lotion is to be applied twice daily.  
On days of morning radiation treatments, the patient will apply the study drug at the radiation 
treatment center immediately after the radiation therapy concludes and at night before bed.  On 
days of afternoon radiation treatments, the patient will apply the study drug in the morning at 
least 4 hours before radiation treatment and at night before bed.  For each application of study 
drug treatment, a thin layer of lotion will be applied to the irradiated area.  RTA 408 Lotion or 
vehicle lotion should never be applied immediately before radiation treatment, and any residual 
lotion from a prior application should be removed prior to radiation treatment.   
Following randomization, patients will be assessed in person at weekly visits during 
administration of study treatment.  A follow-up visit will occur 4 weeks after last application of 
RTA 408 Lotion or vehicle.  Due to the variation in radiation treatment schedules, exact study 
days or procedures may be shifted to fall within a window of 2 days based on radiation treatment 
schedules.  However, all enrolled patients must continue to apply RTA 408 Lotion for two weeks 
after the completion of radiation.   
7.2. 
Number of Patients 
Approximately 177 patients (59 per treatment group) are to be enrolled in this study.   
7.3. 
Treatment Assignment 
Patients who qualify for the study will be randomized with a 1:1:1 assignment ratio to receive 
RTA 408 Lotion 0.5%, RTA 408 Lotion 3%, or vehicle.   Randomization will be stratified by 
smoking status (smoker or ex-smoker versus non-smoker) and breast cancer treatment prior to 
radiation therapy (full mastectomy versus partial mastectomy or lumpectomy).  Treatment 
assignments will be managed by an IWRS system.   


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7.4. 
Criteria for Study Termination 
Although the Sponsor intends to complete the study, the Sponsor reserves the right to 
discontinue the study at any time for clinical or administrative reasons, or if required by 
regulatory agencies.  If the Sponsor discontinues the study, all study treatment will be 
discontinued, and the investigator will be responsible for any additional therapy to be 
administered. 
7.5. 
Schedules of Assessments 
Table 3 lists the overall schedule of assessments for the study.  
 




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b Visit 2 (7 days prior to radiation treatment) is the day of randomization and application of the first dose, and must occur at least 5 and no more than 9 days prior to the first day of 
radiation treatment.  If the start of radiation treatment is delayed, patients should continue administering study drug twice daily until the first dose of radiation up to a maximum 
of 14 days.  If the time from randomization to first dose of radiation exceeds 14 days, the medical monitor should be contacted to decide on an appropriate action. Patients may 
be randomized after meeting the inclusion / exclusion criteria and before study drug lotion is first administered as long as patients apply study drug lotion for at least 5 days prior 
to the first day of radiation treatment.  Patients with either morning or afternoon randomizations may apply lotion in the clinic and again before bedtime for two doses on that 
day. 
c Visit 3 should occur on the day of the first radiation treatment.  If radiation treatment is in the morning, the radiation treatment will be the third to last procedure (radiation 
treatment > study drug application > PK). If radiation treatment is in the afternoon, radiation treatment will be the second to last procedure, and the last procedure will be PK, as 
study drug will have been applied at least 4 hours prior to radiation treatment. 
d Study visits during radiation treatment therapy must occur weekly beginning with Day 1 of radiation treatment.  
e At the end of radiation treatment, patients must complete Visit 9 assessments. Visit 9 must be the last day of the 10 – 16 Gy boost. Visit 8 is needed for patients who require 
radiation therapy for 6 weeks.  If radiation therapy is extended longer than 6 weeks, then assessments at Visit 8 should be repeated weekly until the end of radiation visit 
(Visit 9). A weekly study visit should not be performed if the visit falls 1 or 2 days prior to the last day of radiation (Visit 9), or 1-2 days after the last day of radiation.   
f Visit 10 should occur approximately 1 week (7 calendar days) after the completion of radiation therapy (Visit 9).  
g Visit 11 should occur approximately 1 week (7 calendar days) after Visit 10 (i.e., 2 weeks after the completion of radiation therapy). 
h Follow-up visit will occur approximately 4 weeks after the final study drug application.  These procedures should be performed at the end of study and for early termination. 
i The ±2 day window is a two-day allowance within which the visit or visit procedures may occur around the scheduled visit date.  
j Medical history includes collection of surgery type (lumpectomy, partial mastectomy (breast conserving surgeries), or full mastectomy). If the patient is to undergo post-
mastectomy reconstruction before radiation treatment, the type of reconstruction should be recorded as well.  
k Procedures that are to be performed as part of the practice of medicine and which would be done whether or not study entry was contemplated, such as for diagnosis or treatment 
of a disease or medical condition, may be performed and the results subsequently used for determining study eligibility without first obtaining consent if done within the 
screening timeframe, and if the site’s IRB is in agreement. 
l The radiation treatment area surface measurements can occur at any time before first day of radiation treatment.
m Breast volume measurements are required for all patients who had breast conserving surgery (lumpectomy or partial mastectomy). Breast tissue should be defined per the RTOG
contouring guidelines (RTOG 2009), but sites may use their local SOP for calculating breast volume. 
n  A serum pregnancy test will be performed at Screening for WOCBP or at any point in time if a pregnancy is suspected.  All other pregnancy assessments will be urine pregnancy 
tests, unless site/local authority mandates serum pregnancy testing. 
o Study drug is to be dispensed to the patients at the scheduled study visits. Additional study drug will be dispensed to patients based on patient need, and will be recorded as an
unscheduled study drug dispensation. Study drug (bottle + lotion) is to be weighed before study drug dispensing.
p When radiation treatment overlaps with study drug administration and radiation treatment is in the morning, RTA 408 Lotion or vehicle should be applied to the breast area 
immediately after radiation treatment concludes.  If radiation treatment is in the afternoon, RTA 408 Lotion or vehicle should be applied at least 4 hours before radiation 
treatment. RTA 408 Lotion or vehicle should also be applied nightly.  
q Planned radiation treatment must be no more than 7.5 weeks. 
r Radiation dermatitis assessments must be performed PRIOR to initiation of that day’s radiation treatment, and only by a trained evaluator. 
 If radiation treatment is delayed or extended, dermatitis assessments should be performed weekly until the end of radiation treatment. 
s The Skindex-16 must be completed prior to initiation of that day’s radiation treatment.
t Screening lab assessments (described in Section 9.8 for chemistry, hematology, urinalysis, and serum pregnancy tests) should be drawn ≤ 14 days prior to randomization in order 
to have current values for inclusion/exclusion assessment. 
u A single PK collection will be obtained on Visit 3, Visit 6, Visit 9, Visit 11 and Visit 12.  If patients are to receive a morning radiation treatment on any of these visits, the PK
sample should be drawn after RTA 408 Lotion or Vehicle Lotion application, which occurs after the completion of radiation treatment. If patients are to receive an afternoon
radiation treatment on any of these visits, the PK sample should be drawn after the radiation treatment.
v Optional photographs may be collected at Sponsor-qualified sites. On Day 1 of radiation treatment and the last day of radiation treatment, photographs must be collected prior to 
radiation treatment. 


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
All patients must meet all of the following criteria to be included in the study: 
1. Adult female patients (18 to 80 years of age, inclusive); 
2. Patients diagnosed with ductal carcinoma in situ or non-inflammatory breast 
adenocarcinoma who have been referred for post-operative radiotherapy and have had no 
prior radiation treatment to that breast;  
3. Patients planning to undergo 3D conformal radiation therapy to the whole breast (as part 
of breast-conservation therapy / lumpectomy) or chest wall (as part of post-mastectomy 
irradiation), with or without treatment of regional lymph nodes (i.e., axillary, 
supraclavicular, or internal mammary), using one of the following treatment schedules: 
a. 45 – 50.4 Gy in 1.8 Gy per day, in addition to a mandatory10-16 Gy boost 
b. 46 – 50 Gy in 2 Gy per day, in addition to a mandatory 10-16 Gy boost; 
4. Patients who received breast-conservation therapy / lumpectomy must be receiving 
≥ 107% of the total radiation dose (calculated from the total radiation dose including 
boost) to any portion of the breast, based on radiation inhomogeneity, and/or have a 
breast volume ≥ 1200 cc; 
5. Female patients of childbearing potential who are willing to practice methods of birth 
control from screening through 1 month after applying the final dose of study drug; 
6. Female patients of childbearing potential who are non-pregnant, non-lactating and have a 
negative pregnancy test result prior to enrollment in the study; 
7. Patients willing and able to give written informed consent for study participation; 
8. Patients willing and able to cooperate with all aspects of the protocol; 
9. Patients for which at least 14 days have elapsed since breast conservation surgery, 
mastectomy surgery and/or chemotherapy prior to randomization; 
10. Have adequate hematologic and organ function at screening as follows: 
a. Hematologic: Absolute neutrophil count ≥ 1.5 x 103 /μL, platelets > 100 x 109/L, 
hemoglobin ≥ 9 g/dL;  
b. Hepatic: total bilirubin ≤ 1.5 times (X) upper limit of normal (ULN), ALT and 
AST ≤ULN; 
c. Renal: serum creatinine ≤1.5 mg/dL 


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8.2. 
Patient Exclusion Criteria 
All patients with any of the following conditions or characteristics must be excluded from the 
study: 
1. Patients with TNM Classification T4 or Stage IV breast cancer; 
2. Patients with prior radiation therapy to the breast treated in this study; 
3. Patients with type V or VI skin according to the Fitzpatrick scale; 
4. Patients with current bilateral breast cancer who are receiving radiation treatment in both 
breasts; 
5. Patients receiving partial breast irradiation therapy; 
6. Patients with uncontrolled diabetes (HbA1c > 11.0%, historical values within 6 months 
of screening are acceptable); 
7. Patients with collagen vascular disease or vasculitis; 
8. Patients with concurrent active malignancy other than adequately treated basal cell 
carcinoma of the skin or carcinoma in situ of the cervix; 
9. Patients with active and not adequately treated bacterial, fungal, or viral skin infections, 
at the investigator’s discretion; 
10. Patients with known active hepatitis B or hepatitis C infection; 
11. Patients who intend to use any other topical cream, lotion or preparation applied to the 
radiation treatment area; 
12. Patients with known or suspected active drug or alcohol abuse; 
13. Patients with any abnormal laboratory test value which, in the opinion of the investigator, 
would put the patient at risk by trial enrollment; 
14. Participation in other interventional clinical studies within 30 days prior to consent; 
15. Patients with known hypersensitivity to excipients in the drug product; 
16. Patients receiving concomitant chemotherapy during the course of the planned radiation 
treatment regimen.  Patients are eligible if they are receiving sequential, neoadjuvant or 
adjuvant chemotherapy that is not anticipated to be delivered during the time course of 
the radiation treatment regimen; 
17. Patients unable to comply with the requirements of the study protocol or are unsuitable 
for the study for any reason in the opinion of the investigator; 
18. Patients receiving any form of brachytherapy radiation treatment including a 
brachytherapy boost; 
19. Patients receiving reverse-planned intensity modulated radiation treatment (IMRT). 


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8.3. 
Patient Re-screening 
Reasons for study re-screening include the following: 
• At the discretion of the investigator, a patient’s planned radiation regimen is changed 
from a non-allowed regimen to a regimen listed in Section 8.1;  
• Patients initially qualified for the study, but radiation treatment was delayed such that 
patients did not begin study drug for >45 days after Screening; 
• Patients have experienced logistical/operational issues and the medical monitor has been 
notified; 
• Patients have no changes in their radiation treatment plan and have undergone prior 
chemotherapy, but did not initially qualify for the study due to bone marrow toxicity 
associated with chemotherapy (absolute neutrophil count ≥ 1.5 x 103 /μL, platelets 
> 100 x 109/L, hemoglobin ≥ 9 g/dL);  
• Patients had untreated bacterial, fungal, or viral skin infections and since have undergone 
treatment for this condition; 
• Patients who may undergo re-screening with the approval of a medical monitor.  
8.4. 
Patient Withdrawal and Discontinuation 
Patients have the right to withdraw from the study at any time for any reason, without prejudice 
to their medical care.  Furthermore, the investigator may discontinue a patient from study drug or 
terminate the patient from the study.  The reason for a patient’s withdrawal or discontinuation 
from the study will be recorded in the Electronic Case Report Form (eCRF).  
8.4.1. 
Patient Discontinuation Criteria 
Discontinuation refers to a patient stopping administration of study drug.  Reasons for study drug 
discontinuation include the following: 
• Occurrence of an adverse event (AE) or change in medical status that leads the 
investigator to be concerned about the patient’s welfare 
• Noncompliance with study procedures 
• Pregnancy during the study 
• Investigator unblinding of patient 
Patients who are discontinued from study drug should still attend all study visits and undergo all 
study assessments, if possible.   
The CTCAE version 4.03 will be used to define patient stopping criteria for systemic adverse 
events, except where related to transaminase laboratory values. The criteria for a stopping 
criteria for adverse events related to transaminase laboratory values will be defined using the 
FDA Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation” (July 2009) rather than CTCAE. 


