A Phase 2 Study of the Safety, Efficacy, and Pharmacodynamics of RTA 408 in the Treatment of Friedreich's Ataxia (MOXIe)
Phase: PHASE2
Conditions: Friedreich Ataxia
Sponsor: Biogen

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RTA 408 
408-C-1402 
 
EUDRACT NUMBER 2015-002762-23 
A PHASE 2 STUDY OF THE SAFETY, EFFICACY, AND 
PHARMACODYNAMICS OF RTA 408 IN THE 
TREATMENT OF FRIEDREICH’S ATAXIA 
  
 
VERSION 11.0 – JUNE 21, 2021 
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-1402 
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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• 
To evaluate the change in pharmacodynamic (PD) markers of activity in platelet, 
 
samples 
• 
To characterize the pharmacokinetics (PK) of RTA 408 and potential metabolites after oral 
administration of RTA 408 Capsules 
 
Part 2: 
Primary: 
• 
To evaluate the change in the mFARS score at Week 48 
• 
To evaluate the safety and tolerability of RTA 408 
Secondary: 
• 
To evaluate the change in peak work during maximal exercise testing at Week 48 
• 
To evaluate the Patient Global Impression of Change at Week 48 
• 
To evaluate the Clinical Global Impression of Change at Week 48 
Exploratory: 
• 
To evaluate the distribution of change in mFARS scores at Week 48 
• 
To evaluate the change in SF-36 score 
• 
To evaluate the change in performance on a 9-HPT  
• 
To evaluate the change in performance on a 25-foot timed walk test  
• 
To evaluate the change in the Activities of Daily Living (ADL) score 
• 
To evaluate the frequency of falls 
• 
To characterize the PK of RTA 408 and potential metabolites after oral administration of 
RTA 408 Capsules 
Extension: 
• 
To provide continuing open-label treatment with RTA 408 while collecting ongoing safety 
and tolerability data with RTA 408 
Methodology:  
This study will evaluate the efficacy, safety, and PD of RTA 408 in the treatment of patients with 
Friedreich’s ataxia.   
Part 1: The first part of the study will be a randomized, placebo-controlled, double-blind, dose-
ranging study to evaluate the safety, efficacy, and PD activity of RTA 408 at 2.5 mg, 5 mg, 10 mg, 20 
mg, and higher dose levels (not to exceed 300 mg) in patients with Friedreich’s ataxia.  A cohort 
consists of the next eight eligible patients randomized 3:1 to RTA 408 at the cohort specific dose 
(n=6) or placebo (n=2).  Up to approximately 9 cohorts will be enrolled in Part 1 to allow for 
adequate dose-ranging for selection of a dose of RTA 408 to be used in Part 2. 
Intra-patient dose-escalation will only be utilized in the first cohort to evaluate RTA 408 at the first 
two dose levels (2.5 mg and 5 mg).  Patients enrolling in the first cohort will be randomized to 
RTA 408 2.5 mg or placebo.  After the Week 2 visit, each patient in the first cohort will dose-escalate 
to 5 mg (or remain on placebo) on Day 15 unless a dose-limiting toxicity (DLT) is reported in that 
patient (Section 7.4.3).  After the last patient in the first cohort completes their Week 4 visit (i.e., 
2 weeks on 2.5 mg daily [or matching placebo] followed by 2 weeks on 5 mg daily [or matching 
placebo]), the data safety monitoring board (DSMB) and Sponsor will review all available safety 
information and make a decision regarding enrollment of the next cohort.   
Beginning with the second 8-patient cohort, once the eighth patient enrolled completes their Week 2 
visit the DSMB will review all available safety information and recommend the dose of RTA 408 for 

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the subsequent cohort.  The DSMB dose recommendation for each cohort must not exceed 100% 
more than the highest dose of RTA 408 previously evaluated in this study, and the maximum 
permitted dose of RTA 408 is 300 mg.  The dose level for each new cohort will not exceed the DSMB 
recommended dose level, and it will be selected by the Sponsor based on review of available safety, 
efficacy, PK, and PD data.  Prior to opening each cohort in Part 1 for enrollment, the Sponsor will 
also evaluate all available data from doses studied in Part 1 to determine if enough information is 
available to select doses for Part 2 of the study.  Once enrollment begins in Part 2, no additional 
cohorts will be enrolled in Part 1. 
If the Sponsor or DSMB considers dose escalation not safe for any reason, no more dose escalation 
will be carried out.  The DSMB may recommend stopping dose escalation at any time, particularly if 
their review of adverse events (AEs) or laboratory data (e.g., aspartate aminotransferase [AST], 
alanine aminotransferase [ALT], bilirubin, alkaline phosphatase (ALP), magnesium, creatinine, 
B-type natriuretic peptide [BNP], etc.), reveals any potential safety concern.  The Sponsor, in addition 
to reviewing all available safety and efficacy data, will also take into consideration the predicted 
systemic exposure to RTA 408 at the next proposed dose in comparison with the exposure vs adverse 
effect profile for RTA 408 in animals.  If systemic exposure is sufficiently high to warrant a potential 
concern based on animal toxicity data, dose escalation may be stopped or paused, if needed, to seek 
additional input from the DSMB or the United States Food and Drug Administration (US FDA). 
 
Part 2: The second part of this study will be a randomized, placebo-controlled, double-blind, parallel-
group study to evaluate the safety and efficacy of RTA 408 150 mg in patients with Friedreich’s 
ataxia.  Patients enrolled in Part 2 will be randomized 1:1 to receive RTA 408 150 mg, or placebo.  
Randomization will be stratified by pes cavus status (pes cavus vs. no pes cavus).  Patients with 
pes cavus, a musculoskeletal foot deformity characterized by high arch of the foot that does not 
flatten with weight-bearing, will not comprise more than 20% of patients enrolled in Part 2.  The 
RTA 408 dose of 150 mg was selected for Part 2 based on DSMB and Sponsor review of available 
data from Part 1, including safety, efficacy, PK, and PD data.  Following randomization on Day 1, 
patients will self-administer study treatment once daily for 48 weeks.  A follow-up visit for safety will 
occur at Week 52 (4 weeks after the last dose).  The DSMB will perform quarterly reviews of 
unblinded data for safety throughout Part 2. 
 
Extension: The extension will assess long-term safety and tolerability of RTA 408 in qualified 
patients with Friedreich’s ataxia following completion of Part 1 or Part 2. Patients will not be 
unblinded to study treatment in Part 1 or Part 2 upon entering the extension study.  
Patients will receive open-label RTA 408 (150 mg) once daily until the drug is available through 
commercial channels, or until patient withdrawal, whichever is sooner.  All patients in the extension 
will follow the same visit and assessment schedule.  Extension Day 1 is defined as the first day 
treatment is dispensed to the patient for the extension, following completion of Part 1 or Part 2.  All 
other extension visits will be relative to extension Day 1.  Patients will be scheduled for in-person 
assessments during treatment in the extension at Day 1, Week 4, Week 24, and every 24 weeks 
thereafter.  Patients will also be assessed by telephone contact on Day 14.   
Since Part 2 patients will be followed continuously within the study, eligibility for the extension 
should be assessed at the Week 52 visit and a separate screening visit is not required.  After 
confirming eligibility for Part 2 patients, study treatment for extension Day 1 should be dispensed 
following the Week 52 assessments.  Part 1 patients will not have been followed continuously within 
this study, and therefore must complete a screening visit to confirm eligibility.  
The conduct of the extension phase, according to protocol specifications, was impacted by the 
Coronavirus Disease 2019 (COVID-19) pandemic.  As a result, and as of Version 10 of the protocol, 

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modifications intended to address access to and administration of investigational product, and 
adherence to protocol-specified visits and laboratory assessments was implemented. These 
modifications are described in Appendix 13 (COVID-19 Mitigations). 
Number of patients (planned):  
Up to approximately 172 patients will be enrolled in this study (up to 72 patients in Part 1 and 
approximately 100 patients in Part 2).   
The extension will only include qualified patients from Part 1 and Part 2.  
Inclusion criteria (Part 1 and Part 2):  
Patients must: 
1. Have genetically confirmed Friedreich’s ataxia  
2. Have an mFARS score ≥ 20 and ≤ 80. The average of the two mFARS values collected at 
Screening and Day 1 visits must fall within the allowable range, and they must be within 
4.5 points of each other 
3. Be male or female and ≥ 16 years of age and ≤ 40 years of age 
4. Have no changes to their exercise regimen within 30 days prior to Study Day 1 and be willing 
to remain on the same exercise regimen during the study period 
5. Have the ability to complete maximal exercise testing 
6. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥ 60 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 4-variable 
formula  
7. Have a left ventricular ejection fraction ≥ 40% (based on echocardiogram performed at 
Screening Visit or within 90 days prior to Screening Visit) 
8. Be able to swallow capsules 
9. Be willing and able to cooperate with all aspects of the protocol 
10. Be willing to practice medically acceptable methods of birth control (Section 9.7.2)  
11. Provide written informed consent for study participation, approved by the appropriate 
Institutional Review Board (IRB) 
 
Exclusion criteria (Part 1 and Part 2): 
Patients must not: 
1. Have uncontrolled diabetes (HbA1c > 11.0%) 
2. Have BNP level > 200 pg/mL 
3. Have a history of clinically significant left-sided heart disease and/or clinically significant 
cardiac disease, with the exception of mild to moderate cardiomyopathy associated with 
Friedreich’s ataxia, including but not limited to any of the following: 
a. Clinically significant congenital or acquired valvular disease  
b. Pericardial constriction (based on echocardiogram performed at Screening Visit or 
within 90 days prior to Screening Visit) 
c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at 
Screening Visit or within 90 days prior to Screening Visit) 
d. Symptomatic coronary disease (prior myocardial infarction, percutaneous coronary 
intervention, coronary artery bypass graft surgery, or angina) 
e. History of hospitalization for heart failure in the last five years 
f. Cardiac insufficiency, defined as New York Heart Association Class > 2 
g. History of atrial fibrillation 
h. History of unstable arrhythmias 