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The determination stopping criteria will be defined in each patient as all toxicity ≥ Grade 3 
(using CTCAE, version 4.03), except as noted below: 
• 
Grade ≥ 3 skin toxicity, with the patient allowed to continue at the discretion of the 
investigator; 
• 
Nausea and vomiting will be considered stopping criteria if Grade 3 toxicity persists 
after optimal medical therapy. 
Any hepatobiliary disorders of ≥ Grade 2 (from CTCAE, version 4.03, pages 24 – 25) will be 
considered adequate stopping criteria. Note that laboratory measurements are included in a 
separate section of the CTCAE. 
Changes in ALT, AST, and total bilirubin levels must meet one of the following criteria to be 
considered a DLT: 
• 
ALT or AST > 8X ULN 
• 
ALT or AST > 5X ULN for more than 2 weeks 
• 
ALT or AST > 3X ULN and (total bilirubin > 2X ULN or INR > 1.5) 
• 
(Repeat testing every 72 to 96 hours until transaminase levels are below three 
times the ULN for at least one week or patient withdraws consent.) 
• 
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
(Repeat testing every 72 to 96 hours until transaminase levels are below three 
times the ULN for at least one week or patient withdraws consent.) 
8.4.2. 
Patient Study Termination Criteria 
Termination refers to a patient stopping study drug and all study assessments and visits.  Reasons 
for patient study termination include the following: 
• 
Failure to return for follow-up 
• 
Death 
• 
Withdrawal of consent 
• 
Investigator decision 
Patients who terminate the study for any reason may not re-initiate study drug at any time.   




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Patients may take ibuprofen, aspirin and/or over-the-counter cough / cold medications, but these 
concomitant medications must be recorded. Patients taking medication chronically should be 
maintained on those same doses and dose schedules throughout the study period, as medically 
feasible. 
If patients develop Grade 2 or higher radiation dermatitis and the radiation dermatitis is believed 
to be inadequately controlled in the opinion of the Investigator, additional topical creams, 
lotions, hydrocortisone or other escape medications may be prescribed and then must be 
documented in the CRF.  Patients should apply escape medications 1-3 hours after study drug 
application.  Any residual escape medication should be removed prior to study drug application. 
However, in patients with radiation dermatitis < Grade 2, no concomitant medications may be 
prescribed or administered to prophylactically prevent the incidence of Grade 2 or higher 
radiation dermatitis. 
9.3. 
Treatment Compliance 
The investigator or his/her designated and qualified representatives will only dispense study drug 
to patients enrolled in the study in accordance with the protocol.  Study drug is to be dispensed to 
the patients at the scheduled study visits.  Additional study drug will be dispensed to patients 
based on patient need and will be recorded as an unscheduled study drug dispensation.   The 
study drug must not be used for reasons other than that described in the protocol.  A maximum of 
14 consecutive missed doses (7 days of twice daily dosing) or no more than 28 total non-
consecutive missed doses are permitted during the study.  Additionally, a maximum of 6 total 
missed doses is permitted in the 7 day run-in period prior to the start of radiation treatment.  
Patients who exceed the number of allowed missed doses will be considered not compliant with 
dosing and will have a protocol deviation recorded, but these patients will be encouraged to 
continue with dosing and will not be discontinued from the study.  
In cases where radiation treatment is delayed (e.g., delayed start of radiation treatment or 
radiation treatment interruptions), the study drug application period may be extended from the 
expected 8-9 weeks up to a maximum of 13 weeks.  If the start of radiation treatment is delayed, 
patients should continue administering study drug twice daily until the first dose of radiation up 
to a maximum of 14 days.  If the time from randomization to first dose of radiation exceeds 
14 days, the medical monitor should be contacted to decide on an appropriate action.  
9.4. 
Randomization 
The study will be conducted using double-blind procedures with limited access to the 
randomization code.  Patients will be randomly assigned to RTA 408 Lotion 0.5%, 3% or vehicle 
using a 1:1:1 assignment ratio.  Randomization will be stratified by smoking status (smoker or 
ex-smoker versus non-smoker) and breast cancer treatment prior to radiation therapy (full 
mastectomy versus partial mastectomy or lumpectomy).  Randomization occurs approximately 
one week prior to the start of radiation treatment (Day 1).   
9.5. 
Blinding 
In this double-blind study all patients, investigators, site personnel and laboratories with direct 
involvement in the conduct of the study or their designees will be blinded to treatment 
assignments.  Appropriate measures will be taken to ensure the blind is maintained for the 


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patients and personnel mentioned previously to reduce potential bias.  To maintain the blind, 
blinded study drug kits will be distributed to patients as directed by the IWRS. Treatment 
assignments will be managed by an IWRS system. Additionally, some Sponsor personnel will be 
unblinded to individual treatment assignments.  
9.5.1. 
Patient Unblinding 
Although there is no known antidote to RTA 408, under rare circumstances unblinding may be 
considered medically necessary.  Unless faced with a life-threatening medical situation, the 
investigator should contact the medical monitor to discuss if there is a medically compelling 
reason to unblind the patient’s treatment assignment.  After the discussion, the investigator may 
proceed to unblind the patient, as appropriate.  If unblinding is required, the investigator will 
utilize the IWRS to perform the unblinding.  If a study drug assignment is unblinded, a 
description of the event that required unblinding must be documented by the investigator in the 
patient’s source documents.  Patients must discontinue taking study drug if their treatment 
assignment has been unblinded to the investigator (or designee).  Such patients must undergo the 
same early termination procedures as those patients who discontinue taking study drug for other 
reasons.  Patient treatment assignments must not be unblinded in the case of an AE or SAE, 
except as described above. 
9.5.2. 
Unblinding for Regulatory Submission 
In situations where a regulatory body requires unblinding and reporting of a particular serious 
adverse event, the appropriate bodies (e.g., ethics committees, IRBs) must be provided with 
unblinded information according to the applicable regulatory requirement.  This information 
must not be conveyed to investigator, site personnel or patient; therefore, this type of unblinding 
does not necessitate that the patient discontinue taking study drug.  In cases when unblinded 
information must be conveyed to local health authorities, personnel without direct involvement 
in the conduct of the study must be responsible for unblinding the patient’s treatment using the 
IWRS and conveying the necessary information. 
9.6. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
• Patient re-screening; 
• Management of an adverse event or serious adverse event; 
• Performance of additional laboratory tests for clinically abnormal test values or to 
confirm a possible pregnancy; 
• Any time the investigator feels that it is clinically appropriate for patient safety. 
9.7. 
Pregnancy 
9.7.1. 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) are female patients who are not surgically sterile (no 
history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), do not have 
fallopian inserts with confirmed blockage and are not postmenopausal for at least 1 year. 


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9.7.2. 
Methods of Birth Control 
During screening, while taking study drug and until the final visit indicated in Table 3, per the 
International Conference on Harmonization (ICH) M3 Guidance for Industry 
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M3
_R2/Step4/M3_R2__Guideline.pdf), WOCBP must practice one of the following highly 
effective methods of birth control: 
• Use double-barrier contraception method defined as male use of a condom and female 
use of a barrier method (e.g., contraceptive sponge, spermicidal jelly or cream, 
diaphragm [always use with spermicidal jelly/cream]); 
• Established use of hormonal contraceptives (oral, parenteral, vaginal or transdermal) 
for at least 3 months prior to study drug administration; 
• Use of an intrauterine device; 
• Have a partner who has had a vasectomy (applies to any and all partners);   
• Abstain from sexual intercourse completely. 
9.7.3. 
Suspected Pregnancy 
During the study, all WOCBP must be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., late or missed menstrual period).   
If a patient or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If pregnancy is confirmed with 
a positive serum pregnancy test result, the patient must discontinue applying study drug and be 
discontinued from the study.  The investigator must immediately report a pregnancy associated 
with study drug exposure and record the event.  Protocol-required last-day-of-treatment and 
early-termination procedures must be performed on the patient.  Other appropriate follow-up 
procedures should be considered if indicated.  
Pregnancy is not considered an AE; however, the investigator must follow a pregnant patient 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 CRF and on an SAE form: 
• Congenital anomaly/birth defect 
• Stillbirth 
• Spontaneous miscarriage 


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9.8. 
Study Procedures  
9.8.1. 
Informed Consent 
Written informed consent (see Section 16.3) must be obtained from the patient before any 
study-related procedures are performed. 
9.8.2. 
Inclusion/Exclusion 
Inclusion and exclusion criteria should be reviewed at the times indicated in Table 3.  Patients 
must meet all of the inclusion and none of the exclusion criteria for entry into the study.  
9.8.3. 
Demographics and Baseline Disease Characteristics 
Demographic data includes sex, age, race and ethnicity and will be collected at the times 
indicated in Table 3.  Baseline disease characteristics will be collected at the time point indicated 
in Table 3.  
9.8.4. 
Concomitant Medications 
The name, dose, and frequency must be recorded for all medications that the patient is taking or 
applying to the treatment area.  All allowed and excluded medications should be recorded 
including all prescription drugs, herbal products, vitamins, minerals and over-the-counter 
medications.  Trade or generic drug names should be used where possible.  Concomitant 
medications will be collected at the times indicated in Table 3.  
9.8.5. 
Medical History 
A complete medical history (e.g., per patient report) that includes all medical history within the 
past 5 years must be collected.  Medical history includes collection of surgery type (lumpectomy, 
partial mastectomy, or full mastectomy).  If the patient is to undergo post-mastectomy 
reconstruction before radiation treatment, the type of reconstruction should be recorded as well.  
Medical history also includes date of breast cancer diagnosis, clinical stage at diagnosis, date of 
breast surgery, and breast surgery type. Medical history will be recorded at the times indicated in 
Table 3. 
9.8.6. 
Height 
Height in centimeters should be measured without footwear, or limb prosthetics at the time 
indicated in Table 3. 
9.8.7. 
Weight and Body Mass Index (BMI) 
Weight in kilograms should be measured at the times indicated in Table 3.  Weight should be 
measured without footwear, or limb prosthetics.  Body mass index (BMI) will be calculated 
automatically each time the weight is recorded. 
9.8.8. 
Vital Signs 
Vital sign measurements include the patient’s heart rate (beats/minute taken for at least 
15 seconds), blood pressure (mm Hg) and oral, tympanic or temporal body temperature (°C or 