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4. Have known active fungal, bacterial, and/or viral infection, including human 
immunodeficiency virus (HIV) or hepatitis virus (B or C)  
5. Have known or suspected active drug or alcohol abuse, as per investigator judgment 
6. Have clinically significant abnormalities of clinical hematology or biochemistry, including 
but not limited to elevations greater than 1.5 times the upper limit of normal (ULN) of AST 
or ALT.  Levels above this threshold are allowable if attributable to muscle injury 
7. Have any abnormal laboratory test value or clinically significant pre-existing medical 
condition that, in the opinion of the investigator, would put the patient at risk by study 
enrollment 
8. Have taken any of the following drugs within 7 days prior to Study Day 1 or plan to take any 
of these drugs during the time of study participation: 
a. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, 
sildenafil) 
b. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
c. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
9. Have a history of clinically significant liver disease (e.g., fibrosis, cirrhosis, hepatitis), or has, 
at screening, clinically relevant deviations in laboratory tests including any one of the 
following: 
a. ALT and/or AST > 1.5-fold ULN 
b. bilirubin > 1.2-fold ULN 
c. ALP > 2-fold ULN 
d. albumin < lower limit of normal (LLN) 
10. Have participated in any other interventional clinical study within 30 days prior to Study 
Day 1 
11. Have a cognitive impairment that may preclude ability to comply with study procedures 
12. Be unable to comply with the requirements of the study protocol or be unsuitable for the 
study for any reason, in the opinion of the investigator 
13. Have used antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and vitamin E above the recommended daily allowance, within 14 days prior to 
Study Day 1, or plan to take any of these supplements during the time of study participation 
14. Have previously documented mitochondrial respiratory chain disease 
15. Have a history of thromboembolic events within the past 5 years 
16. Have taken anticoagulant therapy within 30 days prior to Study Day 1 
17. Have scheduled surgical treatment for scoliosis or foot deformity during the study 
18. Have had significant suicidal ideation within 1 month prior to Screening Visit as per 
investigator judgment or any history of suicide attempts 
19. Be pregnant or breastfeeding 
20. Prior participation in a trial with RTA 408 
 
Extension eligibility:  
Patients must complete 12 weeks of treatment in Part 1 or 48 weeks of treatment in Part 2, have no 
major protocol deviations, and continue to meet inclusion and exclusion criteria as specified in 
Appendix 1.  
Investigational product, dosage and mode of administration:  
RTA 408 Capsules (2.5 mg, 10 mg, or 50 mg) will be administered orally. 

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3. 
TABLE OF CONTENTS AND LISTS OF TABLES AND FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
SPONSOR APPROVAL AND SIGNATURE PAGE .....................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS AND LISTS OF TABLES AND FIGURES .....................12 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................19 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................24 
5.1. 
Background and Rationale for RTA 408 in Friedreich’s Ataxia ................................24 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................28 
6.1. 
Part 1 Objectives .........................................................................................................28 
6.1.1. 
Primary Objectives .....................................................................................................28 
6.1.2. 
Secondary Objective ...................................................................................................28 
6.1.3. 
Exploratory Objectives ...............................................................................................28 
6.2. 
Part 2 Objectives .........................................................................................................28 
6.2.1. 
Primary Objectives .....................................................................................................28 
6.2.2. 
Secondary Objective ...................................................................................................29 
6.2.3. 
Exploratory Objectives ...............................................................................................29 
6.3. 
Extension ....................................................................................................................29 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.2. 
Number of Patients .....................................................................................................32 
7.3. 
Treatment Assignment ................................................................................................32 
7.4. 
Dose Selection and Escalation Scheme ......................................................................32 
7.4.1. 
Selection of Doses ......................................................................................................32 
7.4.2. 
Dose-Escalation Scheme ............................................................................................33 
7.4.3. 
Criteria for Determining Dose-Limiting Toxicity ......................................................33 
7.4.4. 
Intra-patient Dose Escalation ......................................................................................34 
7.4.5. 
Additional Considerations for Dose Escalation Decisions in Part 1 ..........................34 

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7.5. 
Data Safety Monitoring Board ....................................................................................34 
7.6. 
Criteria for Study Termination ...................................................................................35 
7.7. 
Schedule of Assessments ............................................................................................35 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................43 
8.1. 
Patient Inclusion Criteria (Part 1 and Part 2) ..............................................................43 
8.2. 
Patient Exclusion Criteria (Part 1 and Part 2) .............................................................43 
8.3. 
Extension Eligibility ...................................................................................................45 
8.4. 
Patient Rescreening ....................................................................................................45 
8.5. 
Patient Discontinuation and Termination ...................................................................46 
8.5.1. 
Patient Discontinuation Criteria .................................................................................46 
8.5.2. 
Patient Termination Criteria .......................................................................................47 
9. 
TREATMENT OF PATIENTS ..................................................................................48 
9.1. 
Description of Study Drug ..........................................................................................48 
9.1.1. 
Management of Elevated Transaminase Levels (ALT and/or AST) ..........................48 
9.2. 
Prior and Concomitant Medications ...........................................................................49 
9.2.1. 
Excluded Medications ................................................................................................49 
9.2.2. 
Permitted Medications ................................................................................................50 
9.3. 
Compliance with Study Drug .....................................................................................50 
9.4. 
Randomization ............................................................................................................51 
9.5. 
Blinding ......................................................................................................................51 
9.5.1. 
Patient Unblinding ......................................................................................................51 
9.5.2. 
Unblinding for Regulatory Submission ......................................................................52 
9.6. 
Unscheduled Visits .....................................................................................................52 
9.7. 
Pregnancy ...................................................................................................................52 
9.7.1. 
Women of Childbearing Potential ..............................................................................52 
9.7.2. 
Methods of Birth Control............................................................................................52 
9.7.3. 
Suspected Pregnancy ..................................................................................................53 
9.8. 
Treatment Interruption ................................................................................................53 
9.9. 
Study Procedures ........................................................................................................54 
9.9.1. 
Informed Consent .......................................................................................................54 
9.9.2. 
Inclusion/Exclusion Criteria .......................................................................................54 
9.9.3. 
Demographics and Baseline Disease Characteristics .................................................54 
9.9.4. 
Pes Cavus Assessment ................................................................................................54 

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9.9.5. 
Foot X-Ray .................................................................................................................54 
9.9.6. 
Prior and Concomitant Medications ...........................................................................55 
9.9.7. 
Medical History ..........................................................................................................55 
9.9.8. 
Height .........................................................................................................................55 
9.9.9. 
Echocardiogram ..........................................................................................................55 
9.9.10. 
Electrocardiogram .......................................................................................................55 
9.9.11. 
Vital Sign Measurements ............................................................................................55 
9.9.12. 
Weight and Body Mass Index .....................................................................................56 
9.9.13. 
Physical Examination .................................................................................................56 
9.9.14. 
Adverse Event Collection ...........................................................................................56 
9.9.15. 
Clinical Chemistry ......................................................................................................56 
9.9.16. 
Hematology .................................................................................................................57 
9.9.17. 
Urinalysis and Microscopy .........................................................................................58 
9.9.18. 
N-Terminal Prohormone of B-Type Natriuretic Peptide and B-Type 
Natriuretic Peptide ......................................................................................................58 
9.9.19. 
Hepatitis B and C and Human Immunodeficiency Virus ...........................................59 
9.9.20. 
Pregnancy Test ............................................................................................................59 
9.9.21. 
Exercise Regimen Reporting ......................................................................................59 
9.9.22. 
Study Drug Dispensation ............................................................................................59 
9.9.23. 
Study Drug Return and Pill Count ..............................................................................59 
9.9.24. 
Study Drug Administration.........................................................................................59 
9.9.25. 
Telephone Contact ......................................................................................................60 
9.9.26. 
Maximal Exercise Test ...............................................................................................60 
9.9.27. 
Friedreich’s Ataxia Rating Scale ................................................................................60 
9.9.28. 
9-Hole Peg Test ..........................................................................................................61 
9.9.29. 
25-Foot Timed Walk Test ...........................................................................................61 
9.9.30. 
Video Collection of Patients Walking 25-ft with Their Natural Gait .........................61 
9.9.31. 
SF-36 Health Survey Update ......................................................................................61 
9.9.32. 
Activities of Daily Living ...........................................................................................62 
9.9.33. 
Patient Global Impression of Change .........................................................................62 
9.9.34. 
Clinical Global Impression of Change .......................................................................62 
9.9.35. 
Falls Diary ..................................................................................................................62 
9.9.36. 
Pharmacokinetic Analysis (Part 1 and Part 2) ............................................................63 

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9.9.37. 
Home Health Visits .....................................................................................................63 
9.9.38. 
Low-Contrast Letter Visual Acuity Test (Part 1 Only) ..............................................63 
9.9.39. 
Fatigue Severity Scale (Part 1 Only) ..........................................................................63 
 
 
 
 
 