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°F).  Blood pressure should be taken after the patient has rested in a sitting position for at least 
5 minutes.  The same arm (usually the non-dominant arm if appropriate) and the appropriate size 
cuff should be used for each measurement.  Vital sign measurements should be taken at the times 
indicated in Table 3. 
9.8.9. 
Physical Exam 
A comprehensive physical examination must be performed by a physician, physician assistant or 
registered nurse practitioner at the time points indicated in Table 3.  If the physical exam is to be 
performed as part of the practice of medicine and would be done whether or not study entry was 
contemplated, such as for diagnosis or treatment of a disease or medical condition, the physical 
exam may be performed and the results subsequently used for determining study eligibility 
without first obtaining consent as long as the exam is done within the study screening timeframe, 
and the site’s IRB is in agreement. The examination must include the following organ or body 
system assessments: general appearance, head, eyes, ears, nose, throat, neck, musculoskeletal, 
cardiovascular, lymphatic, respiratory, abdomen, dermatologic, extremities and neurological.  
Assessments of any specific signs or symptoms reported by the patient must also be performed 
and documented along with any other findings of note.  Findings at Screening must be 
characterized as either normal or abnormal, and if abnormal, a description of the abnormality 
must be provided.  Each body system must be assessed for clinical significance.  Clinically 
significant findings at Screening must be included in the patient’s medical history.  New 
clinically significant findings after first dose must be included as adverse events. 
9.8.10. 
Fitzpatrick Skin Score 
Determination of the Fitzpatrick skin score must be performed at the time point indicated in 
Table 3.  Patients with type V or VI skin are excluded from the study.  Refer to Appendix A for 
the Fitzpatrick Skin Scale. 
9.8.11. 
Pregnancy Test 
WOCBP (see Section 9.7.1) will complete a pregnancy test at the time points indicated in Table 
3.  Negative test results are required on Day 1 (Study Visit 2) before study drug administration.  
Any patient who becomes pregnant during the study must discontinue taking study drug 
immediately.  See Section 9.7 for a description of procedures to be followed in case of 
pregnancy. 
9.8.12. 
Smoking Status 
The smoking status of the patient (current smoker, former smoker, or never smoked) is to be 
recorded at the time points indicated in Table 3. 
9.8.13. 
Study Drug Administration 
Patients may be randomized after meeting the inclusion / exclusion criteria and before study drug 
lotion is first administered, as long as patients apply study drug lotion for at least 5 days prior to 
the first day of radiation treatment. Patients should self-administer the lotion at the time points 
indicated in Table 3.  Study drug is to be applied twice daily. The amount of lotion used will 
depend on the size of the radiation treatment area. On days of morning radiation treatments, the 
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therapy concludes and at night before bed.  On days of afternoon radiation treatments, the patient 
will apply the study drug in the morning at least 4 hours before radiation treatment and at night 
before bed.  A thin layer of lotion will be applied to the indicated or planned radiation treatment 
area, which includes any regional irradiated lymph nodes.  RTA 408 Lotion or vehicle lotion 
should never be applied immediately before radiation treatment, and any residual lotion from a 
prior application should be removed prior to radiation treatment.  On the last day of study drug 
administration, patients will only have a morning study drug application as the study drug will be 
collected that day. If patients develop grade 2 or higher radiation dermatitis and the radiation 
dermatitis is believed to be inadequately controlled in the opinion of the Investigator, additional 
topical creams, lotions, hydrocortisone or other escape medications may be prescribed and then 
must be documented.  Patients should continue study drug administration in addition to escape 
medications prescribed by the Investigator. Patients should apply escape medications 1-3 hours 
after study drug application.  Any residual escape medication should be removed prior to study 
drug application. 
9.8.14. 
Study Drug Dispensation 
Study drug will be dispensed to the patient along with the dosing diary and collected from the 
patient at the time points indicated in Table 3. 
9.8.15. 
Adverse Event Collection 
Patients should be observed for general appearance, presence of illness or injury, or signs 
indicative of a concurrent illness at the time points indicated in Table 3.  Patients should be 
instructed to volunteer any information regarding AEs at any time during the study, or query the 
patients with an open question regarding any AEs they may be experiencing (e.g., “How do you 
feel?” or “How have you been feeling since your last visit?”).  Any findings are to be 
documented. 
9.8.16. 
Clinical Chemistry 
Samples will be collected for the following clinical chemistry analyses at the time points 
indicated in Table 3: urea nitrogen (BUN), creatinine enzymatic, total bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, 
potassium, calcium, phosphorus, uric acid, cholesterol, total protein, albumin, chloride and 
bicarbonate.  
9.8.17. 
Hematology 
Samples will be collected for the following hematology assessments at the time points indicated 
in Table 3: hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count, 
neutrophils, bands (if detected), lymphocytes, monocytes, basophils (if detected), eosinophils (if 
detected), absolute platelet count, mean corpuscular hemoglobin (MCH), mean corpuscular 
volume (MCV) and mean corpuscular hemoglobin concentration (MCHC).  
9.8.18. 
Urinalysis and Microscopy 
Samples will be collected for the following urinalysis assessments at the time points indicated in 
Table 3: specific gravity, ketones, pH, protein, blood, glucose, urobilinogen and bilirubin. 


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9.8.19. 
Chest Wall Separation  
Chest wall separation measurements must be collected by CT scanning at the time points 
indicated in Table 3.  Institutions may use their local SOP for determination of chest wall 
separation as measured by CT. Chest wall separation will be reported in centimeters (cm).  
9.8.20. 
Breast Volume 
Breast volume measurements in patients that have undergone breast conserving surgery must be 
collected by CT scanning at the time points indicated in Table 3, which should correspond with 
the radiation treatment planning visit. Breast tissue should be defined per the RTOG contouring 
guidelines (RTOG 2009), but sites may use their local SOP for calculating breast volume.  
9.8.21. 
Radiation Treatment 
Planned radiation treatment must be no more than 7.5 weeks, and the dates of radiation treatment 
will be recorded in the eCRF at the time points indicated in Table 3.  The dates of missed 
radiation treatment, the type of radiation treatment (regular radiation or boost treatment), and the 
use of a bolus will also be recorded in the eCRF. For patients for whom a bolus is used, an 
indicator other than redness of the skin surface (e.g., dosimeter at the skin surface) may be 
considered for decisions regarding radiation treatment dose and frequency.  
9.8.22. 
Radiation Treatment Area 
The surface area (cm2) of the breast skin region treated with radiation must be measured and 
recorded as indicated in Table 3.  The area (cm2) of the breast skin area treated with radiation 
will be measured as defined in the study manual.  The radiation treatment area surface 
measurements can occur at any time before Day 1 of radiation treatment. 
9.8.23. 
Weigh Study Drug 
The combined weight of the study drug and the lotion bottle (without box) must be recorded at 
the times listed in Table 3.  Empty lotion bottles will not be provided to sites, and sites should 
not attempt to tare the scale with an empty lotion bottle before weighing.  Study drug and lotion 
bottle weight should be recorded in units of grams, with 0.1 gram precision.  
9.8.24. 
Pharmacokinetic (PK) Blood Samples 
Blood samples for the determination of plasma RTA 408 and potential metabolite concentrations 
will be drawn at the time points indicated in Table 3.  Blood sample collection instructions will 
be provided in the laboratory manual. The date and time of collection of all PK blood samples 
should be recorded; however, any deviations from the protocol-specified sampling times will not 
be considered protocol deviations.  Sample time deviations will be summarized in the study 
report.  Dates in the case report form should be recorded in an unambiguous format 
(e.g., DD MMM YYYY) and time should be recorded to the nearest minute (e.g., HH:MM using 
the 24-hour clock).  Blood samples not drawn should be recorded as such.  The date and time of 
the last two applications of study drug should also be collected on the PK case report form. 


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9.8.25. 
Dermatitis Assessment 
The CTCAE v4.03 radiation dermatitis grade will be assessed by a local, trained physician, nurse 
or appropriately trained site staff member.  Components of the CTCAE will be recorded 
separately by a local, trained physician, nurse or appropriately trained site staff member. 
Dermatitis assessment at each visit is performed before initiation of radiation therapy. Dermatitis 
assessments must be performed by trained evaluator(s) at each time point indicated in Table 3.  
These components include the severity of erythema, the extent and severity of dry desquamation, 
the extent and severity of wet desquamation and the presence of edema. Refer to Section 13.2.2.1 
for the CTCAE scoring.   
New or worsening of radiation dermatitis signs/symptoms should not be captured as individual 
AEs, but rather are captured in the Dermatitis Assessment process and documentation.  These 
signs / symptoms are being assessed as study endpoints. Thus, if investigators seek to enter 
“radiation dermatitis”, “erythema”, “desquamation” or other signs / symptoms of radiation 
dermatitis as adverse events, they should first discuss the signs/symptoms with the medical 
monitor. The investigator, in coordination with the medical monitor, will determine the process 
for capturing these signs/symptoms.  
9.8.26. 
Photographs of Radiation Treatment Area 
Optional photographs may be collected at Sponsor-qualified sites at the times indicated in Table 
3. The local, trained physician, nurse or appropriately trained site staff member who performs the 
dermatitis assessment should also collect photographs of the patient. Details of photography 
assessments will be outlined in a study specific manual. On Day 1 of radiation treatment and the 
last day of radiation treatment, photographs must be collected prior to radiation treatment. 
9.8.27. 
Skindex-16 Assessment 
The Skindex-16 quality-of-life tool will be used to assess patient responses to skin toxicity 
during and after radiation therapy at the time points indicated in Table 3.  The Skindex-16 is a 
short 16-item patient-completed assessment using numerical analogue scales (0=never bothered 
to 6=always bothered). Responses to the Skindex-16 are categorized into three subscales: 
symptom, emotional and functional. The tool should be completed by the patient prior to 
initiation of that day’s planned radiation therapy. Refer to Appendix B for the Skindex-16 
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unless directed to do so by the Sponsor or its designee.  All study drug containers will be 
weighed prior to dispensation and upon collection. 
10.6. 
Study Drug Handling and Disposal 
At the conclusion of the study, the Sponsor or its designee will direct the site regarding the final 
disposition of any remaining study drug. 


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11. 
PHARMACOKINETIC, PHARMACODYNAMIC, AND 
EFFICACY ASSESSMENTS 
11.1. 
Pharmacokinetic Samples 
Pharmacokinetic samples will be analyzed for RTA 408 using a validated analytical method.  
Samples may be analyzed for potential metabolites of RTA 408 using non-validated analytical 
methods.  


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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all safety assessments.  Safety 
parameters include weight, BMI, vital sign measurements, physical examination results, adverse 
events, serious adverse events and laboratory test results (clinical chemistry, hematology, 
urinalysis and microscopy).  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient regardless of 
its causal relationship to study treatment.  An AE can be any unfavorable and unintended sign 
(including any clinically significant abnormal laboratory test result), symptom or disease 
temporally associated with the use of the study drug, whether or not it is considered to be study-
drug related.  Included in this definition are any newly-occurring events or previous condition 
that has increased in severity or frequency since the administration of study drug.  
New or worsening radiation dermatitis signs/symptoms should not be captured as individual 
AEs, but rather are captured in the Dermatitis Assessment documentation as these 
signs/symptoms are being assessed as study endpoints. Thus, if investigators seek to enter 
“radiation dermatitis”, “erythema”, “desquamation” or other signs/symptoms of radiation 
dermatitis as adverse events, they should first discuss the signs/symptoms with the medical 
monitor. The investigator in coordination with the medical monitor will determine how these 
signs/symptoms are to be recorded. 
All AEs that are observed or reported by the patient during the study (from the time of first dose 
until the final visit indicated in Table 3) must be reported, regardless of their relationship to 
study drug or their clinical significance. 
12.2.1.2. Serious Adverse Event 
A serious adverse event (SAE) is any AE occurring at any dose and regardless of causality that: 
• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Is a congenital anomaly or birth defect in an offspring of a patient taking study drug; 
• Is an important medical event.  


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The term "life-threatening" refers to an event in which the patient was at immediate risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above, however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
which occur during the study (from the time of administration of the first dose of study drug until 
the final visit indicated in Table 3).  Certain pregnancy outcomes will require submission as an 
SAE. (See Section 9.7) 
The investigator is responsible for reporting to Reata or designee all AEs and SAEs that are 
observed or reported by the patient during the study (from the time of first dose until the final 
visit indicated in Table 3), regardless of their relationship to study drug or their clinical 
significance.  All SAEs reported or observed during the study must be followed to resolution or 
until the investigator deems the event to be chronic or the patient to be stable.  Reata or designee 
may contact the investigator to obtain additional information on any SAE which has not resolved 
at the time the patient completes the study. 
12.3. 
Eliciting Adverse Event Information  
At every study visit, patients must be asked a standard, non-directed question, such as, “How do 
you feel?” or “How have you been feeling since your last visit?” to elicit any medically related 
changes in their well-being.  They may also be asked if they have been hospitalized, had any 
accidents, used any new medications or changed concomitant medication regimens (including 
prescription drugs, over-the-counter medications, vitamins, herbal products and minerals).  
Responses to questions asked must be documented in the source documents. 
In addition to patient observations, AEs must be documented for any clinically significant 
diagnosis resulting from abnormal laboratory test values, physical examination findings, or ECG 
abnormalities, or from other documents that are relevant to patient safety. 
12.4. 
Assessment of Causality  
The investigator must use the following classifications and criteria to characterize the 
relationship or association of the study drug in causing or contributing to the AE: 
Unrelated: This relationship suggests that there is no association between the study drug and the 
reported event. 
Unlikely: This relationship suggests that the temporal sequence of the event with study drug 
administration makes a causal relationship improbable and/or other factors also provide plausible 
explanations. 
Possible: This relationship suggests that treatment with the study drug caused or contributed to 
the AE.  That is, the event follows a reasonable temporal sequence from the time of study drug 
administration, and/or, follows a known response pattern to the study drug, but could have been 
produced by other factors. 