 
9.9.43. 
Platelet Collection (Part 1 Only) .................................................................................64 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................65 
10.1. 
Study Drug ..................................................................................................................65 
10.2. 
Study Drug Packaging and Labeling ..........................................................................65 
10.3. 
Study Drug Storage .....................................................................................................66 
10.4. 
Study Drug Administration.........................................................................................66 
10.5. 
Study Drug Accountability .........................................................................................66 
10.6. 
Study Drug Handling and Disposal ............................................................................66 
11. 
EFFICACY ASSESSMENTS ....................................................................................67 
11.1. 
Part 1 ...........................................................................................................................67 
11.1.1. 
Maximal Exercise Test ...............................................................................................67 
11.1.2. 
Friedreich’s Ataxia Rating Scale ................................................................................67 
11.1.3. 
25-Foot Timed Walk Test ...........................................................................................67 
11.1.4. 
Low-Contrast Letter Visual Acuity Test ....................................................................67 
11.1.5. 
9-Hole Peg Test ..........................................................................................................67 
11.1.6. 
Fatigue Severity Scale ................................................................................................67 
11.1.7. 
SF-36 Health Survey Update ......................................................................................67 
 
 
11.2. 
Part 2 ...........................................................................................................................67 
11.2.1. 
Friedreich’s Ataxia Rating Scale ................................................................................67 
11.2.2. 
Patient Global Impression of Change .........................................................................68 
11.2.3. 
Clinical Global Impression of Change .......................................................................68 
11.2.4. 
Maximal Exercise Test ...............................................................................................68 
11.2.5. 
9-Hole Peg Test ..........................................................................................................68 
11.2.6. 
25-Foot Timed Walk Test ...........................................................................................68 
11.2.7. 
SF-36 Health Survey Update ......................................................................................68 
11.2.8. 
Activities of Daily Living ...........................................................................................68 

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11.2.9. 
Frequency of Falls ......................................................................................................68 
11.2.10. 
Distribution of Change in mFARS Scores..................................................................68 
12. 
SAFETY ASSESSMENTS ........................................................................................69 
12.1. 
Safety Parameters .......................................................................................................69 
12.2. 
Adverse and Serious Adverse Events .........................................................................69 
12.2.1. 
Definition of Adverse Events .....................................................................................69 
12.2.1.1. 
Adverse Event .............................................................................................................69 
12.2.1.2. 
Serious Adverse Event ................................................................................................69 
12.3. 
Eliciting Adverse Event Information ..........................................................................70 
12.4. 
Assessment of Causality .............................................................................................70 
12.5. 
Assessment of Severity ...............................................................................................71 
12.6. 
Recording Adverse Events .........................................................................................71 
12.7. 
Reporting Serious Adverse Events .............................................................................72 
13. 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............74 
13.1. 
Pharmacokinetic Samples ...........................................................................................74 
13.2. 
Pharmacodynamic Samples (Part 1 Only) ..................................................................74 
 
 
13.2.2. 
Platelet Analysis .........................................................................................................74 
 
 
14. 
STATISTICS ..............................................................................................................75 
14.1. 
Sample Size ................................................................................................................75 
14.2. 
Study Variables ...........................................................................................................75 
14.2.1. 
Pharmacokinetic Variables .........................................................................................75 
14.2.2. 
Pharmacodynamic Variables (Part 1 Only) ................................................................75 
14.2.3. 
Efficacy Variables ......................................................................................................75 
14.2.4. 
Safety Variables ..........................................................................................................76 
14.3. 
Statistical Analyses .....................................................................................................76 
14.3.1. 
Analysis Sets ...............................................................................................................76 
14.3.2. 
Primary Efficacy Analysis ..........................................................................................76 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................78 
15.1. 
Study Monitoring ........................................................................................................78 
15.2. 
Audits and Inspections ................................................................................................78 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................79 

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APPENDIX 13. COVID-19 MITIGATIONS ...........................................................................119 
1. 
SITE OPERATIONS & PATIENT MANAGEMENT ............................................119 
2. 
COVID-19 TESTING AND INVESTIGATIONAL PRODUCT USE....................119 
2.1. 
Resumption of Investigational Product after Recovery from COVID-19 
Infection ....................................................................................................................119 
3. 
INVESTIGATIONAL PRODUCT (IP) ACCESS ...................................................119 
4. 
STUDY VISIT ..........................................................................................................120 
4.1. 
United Kingdom Site ................................................................................................120 
ATTACHMENT 1 .......................................................................................................................122 
 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
List of Abbreviations ..................................................................................................20 
Table 3: 
Part 1 Schedule of Assessments .................................................................................36 
Table 4.  
Part 2 Schedule of Assessments .................................................................................38 
Table 5: 
Extension Schedule of Assessments ...........................................................................41 
Table 6: 
Clinical Chemistry Assessments.................................................................................57 
Table 7: 
Hematology Assessments ...........................................................................................58 
Table 8: 
Urinalysis/Microscopy Assessments ..........................................................................58 
Table 9: 
Study Drug Information ..............................................................................................65 
Table 10: Serious Adverse Event Reporting Contact Information .............................................72 
 
 
LIST OF FIGURES 
Figure 1: 
Schema for Part 1 and Part 2 Evaluation of RTA 408 in Patients with 
Friedreich’s Ataxia .....................................................................................................31 
Figure 2: 
Schema for Open-Label Extension .............................................................................32 
 
 

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5. 
INTRODUCTION 
5.1. 
Background and Rationale for RTA 408 in Friedreich’s Ataxia 
Friedreich’s ataxia is an autosomal recessive cerebellar ataxia caused by triplet-repeat 
expansions.  The causative mutation is a trinucleotide (GAA) repeat expansion in the first intron 
of the frataxin gene, leading to impaired transcription of frataxin.  Frataxin is involved in iron 
homeostasis and may protect mitochondria from oxidative damage.  Consequently, frataxin 
mutations result in a phenotype of mitochondrial iron overload and oxidative stress.  The 
pathological consequences of frataxin deficiency include a severe disruption of iron–sulfur 
cluster biosynthesis, mitochondrial iron overload coupled to cellular iron dysregulation, and an 
increased sensitivity to oxidative stress (Dürr, 2002).  The majority of patients have disease onset 
before 15 years of age, with a mean duration until wheelchair use of 11 to 14 years after disease 
onset and a median survival of 34 to 37 years after disease onset (Klockgether, 1998).   
No effective therapies are available for the treatment of Friedreich's ataxia.  Clinical trials with 
weak exogenous antioxidants, such as coenzyme Q10 derivatives, and various antioxidant 
cocktails containing supplements, such as vitamin E (or derivatives), have not resulted in 
physiological improvements nor have they affected disease progression (Marmolino, 2011).  
Notably, prior clinical studies with exogenous antioxidants were unable to reduce the excess 
reactive oxygen species (ROS) produced by the dysfunctional iron homeostasis and resulting 
mitochondrial damage (Di Prospero, 2007).   
A hallmark of Friedreich’s ataxia is impairment of antioxidative defense mechanisms, which 
play a major role in disease progression.  Studies have demonstrated that nuclear factor 
erythroid-derived 2-related factor 2 (Nrf2) is impaired in cells isolated from patients with 
Friedreich’s ataxia.  Similar findings have been observed in preclinical studies (in vitro and 
in vivo).  When fibroblasts isolated from patients with Friedreich’s ataxia are challenged with 
agents that induce oxidative stress (e.g., tertiary butylhydroquinone or oligomycin), Nrf2 fails to 
activate, which, in turn, prevents induction of antioxidant Nrf2 target genes (Paupe, 2009).  
Further, silencing of frataxin gene expression in mouse motor neuron cells also decreases 
expression of Nrf2 and its target genes.  When frataxin was knocked down approximately 40% 
by short hairpin RNA in mouse NSC34 motor neurons, Nrf2 mRNA expression was also 
decreased approximately 35%, along with the protein expression of the Nrf2 target genes 
superoxide dismutase and glutathione S-transferase π (D’Oria, 2013).  Collectively, the data 
demonstrate that Nrf2 signaling is grossly impaired in patients with Friedreich’s ataxia and in 
preclinical in vitro and in vivo models of frataxin deficiency.  Therefore, the ability of RTA 408 
to activate Nrf2 and induce its target genes is hypothesized to be therapeutic in patients with 
Friedreich’s ataxia.  
Several lines of evidence suggest that Nrf2 activation can increase mitochondrial respiration and 
biogenesis.  First, activation of peroxisome proliferator-activated receptor gamma coactivator 
1-alpha (PGC-1α) in a mouse model of mitochondrial myopathy showed increased mitochondrial 
mass and improved adenosine triphosphate (ATP) production.  In addition, Uruno et al. (2013) 
demonstrated that genetic activation of Nrf2 signaling by Kelch-like ECH-associated protein 1 
(Keap1) gene hypomorphic knockdown in mice (Keap1MuKO) markedly increased energy 
consumption–related genes in skeletal muscle.  Genetic Nrf2 activation led to increased 
locomotor activity, as compared with control (Keap1F/F) mice.  Locomotor activity was 