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Probable: This relationship suggests that a reasonable temporal sequence of the event with study 
drug administration exists and, based upon the known pharmacological action of the drug, 
known or previously reported adverse reactions to the drug or class of drugs, or judgment based 
on the investigator’s clinical experience, the association of the event with study drug 
administration seems likely. 
12.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as Grades 1, 2, 3, 4, or 5 based on the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.03.  If the criteria in the CTCAE version 4.03 do not apply, severity should be defined 
as follows: 
Table 4: 
AE Severity Grades 
Grade 
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
The NCI CTCAE, version 4.03 will be provided to the investigator. 
12.6. 
Recording Adverse Events 
All conditions present prior to the first dose of study drug should be documented as medical 
history.  Documentation of AEs shall continue until the final visit indicated in Table 3, regardless 
of the relationship of the AE to study drug.  Information to be collected includes type of event, 
date of onset, date of resolution, investigator-specified assessment of severity and relationship to 
study drug, seriousness, as well as any action taken.  
While an AE is ongoing, changes in the severity (e.g., worsening and improving) should be 
noted in the source documents but, when documenting the AE, only the total duration and 
greatest severity should be recorded in the case report form.  AEs characterized as intermittent 
require documentation of onset and duration. 
All drug-related (Possible or Probable, see Section 12.4) AEs and abnormal laboratory test 
results reported or observed during the study must be followed to resolution (either return to 
baseline or within normal limits).  All other AEs will be followed throughout the study. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications or progression of disease states must also be reported.  Preexisting conditions 
(present before the start of the AE collection period) are considered concurrent medical 
conditions and should NOT be recorded as AEs.  However, if the patient experiences a 




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Any additional information that becomes available later should be submitted to the above 
number within 1 working day of receipt. 
Reata or designee will notify regulatory agencies of any fatal or life-threatening unexpected 
events associated with the use of the study drug as soon as possible but no later than 7 calendar 
days after the initial receipt of the information.  Initial notification will be followed by a written 
report within the timeframe established by the appropriate regulatory agency.  For other SAEs 
that do not meet the fatal or life-threatening unexpected criteria, but are reported to be associated 
with the use of the study drug, Reata or designee will notify the appropriate regulatory agencies 
in writing within the timeframe established by those regulatory agencies.  Reata or designee will 
provide copies of any reports to regulatory agencies regarding serious and unexpected SAEs to 
the investigators for review and submission to their institutional review board (IRB).  
Principal investigators are responsible for informing their IRB of any SAEs at their site.  SAE 
correspondence with regulatory authorities or IRBs must be submitted to Reata or designee for 
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Responses to the Skindex-16 are categorized into three subscales: symptom, emotional and 
functional.  Refer to Appendix B for the Skindex-16 assessment.  
13.2.3. 
Safety Variables 
The safety variables include vital sign measurements, results of physical examinations, 
laboratory test results (clinical chemistry, hematology, urinalysis and microscopy), concomitant 
medications, adverse events, and serious adverse events. 
13.3. 
Statistical Analyses 
A statistical analysis plan (SAP) detailing the analyses will be developed prior to the database 
lock.  All statistical analyses and data summaries will be performed using SAS® (Version 9.1 or 
higher) or other similar software.  The SAP will serve as the final arbiter of all statistical 
analyses.  Data will be summarized overall using descriptive statistics.  Continuous data will be 
summarized with number of patients (n), mean, median, minimum, maximum, standard 
deviation, coefficient of variation and geometric mean (where applicable).  Categorical data will 
be summarized using number of patients (n), mean, median, minimum, maximum, standard 
deviation, coefficient of variation, geometric mean (where applicable), frequency counts and 
percentages. 
13.3.1. 
Primary Efficacy Analysis 
For the primary efficacy analysis, a longitudinal mixed-model will be used to analyze the 
CTCAE dermatitis grades over time, incorporating the repeated measures design of the study. 
Treatment group and week of visit will constitute the main fixed effects of the model; study 
subject will represent the random effect; smoking status (smoker or ex-smoker versus non-
smoker), breast cancer treatment prior to radiation therapy (full mastectomy versus partial 
mastectomy or lumpectomy), and other covariates (such as cumulative radiation exposure) will 
be evaluated for inclusion in the model as covariates. A generalized mixed model will be used as 
the primary longitudinal model with additional sensitivity analyses performed as appropriate.  A 
hierarchical approach will be used for analysis of the primary endpoint to control the type I error.  
The primary efficacy analyses will first test the difference between RTA 408 Lotion pooled and 
vehicle lotion.  If the first comparison is statistically significant, RTA 408 Lotion 3.0% will be 
compared to vehicle lotion.  Otherwise, the second comparison will not be performed or the p-
value will be considered nonsignificant.  Similarly, only if the second comparison is statistically 
significant, RTA 408 lotion 0.5% will be compared to vehicle lotion. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
The study monitor, as a representative of the Sponsor, has the obligation to follow the study 
conduct closely.  In doing so, the  monitor will visit the principal investigator and study facilities 
periodically, in addition to maintaining necessary telephone and letter contact.  The monitor will 
maintain current knowledge of the study activity of the investigator and his/her staff through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigators and staff. 
The Sponsor or designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the ICH guideline E6(R1): Good Clinical Practice: 
Consolidated Guideline and current standard operating procedures (Section 16.2). 
Each investigator is expected to make a reasonable effort to accommodate the monitor when 
monitoring visits are necessary and to be available during the site visit.  Furthermore, the 
monitor should be provided direct access to source data and documents for trial-related 
monitoring and internet during the visit. 
14.2. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, and IRB review, and regulatory inspection(s), by providing direct access to 
all study records.  In the event of an audit, the principal investigator agrees to allow the Sponsor, 
representatives of the Sponsor, the US Food and Drug Administration (FDA) or other relevant 
regulatory authorities access to all study records. 
The principal investigator should promptly notify the Sponsor or designee of any audits 
scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the Sponsor or designee. 
 
 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1. 
Quality Assurance 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Reata may conduct a quality assurance audit.  Please see Section 14.2 for more details regarding 
the audit process. 
15.2. 
Financial Disclosure  
Principal investigators and sub-investigators are required to provide financial disclosure 
information prior to starting the study.  In addition, the principal investigator and sub-
investigators must provide the Sponsor or designee with updated information, if any relevant 
changes occur during the course of the investigation and for one year following the completion 
of the study. 
Any potential investigator who has a vested financial interest in the success of this study may not 
participate in this study. 
15.3. 
Sponsor Obligations  
The Sponsor or designee is not financially responsible for further testing/treatment of any 
medical condition that may be detected during the screening process.  In addition, in the absence 
of specific arrangements, the Sponsor or designee is not financially responsible for treatment of 
the patient’s underlying disease. 
15.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R1) 
8.2 and Title 21 of the Code of Federal Regulations (CFR) by providing the essential documents 
to the Sponsor or designee, which include but are not limited to the following: 
• An original investigator-signed investigator agreement page of the protocol;  
• The IRB approval of the protocol; 
• The IRB-approved informed consent, samples of site advertisements for recruitment 
for this study, and any other written information regarding this study that is to be 
provided to the patient or legal guardians; 
• A Form FDA 1572, fully executed, and all updates on a new fully executed Form 
FDA 1572; 
• Curricula vitae for the principal investigator and each sub-investigator listed on Form 
FDA 1572.  A curricula vitae and current licensure, as applicable, must be provided.  
The curricula vitae must have been signed and dated by the principal investigators 
and sub-investigators within 2 years before study start-up to indicate the documents 
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• Completed financial disclosure forms (Section 15.2) to allow the Sponsor or designee 
to submit complete and accurate certification or disclosure statements required under 
US Title 21 CFR 54.  In addition, the investigators must provide to the Sponsor or 
designee a commitment to update this information promptly if any relevant changes 
occur during the course of the investigation and for 1 year following the completion 
of the study; 
• Laboratory certifications and normal ranges for any laboratories used by the site for 
the conduct of this study. 
15.5. 
Clinical Study Insurance 
In accordance with the respective national drug laws, the Sponsor has taken out patient liability 
insurance for all patients who give their consent and enroll in this study.  This insurance covers 
potential fatalities, physical injuries, or damage to health that may occur during the clinical 
study. 
15.6. 
Use of Information  
All information regarding RTA 408 supplied by Sponsor to the investigator is privileged and 
confidential.  The investigator agrees to use this information to accomplish the study and will not 
use it for other purposes without consent from the Sponsor.  Furthermore, the investigator is 
obligated to provide the Sponsor with complete data obtained during the study.  The information 
obtained from the clinical study will be used towards the development of RTA 408 Lotion and 
may be disclosed to regulatory authority(ies), other investigators, corporate partners or 
consultants, as required. 
 


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16. 
ETHICS 
16.1. 
Institutional Review Board (IRB) Review 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted IRB before study start.  Each site must provide the Sponsor or its designee a 
signed and dated statement that the protocol and informed consent have been approved by the 
IRB before consenting patients.  Prior to study initiation, the investigator is required to sign a 
protocol signature page confirming agreement to conduct the study in accordance with this 
protocol and to give access to all relevant data and records to the Sponsor, its designee and 
regulatory authorities as required. 
The IRB chairperson or designee must sign all IRB approvals and must identify the IRB by name 
and address, the clinical protocol, and the date approval and/or favorable opinion was granted. 
The principal investigator is responsible for obtaining reviews of the clinical research at intervals 
specified by the IRB, but not exceeding 1 year.  The principal investigator must supply the 
Sponsor or designee with written documentation of reviews of the clinical research. 
16.2. 
Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (e.g., US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki.  
The principal investigator agrees to conduct the study in accordance with the ICH E6(R1) 
Guidance for Industry on Good Clinical Practice 
[http://www.ich.org/fileadmin/Public Web Site/ICH Products/Guidelines/Efficacy/E6/E6 R1
Guideline.pdf].  The principal investigator must conduct all aspects of this study in accordance 
with all national, state, and local laws or regulations, and the principles of the Declaration of 
Helsinki [http://www.wma.net/en/30publications/10policies/b3/]. 
16.3. 
Written Informed Consent 
Because the study will be conducted under a United States Investigational New Drug 
Application, a signed informed consent form, in compliance with Title 21 of the United States 
Code of Federal Regulations (CFR) Part 50, will be obtained from each patient before the patient 
enters the study.  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 
submission.  Once reviewed, the consent will be submitted by the principal investigator to his or 
her IRB 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-approved consent form. 
Before enrollment, each prospective patient will be given a full explanation of the study and be 
allowed to read the approved informed consent form.  Once the principal investigator or designee 


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is assured that the patient understands the implications of participating in the study, the patient 
will be asked to give consent to participate in the study by signing the informed consent form.  
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB-approved informed consent.  Informed consent must be 
obtained before conducting any study-specific procedures (i.e., all of the procedures described in 
the protocol).  The process of obtaining informed consent must be documented in the patient 
source documents. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
the Sponsor before submission to the IRB, and a copy of the approved version and the notice of 
approval must be provided to the Sponsor’s designated monitor after IRB approval. 
The principal investigator or designee will provide a copy of the informed consent form (signed 
copy to be provided per applicable law) to the patient and/or legal guardian.  The original form 
will be maintained in the patient’s medical records at the site. 
16.4. 
Confidentiality 
All laboratory specimens, evaluation forms, reports and other records will be identified in a 
manner designed to maintain patient confidentiality.  All records will be kept in a secure storage 
area with limited access.  Clinical information will not be released without the written 
permission of the patient (or the patient’s guardian), except as necessary for monitoring and 
auditing by the Sponsor, its designee, the FDA or applicable regulatory authorities, or the IRB. 
The principal investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study, any data, record or other 
unpublished confidential information disclosed to them for the purpose of the study.  Prior 
written agreement from the Sponsor or designee must be obtained for the disclosure of any said 
confidential information to other parties. 
16.5. 
Modification of the Protocol 
Any changes, which arise after the approval of the protocol, must be documented as protocol 
amendments.  FDA must be notified of protocol amendments.  The changes will become 
effective only after approval of the Sponsor, the investigator and the IRB.  In cases when the 
protocol is modified to enhance patient safety, changes may be implemented and the amendment 
must be immediately submitted to the IRB. 
The investigator is responsible for informing the IRB of all problems involving risks to patients 
according to national legislation.  In case of urgent safety measures, the Sponsor will 
immediately notify FDA in accord with 21 CFR 312.32. 
16.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviation.  The IRB must be 
notified of all protocol deviations in a timely manner by the investigator as appropriate.  Protocol 
deviations will be documented by the responsible monitor during monitoring visits, and those 
observations will be communicated to the investigator. 


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If there is an immediate hazard to a patient the principal investigator may deviate from the 
protocol without prior Sponsor and IRB approval.  The Sponsor and IRB must be notified of the 
deviation. 
 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Retention of Records 
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
submission or 2 years after formal discontinuation of the clinical development of the 
investigational product.  If the investigator withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the responsibility.  The 
Sponsor must be notified in writing if a custodial change occurs.  
17.2. 
Case Report Forms 
All case report form data will be entered in paper or electronic forms at the investigational site.  
If an Electronic Data Capture system (EDC) is used to capture data electronically for all 
randomized patients, it will be 21 CFR Part 11 compliant. 
 


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18. 
PUBLICATION POLICY 
Reata 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.  Reata supports communication and 
publication of study results whatever the findings of the study.  Reata also requires 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 publications committee for the study. 


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19. 
LIST OF REFERENCES 
Berthelet E, Truong PT, Musso K, et al. Preliminary reliability and validity testing of a new skin 
toxicity assessment tool (STAT) in breast cancer patients undergoing radiotherapy. Am J Clin 
Oncol 2004;27;626-631. 
Cernuda-Morollon E, Pineda-Molina E, Canada FJ, et al. 15-deoxy-Δ12,14-prostaglandin J2 
inhibition of NF-κB-DNA binding through covalent modification of the p50 subunit. J Biol 
Chem 2001;276:35530-35536. 
Cuzzocrea S, Wayman NS, Mazzon E, et al. The cyclopentenone prostaglandin 15-deoxy-
Δ12,14-prostaglandin J2 attenuates the development of acute and chronic inflammation. Br J 
Pharmacol 2003;138:678-688. 
Dinkova-Kostova AT, Liby KT, Stephenson KK, et al. Extremely potent triterpenoid inducers of 
the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc 
Natl Acad Sci USA 2005;102:4584-4589. 
Honda T, Rounds BV, Bore L, et al. Novel synthetic oleanane triterpenoids: a series of highly 
active inhibitors of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett 
1999;9:3429-3434. 
Kawamoto Y, Nakamura Y, Naito Y, et al. Cyclopentenone prostaglandins as potential inducers 
of phase II detoxification enzymes. 15-deoxy-Δ(12,14)-prostaglandin j2-induced expression of 
glutathione S-transferases. J Biol Chem 2000;275:11291-11299. 
Levonen AL, Landar A, Ramachandran A, et al. Cellular mechanisms of redox cell signalling: 
role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid 
oxidation products. Biochem J 2004;378:373-382. 
Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 1995;49:57-68. 
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.03 Radiation 
Recall Reaction. 2010.  
Reisman SA, Lee CY, Meyer CJ, et al. Topical application of the synthetic triterpenoid RTA 408 
activates Nrf2 and induces cytoprotective genes in rat skin. Arch Dermatol Res 2013. Epub 2013 
Dec 22. 
Reisman SA, Lee CY, Meyer CJ, et al.  Topical application of the synthetic triterpenoid 
RTA 408 protects mice from radiation-induced dermatitis.  Rad Res 2014;181:512-20. 
Rossi A, Kapahi P, Natoli G, et al. Anti-inflammatory cyclopentenone prostaglandins are direct 
inhibitors of IκB kinase. Nature 2000;403:103-118. 
RTOG. Breast Cancer Atlas for Radiation Therapy Planning: Consensus Definitions. 2009 
Ryan JL. Ionizing radiation: The good, the bad, and the ugly. J Invest Dermatol 2012;132:985-
993. 
Salvo N, Barnes E, van Draanen J, et al. Prophylaxis and management of acute radiation-induced 
skin reactions: a systematic review of the literature. Curr Oncol 2010;17:3429-3434. 


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Sporn MB, Liby KT, Yore MM, et al. New synthetic triterpenoids: potent agents for prevention 
and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 
2011;74:537-545. 
Straus DS, Pascual G, Li M, et al. 15-deoxy-Δ12,14-prostaglandin J2 inhibits multiple steps in 
the NF-κB signaling pathway. Proc Natl Acad Sci USA 2000;97:4844-4849. 
United States Food and Drug Administration [Web site]. Guidance for Industry Drug-Induced 
Liver Injury: Premarketing Clinical Evaluation. Accessed July 21, 2014.  Available at: 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf 
 


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20. 
APPENDICES 
 


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APPENDIX A. FITZPATRICK SKIN TYPE ASSESSMENT 
Study personnel will read the questions and possible answers below to each subject and record 
the answers.  After all answers have been recorded, study personnel will tally the scores and 
record the Fitzpatrick Skin Type of the subject.   
The worksheet is not to be handed to or completed by subjects. 
 
 


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APPENDIX B. SKINDEX-16 ASSESSMENT 
Patients should check one box for each question.  Study personnel should specify that the patient 
answers should reflect the patient’s responses during the past week.  Patients should answer 
every question.  
 
During the past week, how often have you been bothered by: 
 
Never 
Bothered 
  
  
  
  
  
Always 
Bothered 
Your skin condition itching 
0 
1 
2 
3 
4 
5 
6 
Your skin condition burning or stinging 
0 
1 
2 
3 
4 
5 
6 
Your skin condition hurting 
0 
1 
2 
3 
4 
5 
6 
Your skin condition being irritated 
0 
1 
2 
3 
4 
5 
6 
The persistence / recurrence of your skin 
condition 
0 
1 
2 
3 
4 
5 
6 
Worry about your skin condition (for 
example: that it spread, get worse, scar, be 
unpredictable, etc.) 
0 
1 
2 
3 
4 
5 
6 
The appearance of your skin condition 
0 
1 
2 
3 
4 
5 
6 
Frustration about your skin condition 
0 
1 
2 
3 
4 
5 
6 
Embarrassment about your skin condition 
0 
1 
2 
3 
4 
5 
6 
Being annoyed about your skin condition 
0 
1 
2 
3 
4 
5 
6 
Feeling depressed about your skin 
condition 
0 
1 
2 
3 
4 
5 
6 
The effects of your skin condition on your 
interactions with others (for example: 
interactions with family, friends, close 
relationships, etc.) 
0 
1 
2 
3 
4 
5 
6 
The effects of your skin condition on your 
desire to be with people 
0 
1 
2 
3 
4 
5 
6 
Your skin condition making it hard to show 
affection 
0 
1 
2 
3 
4 
5 
6 
The effects of your skin condition of your 
daily activities 
0 
1 
2 
3 
4 
5 
6 
Your skin condition making it hard to work 
or do what you enjoy 
0 
1 
2 
3 
4 
5 
6 
 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
A Randomized, Double-Blind, Vehicle-Controlled, 
Parallel-Group Phase 2 Study of the Efficacy, Safety, 
Pharmacokinetics, and Pharmacodynamics of RTA 408 
Lotion in the Treatment of Patients at Risk for 
Radiation Dermatitis 
 
 
Name of Test Drug: 
RTA 408 Lotion 
 
 
Indication: 
Radiation Dermatitis 
 
 
Sponsor: 
Reata Pharmaceuticals, Inc. 
 
 
Protocol No.: 
RTA 408-C-1306 
 
 
Protocol Version/Date 
Version 4.0 (October 17, 2014) 
 
 
Author Biostatistician: 
 
 
 
Analysis Plan Version/Date: 
Version 2.0 / 29-Apr-2015 
 
 
 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
 
CONFIDENTIAL 
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RTA 408-C-1306 
Statistical Analysis Plan 
Version 2.0 
TABLE OF CONTENTS 
1. 
INTRODUCTION ......................................................................................................................................... 5 
1.1 
Study Objectives ............................................................................................................................... 5 
1.1.1 
Primary Objectives .......................................................................................................... 5 
1.1.2 
Secondary Objective ....................................................................................................... 5 
1.2 
Study Design ..................................................................................................................................... 6 
1.2.1 
Study Visits and Assessments ......................................................................................... 6 
1.2.2 
Discontinuation of Treatment .......................................................................................... 6 
1.2.3 
Patient Termination ......................................................................................................... 7 
1.2.4 
Randomization and Blinding ........................................................................................... 7 
1.3 
Sample Size and Power ..................................................................................................................... 7 
2. 
PLANNED ANALYSIS ................................................................................................................................ 8 
2.1 
Final Analysis ................................................................................................................................... 8 
2.2 
Endpoint Measures ............................................................................................................................ 8 
2.2.1 
Efficacy Endpoints .......................................................................................................... 8 
2.2.2 
Radiation Dermatitis Assessment .................................................................................... 8 
2.2.3 
Safety Endpoints ............................................................................................................. 8 
2.2.4 
Pharmacokinetics Endpoints ........................................................................................... 8 
2.3 
Changes from Protocol-Specified Analysis....................................................................................... 9 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ...................................................................... 10 
3.1 
Analysis Considerations .................................................................................................................. 10 
3.2 
Analysis Populations ....................................................................................................................... 10 
3.2.1 
Intent-to-treat Population (ITT) ..................................................................................... 10 
3.2.2 
Safety Population .......................................................................................................... 10 
3.3 
Strata and Covariates ....................................................................................................................... 10 
3.4 
Examination of Patient Subsets ....................................................................................................... 10 
3.5 
Multiple Comparisons ..................................................................................................................... 11 
3.6 
Missing Data ................................................................................................................................... 11 
3.7 
Visit Windows ................................................................................................................................. 11 
3.7.1 
Definition of Study Day ................................................................................................ 11 
3.7.2 
Definition of Study Baseline ......................................................................................... 11 
3.7.3 
Unscheduled Visits ........................................................................................................ 11 
3.8 
Rounding ......................................................................................................................................... 11 
4. 
BASELINE CHARACTERISTICS AND PATIENT DISPOSITION ........................................................ 12 
4.1 
Disposition of Patients .................................................................................................................... 12 
 
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Statistical Analysis Plan 
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4.2 
Demographics and Baseline Characteristics, Baseline Disease Characteristics, and Radiation 
Treatment Plan ................................................................................................................................ 12 
4.3 
Study Drug Exposure ...................................................................................................................... 13 
4.4 
Inclusion and Exclusion Criteria ..................................................................................................... 13 
4.5 
Medical History ............................................................................................................................... 14 
4.6 
Prior and Concomitant Medications ................................................................................................ 14 
4.7 
Protocol Deviations ......................................................................................................................... 14 
5. 
EFFICACY ANALYSIS .............................................................................................................................. 15 
5.1 
Primary Efficacy ............................................................................................................................. 15 
5.2 
Secondary Efficacy ......................................................................................................................... 15 
5.2.1 
Mean Maximum Radiation Dermatitis Grade of RTA 408 Lotion 
Compared to Administration of Vehicle ....................................................................... 15 
5.2.2 
Proportion Patients with Post-baseline Maximum Dermatitis Grade <2 
Using the CTCAE Criteria ............................................................................................ 16 
5.2.3 
Mean Duration of Grade ≥ 2 Radiation Dermatitis Using the CTCAE 
Criteria........................................................................................................................... 16 
5.2.4 
Dermatitis Assessment .................................................................................................. 16 
5.2.5 
Patient-reported Outcomes (Skindex-16) ...................................................................... 16 
6. 
PHARMACOKINETIC ANALYSIS .......................................................................................................... 18 
7. 
SAFETY ANALYSIS .................................................................................................................................. 19 
7.1 
Adverse Events................................................................................................................................ 19 
7.1.1 
General Considerations for Analysis of Adverse Events .............................................. 19 
7.1.2 
Adverse Event Dictionary ............................................................................................. 19 
7.1.3 
Treatment-Emergent Adverse Events ............................................................................ 19 
7.1.4 
Adverse Event Severity ................................................................................................. 20 
7.1.5 
Relationship of Adverse Events to Study Drug ............................................................. 20 
7.1.6 
Serious Adverse Events ................................................................................................. 20 
7.2 
Clinical Laboratory Evaluations ...................................................................................................... 21 
7.2.1 
General Considerations for Analyses of Laboratory Data ............................................. 21 
7.2.2 
Summaries of Laboratory Results ................................................................................. 21 
7.2.3 
Laboratory Abnormalities ............................................................................................. 21 
7.2.4 
Treatment-Emergent Abnormalities .............................................................................. 21 
7.2.5 
Summaries of Laboratory Abnormalities ...................................................................... 21 
7.3 
Vital Signs ....................................................................................................................................... 22 
8. 
REFERENCES ............................................................................................................................................ 23 
9. 
APPENDICES ............................................................................................................................................. 24 
 