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increased as determined in an open-field test and quantitated in terms of total distance traveled, 
as well as the number of zones crossed during the testing period (0 to 20 min).  These results 
suggest that activation of Nrf2 in skeletal muscle results in locomotor improvement due to 
increased efficiency of oxidative phosphorylation. 
Moreover, 2 recent studies demonstrated that genetic Nrf2 activation in Keap1-knockout mice 
increased mitochondrial respiration, oxygen consumption, and ATP production compared with 
Nrf2-deficient mice (Holmström, 2013; Ludtmann, 2014).  In essence, Nrf2 activation increased 
substrate availability for mitochondrial respiration, which led to improvements in ATP 
production. 
Natural triterpenoids, such as oleanolic acid and ursolic acid that are derived from plant extracts, 
have been used extensively in Asian medicine for their antioxidant, anti-inflammatory, and 
anticancer properties (Liu, 1995).  RTA 408 is one of a class of semi-synthetic triterpenoids 
discovered through a medicinal chemistry effort to optimize the ability of these compounds to 
inhibit the induction of nitric oxide (NO) in primary mouse macrophages treated with 
interferon-gamma (IFNγ Honda, 1999).  Subsequent mechanistic studies have revealed that 
RTA 408 and the semi-synthetic triterpenoids are potent activators of Nrf2 and inhibitors of 
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and thus induce an 
antioxidant and anti-inflammatory phenotype.   
Several preclinical studies have highlighted the beneficial effects of RTA 408 analogs on muscle 
function, oxidative phosphorylation, and mitochondrial biogenesis.  Shin et al. (2009) 
demonstrated that potent Nrf2 activation with a 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid 
(CDDO)-imidazolide (CDDO-Im) triterpenoid prevented high-fat diet-induced increases in body 
weight, adipose mass, and hepatic lipid accumulation in wild-type mice.  Wild-type mice on a 
high-fat diet and treated with CDDO-Im exhibited higher oxygen consumption and energy 
expenditure than vehicle-treated mice, while food intake was lower in CDDO-Im-treated than 
vehicle-treated mice.  These results highlight the ability of potent Nrf2 activation to increase 
mitochondrial respiration.   
Saha et al. (2010) demonstrated that in high-fat diet-fed type 2 diabetic mice, oral treatment with 
the RTA 408 analog, bardoxolone methyl (also referred to as CDDO-methyl ester [CDDO-Me]), 
for 2 weeks improved glucose uptake, fatty acid oxidation, and oxygen consumption.  
Specifically, treatment with bardoxolone methyl led to a 48% increase in the mean glucose 
disposal rate, reflecting increased peripheral insulin responsiveness induced by bardoxolone 
methyl.  The bardoxolone methyl treatment also increased insulin-stimulated glucose transport 
activity in skeletal muscles by 71% in the soleus and by 58% in the gastrocnemius.  These results 
demonstrate that the glucose-lowering activity of bardoxolone methyl results from enhanced 
insulin action and glucose delivery to the muscles, which was associated with an increased rate 
of oxidative phosphorylation within the skeletal muscle.  
Furthermore, Neymotin et al. (2011) examined 2 additional RTA 408 analogs, 
CDDO-ethylamide (CDDO-EA) and CDDO-trifluoroethylamide (CDDO-TFEA), that potently 
activate Nrf2 in the G93A superoxide dismutase 1 (SOD1) mouse model of amyotrophic lateral 
sclerosis (ALS).  CDDO-EA and CDDO-TFEA significantly induced the mRNA expression of 
the Nrf2 target genes NAD(P)H dehydrogenase, quinone 1 (NQO1), glutathione 
S-transferase A3 (GSTA3), and heme oxygenase-1 (HO-1) relative to controls while suppressing 
pro-inflammatory NF-κB target genes.  Moreover, genes associated with increased mitochondrial 

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biogenesis were also induced.  Collectively, the data suggest that the ability of RTA 408 to 
activate Nrf2 and induce its target genes could potentially improve muscle function, oxidative 
phosphorylation, antioxidant capacity, and mitochondrial biogenesis in patients with Friedreich’s 
ataxia.  
Regarding the safety profile of RTA 408, no adverse effects were observed in the safety 
pharmacology studies.  The genotoxicity potential of RTA 408 was investigated in 2 in vitro 
genetic toxicity tests and 2 in vivo genotoxicity studies in rats.  The overall weight of evidence 
from the genotoxicity studies indicates that RTA 408 has a low genotoxicity risk to human 
patients.  
The systemic toxicity potential of RTA 408 has been evaluated in multiple nonclinical Good 
Laboratory Practice (GLP) toxicity studies in rats, minipigs, and monkeys after oral and dermal 
(which produces meaningful systemic exposure to RTA 408 in animals) administration.  The 
primary target organs for RTA 408 observed in the rat and monkey include the liver (increased 
liver weight, hepatocellular hypertrophy, bile duct hypertrophy and hyperplasia) and kidney 
(tubular degeneration/regeneration).  These effects are considered to be mostly due to the known 
pharmacologic activity of RTA 408 in animals and likely do not reflect off-target toxicity.  In 
rats (but not monkeys or minipigs), minimal to mild squamous cell hyperplasia of the 
forestomach and/or the limiting ridge of the stomach was observed and was fully reversible on 
treatment discontinuation.  The forestomach and limiting ridge of the stomach do not exist in 
humans, a monogastric species.  Therefore, this finding does not translate to humans and is not 
considered a relevant risk to humans. 
Overall, rats are more sensitive to the toxicologic effects of RTA 408 than minipigs or monkeys.  
In rats, the no-observed-adverse-effect level (NOAEL) following 28 days or 13 weeks or daily 
oral administration was 3 mg/kg/day, corresponding to an area under the plasma drug 
concentration-time curve (AUC(0-24hr)) of approximately 2.0 hr*µg/mL.  Following 6 months of 
oral administration to rats, adverse effects were observed at the lowest dose tested (0.3 mg/kg), 
which was associated with an AUC(0-24hr) of approximately 0.3 hr*µg/mL.  Similar systemic 
exposure was achieved in rats at the lowest dose tested in a 13-week topical dermal toxicity 
study of RTA 408 Lotion, with similar adverse effects observed in males, but not females, in the 
low-dose group.  In monkeys, the NOAEL following 28 days or 13 weeks of daily oral 
administration was at least 100 mg/kg/day and the NOAEL following 9 months of daily oral 
administration was 30 mg/kg/day, corresponding to an AUC(0-24hr) of approximately 
2.0 hr*µg/mL.  In a 13-week minipig dermal GLP toxicity study, the NOAEL was the maximal 
feasible dose of 8% RTA 408 Lotion (twice daily topical administration) with systemic 
exposures up to 1.7 hr*μg/mL.   
Across studies, the adverse liver findings in rats were reversible upon drug discontinuation and 
were associated with moderate to marked increases in serum gamma-glutamyl transpeptidase 
(GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin 
(TBL).  With short treatment duration (i.e., 14 days), tubular degeneration/regeneration in rats 
was reversible with a 28-day treatment-free period in a non-GLP study.  Although the kidney 
findings in rats after 28 days or longer of treatment were not reversible after a 4-week or 8-week 
recovery period, they were minimal to mild, were not associated with evidence of an effect on 
renal function (i.e., no increase in blood urea nitrogen [BUN] or serum creatinine), and were not 
present in minipigs or monkeys with dosing for up to 13 weeks (minipig dermal) or 9 months 