 
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Statistical Analysis Plan 
Version 2.0 
1. INTRODUCTION  
Study 408-C-1306 is a randomized, double blind, vehicle-controlled, parallel-group Phase 2 
study designed to study the efficacy, tolerability and safety of two concentrations of RTA 408 
Lotion (3% and 0.5%) versus vehicle in patients with breast cancer for whom radiation is 
recommended.  This document describes the statistical analysis methods and data presentations 
that Reata Pharmaceuticals, Inc. (Reata) will use to analyze data from the study.  
, 
is the blinded study statistical group responsible for conducting the analyses 
described in this document.  
will remain blinded to study treatment assignments until after 
the database is locked.  Study related documents include the study protocol and case report form.  
This version of the SAP describes the analyses planned prior to the database lock.  Unless 
otherwise specified, the analyses described in this document will be performed after database 
lock for inclusion in the final clinical study report (CSR).  Any substantive changes made to the 
statistical analysis plan after database lock will be clearly documented and a justification will be 
given in the CSR.   
This SAP is based on Version 4 of the study protocol dated October 17, 2014.  If the protocol is 
subsequently amended, this SAP may be amended as well.  Should the SAP and the protocol be 
inconsistent with respect to the planned analyses, the language of the SAP is governing.  All 
analyses will be conducted using SAS version 9.2 or higher. 
1.1 
Study Objectives 
1.1.1 Primary Objectives 
The primary objectives of this study are the following: 
• To determine the time-averaged (averaged effect over time) effect on radiation 
dermatitis grade measured with Common Terminology Criteria for Adverse Events 
(CTCAE, Version 4.03) following 3D conformal radiation therapy to the breast and 
concomitant administration of RTA 408 Lotion (0.5% and 3%) compared to 
administration of vehicle.  
• To evaluate the safety of RTA 408 Lotion 
1.1.2 Secondary Objective 
The secondary objectives of this study are the following: 
• To determine the mean maximum radiation dermatitis grade measured with CTCAE 
of RTA 408 Lotion (0.5% and 3%) on weekly visits compared to administration of 
vehicle  
• To determine the proportion of patients with treatment success, defined as post-
baseline maximum dermatitis grade < 2 using the CTCAE criteria following 
administration of RTA 408 Lotion compared to administration of vehicle  
• To determine the mean duration of grade ≥ 2 radiation dermatitis using the CTCAE 
criteria following administration of RTA 408 Lotion compared to administration of 
vehicle  
• To determine the extent of systemic exposure to RTA 408 following administration of 
RTA 408 Lotion following radiation therapy  
 
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Statistical Analysis Plan 
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• To evaluate patient-reported outcomes (Skindex-16) 
1.2 
Study Design 
This randomized, double-blind, vehicle-controlled, parallel-group study will assess the safety, 
tolerability and efficacy of RTA 408 Lotion (0.5% or 3%) versus vehicle in the treatment of 
patients at risk for radiation dermatitis. Eligible patients will be randomized using a 1:1:1 
assignment ratio to receive RTA 408 Lotion 0.5%, RTA 408 Lotion 3%, or vehicle 1 week (± 2 
days) prior to initiation of radiation therapy. Randomization will be stratified by smoking status 
(smoker or ex-smoker versus non-smoker) and breast cancer treatment prior to radiation therapy 
(mastectomy versus lumpectomy/partial mastectomy).  
Study drug application will start approximately 1 week prior to scheduled initiation of radiation 
therapy with twice daily applications continuing throughout the duration of radiation therapy 
(i.e., 5-6 weeks) and two weeks following completion of radiation therapy, for an expected total 
of up to 9 weeks of study drug application. In cases where radiation treatment is delayed (e.g., 
delayed start of radiation treatment or radiation treatment interruptions), the total study drug 
application period may be extended from the expected 8-9 weeks up to a maximum of 13 weeks. 
Study lotion is to be applied twice daily.  
On days of morning radiation treatments, the patient will apply the study drug at the radiation 
treatment center immediately after the radiation therapy concludes and at night before bed. On 
days of afternoon radiation treatments, the patient will apply the study drug in the morning at 
least 4 hours before radiation treatment and at night before bed. For each application of study 
drug treatment, a thin layer of lotion will be applied to the irradiated area. RTA 408 Lotion or 
vehicle lotion should never be applied immediately before radiation treatment, and any residual 
lotion from a prior application should be removed prior to radiation treatment.  
Following randomization, patients will be assessed in person at weekly visits during 
administration of study treatment. A follow-up visit will occur 4 weeks after last application of 
RTA 408 Lotion or vehicle. Due to the variation in radiation treatment schedules, exact study 
days or procedures may be shifted to fall within a window of 2 days based on radiation treatment 
schedules. However, all enrolled patients must continue to apply RTA 408 Lotion for two weeks 
after the completion of radiation. If a radiation therapy treatment break is extended beyond 5 
days, the medical monitor should be consulted to determine if application of study drug should 
continue. 
1.2.1 Study Visits and Assessments 
Detailed overall schedule of assessments for the study are included in Appendix 1.   
1.2.2 Discontinuation of Treatment 
Discontinuation refers to a patient stopping administration of study drug. Reasons for study drug 
discontinuation may include the following: 
• Occurrence of an adverse event or change in medical status that leads the investigator 
to be concerned about the patient’s welfare 
• Noncompliance with study procedure 
• Pregnancy during the study 
 
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2. PLANNED ANALYSIS 
2.1 
Final Analysis 
The randomization will be released and final analysis will be conducted after all patients have 
completed the study and the database has been locked. 
2.2 
Endpoint Measures 
2.2.1 Efficacy Endpoints 
The primary efficacy endpoint is dermatitis grade (CTCAE v4.03).   
The secondary efficacy endpoints are mean maximal dermatitis grade, proportion of patients 
with maximal dermatitis grade < 2, duration of CTCAE grade ≥ 2, proportion of patients who 
develop moderate erythema, the proportion of patients who develop dry desquamation and the 
proportion of patients who develop moist desquamation. 
2.2.2 Radiation Dermatitis Assessment 
The CTCAE v4.03 radiation dermatitis grade will be assessed by a local, trained physician, nurse 
or appropriately trained site staff member.  Radiation dermatitis scoring will be evaluated as 
follows (National Cancer Institute, 2010):  
CTCAE Radiation Dermatitis Grade 
Grade 0 
No radiation dermatitis 
Grade 1 
Faint erythema or dry desquamation 
Grade 2 
Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin folds and creases; 
moderate edema 
Grade 3 
Moist desquamation in areas other than skin folds and creases; bleeding induced by minor trauma or 
abrasion 
Grade 4 
Life-threatening consequences; skin necrosis or ulceration of full thickness dermis; spontaneous 
bleeding from involved site; skin graft indicated 
Grade 5 
Death 
Components of the CTCAE radiation dermatitis grade will be recorded separately by a local, 
trained physician, nurse or appropriately trained site staff member. These components include: 
the severity of erythema, the extent and severity of dry desquamation, the extent and severity of 
moist desquamation, the presence of edema.  
2.2.3 Safety Endpoints 
Safety endpoints include vital sign measurements, results of physical examinations, laboratory test 
results (clinical chemistry, hematology, urinalysis and microscopy), concomitant medications, 
adverse events, and serious adverse events. 
2.2.4 Pharmacokinetics Endpoints 
Pharmacokinetics endpoints include RTA 408 plasma concentration data for each analyte.  
 
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2.3 
Changes from Protocol-Specified Analysis 
There are no planned changes to analyses from what is described in the protocol. 
 
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Statistical Analysis Plan 
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3. GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
3.1 
Analysis Considerations 
All individual data will be listed as recorded in the database.  All statistical summaries and 
analyses will be performed using SAS® software (SAS Institute, Cary, North Carolina, USA).  
Only patients in the appropriate analysis set will be included in summary statistics.  For 
endpoints discussed in this SAP, all available data from scheduled visits for each patient will be 
included in summaries.  
Individual patient data will be presented in data listings.  The listings will include all available 
data for all patients. 
Continuous data will be summarized by treatment using descriptive statistics (number, mean, 
standard deviation [SD], minimum, median, and maximum).  Categorical data will be 
summarized by treatment using frequency tables (number and percentage). 
3.2 
Analysis Populations 
Additional analysis populations may be defined as needed. 
3.2.1 Intent-to-treat Population (ITT)  
The intent-to-treat (ITT) population includes all randomized patients whether or not they 
received study drug. Patients will be summarized according to the treatment to which they were 
randomized.   
3.2.2 Safety Population 
The safety population includes all patients who received at least 1 dose of study drug.  Patients 
will be summarized according to the treatment they actually received. 
3.3 
Strata and Covariates 
Randomization is stratified by smoking status (smoker or ex-smoker versus non-smoker) and 
breast cancer treatment prior to radiation therapy (full mastectomy versus partial mastectomy or 
lumpectomy).   
Smoking status and breast cancer treatment prior to radiation therapy will be used as covariates 
in the primary efficacy analysis.    
No other covariates will be considered for the primary analysis.  However, other covariates may 
be considered in a post hoc manner.   
3.4 
Examination of Patient Subsets 
Subsets of interest include: (1) smoking status (current or previous smoker vs never smoked), (2) 
breast cancer treatment prior to radiation therapy (breast conservation vs mastectomy), (3) chest 
wall separation (≤23 cm vs>23 cm), and (4) breast volume (>1200 cc vs ≤1200 cc) for breast 
conservation patients. Other subsets of interest may be defined as needed. 
 
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3.5 
Multiple Comparisons 
To maintain control of the family-wise error (FWE) rate at the alpha = 0.05 level with respect to 
the primary endpoint, a fixed sequential step down test procedure will be used.  The first step is 
to compare RTA 408 Lotion pooled versus vehicle lotion for the primary endpoint.  If significant 
at the 0.05 level, the second step of the test is to compare RTA 408 Lotion 3.0% versus vehicle 
lotion for the primary endpoint.  If significant at the 0.05 level, the third step of the test is to 
compare RTA 408 Lotion 0.5% versus vehicle lotion for the primary endpoint.  No other 
adjustments for multiplicity will be considered. 
3.6 
Missing Data  
Missing data will not be imputed for safety endpoints.  Missing efficacy endpoints will be 
imputed using the worst-observation reported for each patient.  Sensitivity analyses for efficacy 
endpoints will be performed with no imputation for missing data.  Additional sensitivity analyses 
may be considered as needed. 
3.7 
Visit Windows 
3.7.1 Definition of Study Day 
Study day is the day relative to the first dose of study drug administration.  Study day for events 
on or after the date of the first dose will be defined as the number of days from the date of the 
first dose of study drug, plus 1 day, so that the date of the first dose will be defined as Day 1. 
For events before the date of the first dose, study day will be calculated as the difference in days 
between the date of the first dose and the date of interest.  Thus, the day before the date of the 
first dose will be defined as Day -1. 
3.7.2 Definition of Study Baseline 
Unless otherwise noted, study baseline is defined as the last observation obtained prior to 
administration of the first dose on Study Day 1.  
Change from baseline is defined as post-baseline assessment minus baseline assessment.  The 
baseline value will not be used to impute the post-baseline values. 
3.7.3 Unscheduled Visits 
The CRF nominal study visits will be used for all safety analyses.  Unscheduled visits will be 
reflected in summarization of changes to worst post-baseline measures. 
Additionally, for missing scheduled assessments with an unscheduled assessment available after 
the previous scheduled visit but before the next scheduled visit, the closest unscheduled 
assessment will be used in the place of missing scheduled efficacy assessments 
All unscheduled visits will be listed. 
3.8 
Rounding 
The method of rounding for data presentation is provided in Appendix 3. 
 
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4. BASELINE CHARACTERISTICS AND PATIENT DISPOSITION 
4.1 
Disposition of Patients 
A disposition summary will include: 
• Number and percentage of patients randomized in each cohort 
• Number and percentage of patients in the safety analysis set 
• Number and percentage of patients completing treatment 
• Number and percentage of patients discontinuing treatment 
• Number and percentage of patients by reason for discontinuing treatment 
• Number and percentage of patients completing study 
• Number and percentage of patients terminating study 
• Number and percentage of patients by reason for terminating study 
Disposition summaries will be presented by randomized treatment.  Percentages will be based on 
the number of randomized patients. 
A listing of patient disposition will include the randomization date, date of the last dose of study 
drug, study completion status, and reason for termination (if applicable). 
4.2 
Demographics and Baseline Characteristics, Baseline Disease Characteristics, and 
Radiation Treatment Plan 
Demographic and baseline characteristics summaries, for patients in the safety analysis set, will 
include: 
• Age (years at study baseline) 
• Sex 
• Race 
• Ethnicity 
• Smoking status 
• Fitzpatrick skin Type 
Baseline disease characteristics will be provided in a separate summary.  Continuous statistics 
will be provided for: 
• Time since diagnosis (years) 
• Time since surgery (days) 
 
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• Breast volume after surgery (cc) 
• Chest wall separation (cm) 
Frequency tables (number and percentage) will be provided for discrete measures: 
• Breast cancer treatment prior to radiation therapy 
• Breast cancer stage 
• T/N/M clarification 
• Post-mastectomy reconstruction 
• Prior receipt of radiation treatment 
Radiation treatment plan will be provided in a separate summary.  Continuous statistics will be 
provided for: 
• Total planned radiation (Gy) 
• Total planned radiation boost (Gy) 
• Total radiation (regular + boost) (Gy) 
• Planned bolus use (days) 
• Radiation treatment surface area (cm2) 
• Radiation inhomogeneity (%) 
Frequency tables (number and percentage) will be provided for discrete measures: 
• Planned radiation treatment area 
All will be summarized by randomized treatment group without stratification and stratified by 
smoking status and breast cancer treatment prior to radiation therapy, respectively. 
4.3 
Study Drug Exposure 
Study treatment exposure (i.e. RTA 408 Lotion 0.5%, RTA 408 Lotion 3%, or vehicle lotion), 
including treatment duration will be summarized by treatment group with descriptive statistics. 
Similarly, the incremental and cumulative radiation exposure will be summarized by treatment 
group. The number of patients with interruptions in radiation treatment due to radiation 
tolerability will be tabulated overall and by study visit. Total study treatment exposure for each 
patient is calculated as follows:  (last date of study treatment) – (first date of study treatment) +1.  
Additionally, treatment compliance will be summarized, and the number of treatment compliant 
patients (i.e., ≥75% compliant with dosing) will be tabulated.  Compliance is calculated as [(total 
exposure days) – (total missed doses)] / (total exposure days).   
4.4 
Inclusion and Exclusion Criteria 
A listing will be provided for all randomized patients who did not meet all study entry criteria as 
defined by inclusion and exclusion criteria. 
 
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4.5 
Medical History 
Medical history will be coded using MedDRA, version 16.0 or higher.  Medical history will be 
summarized by SOC and PT, and will be presented by treatment.  Percentages will be based on 
the number of patients in the safety analysis set.  Medical history tables will be sorted 
alphabetically and all data will be listed chronologically. 
4.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
drug dictionary (December, 2012) for anatomical therapeutic chemical classification (ATC) and 
preferred drug name.  A patient who used multiple medications will be counted only once for 
each ATC and preferred drug name.  ATC and preferred drug name within each ATC will be 
sorted alphabetically. Coded prior and concomitant medications will be summarized by 
treatment.  Percentages will be based on the number of patients in the safety analysis set.   
Prior medications are defined as those medications disclosed as not being taken on Study Day 1 
on the CRF, with an onset date prior to the date of randomization.  Concomitant medications are 
defined as any medications that was either taken on or after Study Day 1, or was started before 
Study Day 1 but was ongoing at time of the first dose administration. 
4.7 
Protocol Deviations 
Protocol deviations as captured on the CRF will be listed.  All protocol deviations will be 
reviewed by the Sponsor according to their SOPs. Major protocol deviations will be identified by 
the Sponsor prior to database lock, and will be flagged in the listing. 
 
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5. EFFICACY ANALYSIS 
The primary population for efficacy analyses will include all randomized patients in this trial 
(intent-to-treat population, ITT population). The ITT analysis will be done by randomized 
treatment, and for each patient subset of interest defined in section 3.4. 
Summary statistics will be presented by randomized treatment group, and will include an 
additional column to summarize the pooled RTA 408 patients. 
5.1 
Primary Efficacy 
The primary efficacy outcome of this study is the radiation dermatitis grade measured with 
Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03) following 3D 
conformal radiation therapy to the breast and concomitant administration of RTA 408 Lotion 
(0.5% and 3%) compared to administration of vehicle. Radiation dermatitis scoring is assessed 
by a local, trained physician, nurse or appropriately trained site staff member based on CTCAE 
v4.03 on a scale of 0 to 5 (National Cancer Institute, 2010). Following randomization, patients 
will be evaluated in person at weekly visits during the administration of the study treatment up to 
a maximum of 13 weeks. 
Longitudinal mixed-models will be used to analyze the dermatitis scores over time, incorporating 
the repeated measures design of the study. Treatment group and week of visit will constitute the 
main fixed effects of the model; study subject will represent the random effect; site, smoking 
status, and breast cancer treatment will be evaluated for inclusion in the model as covariates. The 
distribution of residuals will be examined using a Shapiro-Wilks test.  Interactions of time and 
treatment effect will also be examined in the mixed-model.  
A sensitivity analysis will be performed using the same model, except cumulative radiation 
(expressed as a categorical variable in 2.5 Gy increments from 0 to 70 Gy) will be used as a fixed 
effect instead of visit week. Only those CTCAE grades collected from baseline to the last day of 
radiation treatment for each patient will be considered for this sensitivity analysis. 
The mean CTCAE dermatitis scores will also be plotted in a scatter plot by cumulative radiation 
exposure overall and by patient subsets of interest.  
RTA 408 treatment arms will be compared with vehicle utilizing a hierarchical testing strategy 
described in Section 3.6. 
5.2 
Secondary Efficacy 
The following secondary efficacy endpoints will be analyzed for all randomized patients (i.e., 
ITT population). Interpretations of significance levels (i.e. P-values) will be done with caution 
since there is no formal control of type I error for multiple comparisons on the secondary 
efficacy endpoints. 
5.2.1 Mean Maximum Radiation Dermatitis Grade of RTA 408 Lotion Compared to 
Administration of Vehicle 
The first secondary efficacy endpoint is the mean maximum dermatitis grade. A maximum 
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Descriptive statistics will be summarized for the maximum dermatitis grade overall and by each 
of the subgroups of interest, breaking down by the 3 treatment groups.  
An analysis of Covariance (ANCOVA) model will be conducted to compare the mean maximum 
dermatitis grade among the RTA408 0.5%, RTA408 3% and vehicle groups, adjusted for site, 
smoking status, breast cancer treatment prior to radiation therapy and total duration (in weeks) of 
study drug use. Pairwise RTA 408 lotion group comparisons with vehicle group will be 
estimated using the difference in adjusted means (and 95% confidence intervals, CI) from the 
ANCOVA model.   
5.2.2 Proportion Patients with Post-baseline Maximum Dermatitis Grade <2 Using the 
CTCAE Criteria 
Descriptive statistics (frequencies and percentages) by treatment groups will be provided overall 
and stratified by smoking status and breast cancer treatment prior to radiation therapy, 
respectively. In addition, logistic regression analysis will be performed to assess the dermatitis 
scores over time for the proportion of patients with success, where success is defined as CTCAE 
dermatitis score <2.  The logistic regression model will include covariates for site, smoking 
status (smoker or ex-smoker vs non-smoker) and breast volume with fixed effects for treatment 
group, visit, and the interaction between treatment group and visit. To visualize the grade 
patterns in RTA408 groups and the vehicle group, a bar chart will be plotted for the proportions 
of CTCAE dermatitis scores by treatment groups and study visit. 
5.2.3 Mean Duration of Grade ≥ 2 Radiation Dermatitis Using the CTCAE Criteria 
The total duration is defined as the spanning from first onset date with CTCAE grade ≥ 2 to last 
resolved date (i.e., next dermatitis assessment date after the last grade ≥ 2). Descriptive statistics 
by treatment groups will be summarized for the total duration, overall and by subgroups of 
interest for the subset of patients with at least one CTCAE grade ≥ 2. In addition to the 
descriptive analyses, the mean duration across 3 treatment groups will be compared using an 
ANCOVA model in a similar manner to the analysis in Session 5.2.1. 
5.2.4 Dermatitis Assessment 
Proportion of patients who develop moderate erythema, the proportion of patients who develop 
dry desquamation and the proportion of patients who develop moist desquamation (according to 
eCRF) will be analyzed in a similar manner to the analysis in Session 5.2.2. 
5.2.5 Patient-reported Outcomes (Skindex-16) 
The Skindex-16 quality-of-life tool will be used to assess patient responses to skin toxicity 
during and after radiation therapy. The Skindex-16 is a short 16-item patient-completed 
assessment using numerical analogue scales (0=never bothered to 6=always bothered). 
Responses to the Skindex-16 are categorized into three subscales: symptom, emotional and 
functional. Refer to Appendix C for the Skindex-16 assessment. The Skindex-16 assessment will 
be scored using the tool's scoring algorithm which averages all responses for the total Skindex-
16 score. Subscale scores will be calculated as follows: symptom subscale as the mean of 
questions 1–4, emotional subscale as the mean of questions 5–11 and functional subscale as the 
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Descriptive statistics (means and standard deviation, minimum, median, and maximum) will be 
summarized for the total score and each subscale score for the available patient-reported data, by 
treatment groups. Analysis of variance (ANOVA) will be used to compare the total and subscale 
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6. PHARMACOKINETIC ANALYSIS 
Descriptive statistics will be summarized for RTA 408 plasma concentration by treatment group 
overall and by patient subsets of interest. 
 
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7. SAFETY ANALYSIS 
Safety data (including AEs, laboratory data, vital signs, electrocardiogram [ECG] data, 
echocardiogram data, and physical examinations) will be listed and summarized for patients in 
the safety analysis set.  All safety data collected on or after the date of the first dose of study 
drug through completion of the study will be summarized by treatment. 
The CRF nominal study visits will be used for all safety analyses.  Unscheduled visits will be 
reflected in summarization of changes to worst post-baseline measures where appropriate. 
7.1 
Adverse Events 
New or worsening radiation dermatitis signs/symptoms should not be captured as individual 
AEs, but rather are captured in the Dermatitis Assessment documentation as these 
signs/symptoms are being assessed as study endpoints. 
AEs will be summarized by treatment as defined by the safety analysis set.   
7.1.1 General Considerations for Analysis of Adverse Events 
General considerations for AE summaries and calculations are: 
• Multiple events by preferred term (PT) and system organ class (SOC) will be counted once 
only per patient for each treatment. 
• For summaries by severity, only the most severe event will be counted per patient for each 
treatment. 
• For summaries by relationship, only the most related event will be counted per patient for 
each treatment. 
• An AE with a missing resolution date or incomplete date that is not identified as continuing 
will be assumed to be continuing and no duration will be calculated. 
• AEs will be summarized by the highest dose received. 
• Only treatment-emergent adverse events (TEAEs) will be included in summaries. 
7.1.2 Adverse Event Dictionary 
AEs will be coded using MedDRA (Medical Dictionary for Regulatory Activities) version 16.0 
or higher.  Tables and listings will present data at the SOC and PT level. 
7.1.3 Treatment-Emergent Adverse Events 
7.1.3.1 Definition of Treatment-Emergent 
Treatment-emergent adverse events are events that either: 
• Date of onset on or after the date of the date of first dose and not more than 30 days after the 
date of the last dose of study drug, or  
• Had no recorded date of onset with a stop date after the first dose of study drug, or 
• Had no recorded date of onset or stop date 
 
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7.1.3.2 Incomplete Dates 
If the date of onset is incomplete, then the month and year of onset (or year alone if month is not 
recorded) determines whether the event is treatment-emergent. The event is treatment-emergent 
if the month and year of onset (or year of onset) of the event is: 
− The same as or after the month and year (or year) of the first dose of study drug, and 
− The same as or before the month and year (or year) of the date of the last visit. 
7.1.4 Adverse Event Severity 
The investigator will grade the severity of the AEs as Grades 1, 2, 3, 4, or 5 based on the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
version 4.03. 
7.1.5 Relationship of Adverse Events to Study Drug 
Association or relatedness to the study medication will be graded by the investigator as either 
probably, possibly, unlikely, or unrelated according to criteria specified in the study protocol. 
7.1.6 Serious Adverse Events 
As defined in the protocol and captured on the CRF, an SAE is an adverse event that results in 
any of the following: 
• Death; 
• A life-threatening adverse drug experience; 
• Inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Results in a congenital anomaly or birth defect in an offspring of a patient taking study 
drug; 
• Is an important medical event. 
7.1.6.1 Summaries of Adverse Events 
Treatment-emergent AEs will be summarized by treatment at onset of the AEs.  For each 
treatment, SOC, and PT, the number and percentage of patients reporting an event will be 
calculated.  In summary tables, SOC will be presented alphabetically and events within SOC will 
be presented by decreasing frequency count based on the number of events in the total group. 
Summary tables (number and percentage of patients) of AEs (by SOC and PT) will be provided 
by treatment as follows: 
• All treatment-emergent AEs 
• All treatment-emergent related AEs (probably or possibly related) 
• All treatment-emergent AEs by severity 
• All treatment-emergent serious adverse events (including deaths) 
• All treatment-emergent adverse events leading to discontinuation of study drug 
Listings will be provided showing: 
• All AEs 
 
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• Serious adverse events (including deaths) 
• AEs leading to discontinuation of study drug  
7.1.6.2 Additional Analysis of Adverse Events 
No additional analysis of AEs is planned. 
7.2 
Clinical Laboratory Evaluations 
Laboratory data will be summarized at baseline and at each time point by treatment.  Only values 
obtained at scheduled assessment times will be included in by-visit summary statistics.  When 
appropriate, change from baseline to worst post-baseline (including unscheduled visits) value 
will be summarized.  Specific assessment times are given in Appendix 1 of this analysis plan. 
Continuous laboratory data results which are less than the lower limit of quantification or above 
the upper limit of quantification will be imputed to the value of the lower or upper limit plus or 
minus one significant digit, respectively (e.g., if the result of a continuous laboratory test is < 20, 
a value of 19 will be assigned). A baseline value is defined as the last available measurement 
obtained prior to administration of the first dose.  If multiple values for a given lab test exist for a 
particular day, the last one drawn will be used for summarization. 
7.2.1 General Considerations for Analyses of Laboratory Data 
Clinical laboratory results will be provided by a central lab. Clinical laboratory test results, 
including results from hematology, chemistry and urinalysis will be listed by patient. 
7.2.2 Summaries of Laboratory Results 
Selected laboratory evaluations and change from baseline will be summarized by treatment, 
laboratory category (hematology, chemistry), test, and study visit using continuous statistics.  
Laboratory tests to be summarized are provided in Appendix 2.  
Due to the nature of urinalysis parameters, summaries of continuous statistics will not be 
provided. 
7.2.3 Laboratory Abnormalities 
Laboratory results are not captured on the CRF.  All flags with respect to normal or abnormal 
results will be identified by the central lab. 
7.2.4 Treatment-Emergent Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values with any shift from a normal 
at baseline (Day 1) to abnormal at any time post-baseline up to and including the last dosing 
date.  Additionally, a shift from a low non-normal baseline value to a high non-normal post 
baseline value (and vice versa) will also be considered treatment emergent.  If the relevant 
baseline laboratory values are missing, then any abnormality will be considered treatment 
emergent.   
7.2.5 Summaries of Laboratory Abnormalities 
The number and percentage of patients with laboratory normality and abnormality categories 
(Normal, Low, High) as well as the treatment-emergent shift will be summarized by treatment, 
laboratory category (hematology, chemistry, and urinalysis), test, and study visit.  In addition to 
 
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by-visit frequencies, the most abnormal (low or high separately) as well as the shift to most 
abnormal (low or high) will be summarized. 
7.3 
Vital Signs 
Vital signs assessments include systolic blood pressure (SBP, mmHg) and diastolic blood 
pressure (DBP, mmHg), oral body temperature (°C), heart rate (HR, bpm), respiration rate (RR, 
breaths/min), height (m), weight (kg), and BMI (m2/kg).  
Vital signs will be summarized at baseline and at each time point along with the change from 
baseline by treatment.  Only values obtained at scheduled assessment times will be included in 
by-visit summary statistics.  Specific assessment times are given in Appendix 1 of this analysis 
plan.  All data will be listed. 
 
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8. REFERENCES  
Reisman SA, Lee C-YI, Meyer CJ, et al. Topical application of the synthetic triterpenoid RTA 408 
activates Nrf2 and induces cytoprotective genes in rat skin. Arch Dermatol Res 2013. Epub 2013 Dec 22. 
Ryan JL, Heckler CE, Ling M, Katz A, Williams JP, Pentland AP, Morrow GR. Curcumin for radiation 
dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. 
Radiation Research, 180(1):34-43. 2013. 
Miller RC, Schwartz DJ, Sloan JA, Griffin PC, et al. Mometasone furoate effect on acute skin toxicity in 
breast cancer patients receiving radiotherapy: a phase 3 double-blind, randomized trial from the north 
central cancer treatment group N06C4. Int J Radiat Oncol Biol Phys. 79(5): 1460-1466. 2011 April 1. 
Salvo N, Barnes E, van Draanen J, et al. Prophylaxis and management of acute radiation-induced skin 
reactions: a systematic review of the literature. Curr Oncol. 17: 3429-3434. 2010. 
Sullivan LM, D’Agostino RB. Robustness and power of analysis of covariance applied to ordinal scaled 
data as arising in randomized controlled trials. Statist. Med. 22: 1317-1334. 2003.  
 
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9. APPENDICES 
Appendix 1. 
Overall Schedule of Assessments  
Appendix 2. 
List of Laboratory Tests 
Appendix 3. 
Programming Specifications 
  
 
  
 
 
 
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a The Screening Period (Visit 1) may last up to 45 days prior to Randomization (up to 52 days prior to Day 1 of RT).   
b Visit 2 (7 days prior to radiation treatment) is the day of randomization and application of the first dose, and must occur at least 5 and no more than 9 days prior to the first day of radiation 
treatment.  If the start of radiation treatment is delayed, patients should continue administering study drug twice daily until the first dose of radiation up to a maximum of 14 days.  If the time from 
randomization to first dose of radiation exceeds 14 days, the medical monitor should be contacted to decide on an appropriate action. Patients may be randomized after meeting the inclusion / 
exclusion criteria and before study drug lotion is first administered as long as patients apply study drug lotion for at least 5 days prior to the first day of radiation treatment.  Patients with either 
morning or afternoon randomizations may apply lotion in the clinic and again before bedtime for two doses on that day. 
c Visit 3 should occur on the day of the first radiation treatment.  If radiation treatment is in the morning, the radiation treatment will be the third to last procedure (radiation treatment > study drug 
application > PK). If radiation treatment is in the afternoon, radiation treatment will be the second to last procedure, and the last procedure will be PK, as study drug will have been applied at least 4 
hours prior to radiation treatment. 
d Study visits during radiation treatment therapy must occur weekly beginning with Day 1 of radiation treatment.  
e At the end of radiation treatment, patients must complete Visit 9 assessments. Visit 9 must be the last day of the 10 – 16 Gy boost. Visit 8 is needed for patients who require radiation therapy for 6 
weeks.  If radiation therapy is extended longer than 6 weeks, then assessments at Visit 8 should be repeated weekly until the end of radiation visit (Visit 9). A weekly study visit should not be 
performed if the visit falls 1 or 2 days prior to the last day of radiation (Visit 9), or 1-2 days after the last day of radiation.   
f Visit 10 should occur approximately 1 week (7 calendar days) after the completion of radiation therapy (Visit 9).  
g Visit 11 should occur approximately 1 week (7 calendar days) after Visit 10 (i.e., 2 weeks after the completion of radiation therapy). 
h Follow-up visit will occur approximately 4 weeks after the final study drug application.  These procedures should be performed at the end of study and for early termination. 
i The ±2 day window is a two-day allowance within which the visit or visit procedures may occur around the scheduled visit date.  
j Medical history includes collection of surgery type (lumpectomy, partial mastectomy (breast conserving surgeries), or full mastectomy). If the patient is to undergo post-mastectomy reconstruction 
before radiation treatment, the type of reconstruction should be recorded as well.  
k Procedures that are to be performed as part of the practice of medicine and which would be done whether or not study entry was contemplated, such as for diagnosis or treatment of a disease or 
medical condition, may be performed and the results subsequently used for determining study eligibility without first obtaining consent if done within the screening timeframe, and if the site’s IRB 
is in agreement. 
l The radiation treatment area surface measurements can occur at any time before first day of radiation treatment. 
m Breast volume measurements are required for all patients who had breast conserving surgery (lumpectomy or partial mastectomy). Breast tissue should be defined per the RTOG contouring 
guidelines (RTOG 2009), but sites may use their local SOP for calculating breast volume.  
n  A serum pregnancy test will be performed at Screening for WOCBP or at any point in time if a pregnancy is suspected.  All other pregnancy assessments will be urine pregnancy tests, unless 
site/local authority mandates serum pregnancy testing. 
o  Study drug is to be dispensed to the patients at the scheduled study visits. Additional study drug will be dispensed to patients based on patient need, and will be recorded as an unscheduled study 
drug dispensation. Study drug (bottle + lotion) is to be weighed before study drug dispensing.  
p When radiation treatment overlaps with study drug administration and radiation treatment is in the morning, RTA 408 Lotion or vehicle should be applied to the breast area immediately after 
radiation treatment concludes.  If radiation treatment is in the afternoon, RTA 408 Lotion or vehicle should be applied at least 4 hours before radiation treatment. RTA 408 Lotion or vehicle should 
also be applied nightly.  
q Planned radiation treatment must be no more than 7.5 weeks. 
r Radiation dermatitis assessments must be performed PRIOR to initiation of that day’s radiation treatment, and only by a trained evaluator.  
 If radiation treatment is delayed or extended, dermatitis assessments should be performed weekly until the end of radiation treatment. 
s The Skindex-16 must be completed prior to initiation of that day’s radiation treatment. 
t Screening lab assessments for chemistry, hematology, urinalysis, and serum pregnancy tests should be drawn ≤ 14 days prior to randomization in order to have current values for inclusion/exclusion 
assessment. 
u A single PK collection will be obtained on Visit 3, Visit 6, Visit 9, Visit 11 and Visit 12.  If patients are to receive a morning radiation treatment on any of these visits, the PK sample should be 
drawn after RTA 408 Lotion or Vehicle Lotion application, which occurs after the completion of radiation treatment. If patients are to receive an afternoon radiation treatment on any of these visits, 
the PK sample should be drawn after the radiation treatment. 
v Optional photographs may be collected at Sponsor-qualified sites. On Day 1 of radiation treatment and the last day of radiation treatment, photographs must be collected prior to radiation treatment. 
 
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Appendix 3. 
Programming Specifications 
Continuous data will be listed corresponding to the precision measured or calculated. 
Measures of central tendency will be presented using one additional decimal place than the 
precision of the data.  Variability summaries will be presented using two additional 
significant digits relative to the precision of the underlying data. Quartiles, the minimum, and 
the maximum will be presented using the precision of the data. 
All percentages are to be expressed as integers with one decimal place. The convention for 
rounding percentages is as follows: 
• Values greater than or equal to x.x5% are rounded up 
• Values between 0 and x.x5% are rounded down 
• Values that are between 0 and .5% should be displayed as “<0.5%” 
 
 
 
 
CONFIDENTIAL 
Page 28  
30-Apr-15