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(monkey oral) at doses that produced systemic exposures approximately 10-fold above the 
exposures that elicited adverse kidney findings in rats. 

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• To evaluate the safety and tolerability of RTA 408  
6.2.2. 
Secondary Objective 
• To evaluate the change in peak work during maximal exercise testing at Week 48 
• To evaluate the Patient Global Impression of Change at Week 48 
• To evaluate the Clinical Global Impression of Change at Week 48 
6.2.3. 
Exploratory Objectives 
• To evaluate the distribution of change in mFARS scores at Week 48 
• To evaluate the change in SF-36 score 
• To evaluate the change in performance on a 9-HPT  
• To evaluate the change in performance on a 25-foot timed walk test  
• To evaluate the change in the Activities of Daily Living (ADL) score 
• To evaluate the frequency of falls 
• To characterize the PK of RTA 408 and potential metabolites after oral administration 
of RTA 408 Capsules 
6.3. 
Extension 
The objective of the extension is to provide continuing treatment with RTA 408 as part of this 
extended access program while collecting ongoing safety and tolerability data with RTA 408. 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study will evaluate the efficacy, safety, and PD of RTA 408 in the treatment of patients with 
Friedreich’s ataxia.  A schema summarizing the study parts and cohorts is shown in Figure 1 and 
Figure 2. 
Part 1: The first part of the study will be a randomized, placebo-controlled, double-blind, 
dose-ranging study to evaluate the safety, efficacy, and PD activity of RTA 408 at 2.5 mg, 5 mg, 
10 mg, 20 mg, and higher dose levels (not to exceed 300 mg) in patients with Friedreich’s ataxia.  
A cohort consists of the next eight eligible patients randomized 3:1 to RTA 408 at the cohort 
specific dose (n=6) or placebo (n=2).  Up to approximately 9 cohorts will be enrolled in Part 1 of 
the study to allow for adequate dose-ranging for selection of a dose of RTA 408 to be used in 
Part 2. 
Intra-patient dose-escalation will only be utilized in the first cohort to evaluate RTA 408 at the 
first two dose levels (2.5 mg and 5 mg).  Patients enrolling in the first cohort will be randomized 
to RTA 408 2.5 mg or placebo.  After the Week 2 visit, each patient in the first cohort will dose-
escalate to 5 mg (or remain on placebo) on Day 15 unless a dose-limiting toxicity (DLT) is 
reported in that patient (Section 7.4.3).  After the last patient in the first cohort completes their 
Week 4 visit (i.e., 2 weeks on 2.5 mg daily [or matching placebo] followed by 2 weeks on 5 mg 
daily [or matching placebo]), the data safety monitoring board (DSMB) and Sponsor will review 
all available safety information and make a decision regarding enrollment of the next cohort.   
Beginning with the second 8-patient cohort, once the eighth patient enrolled completes their 
Week 2 visit, the DSMB will review all available safety information and recommend the dose of 
RTA 408 for the subsequent cohort.  The DSMB dose recommendation for each cohort must not 
exceed 100% more than the highest dose of RTA 408 previously evaluated in this study, and the 
maximum permitted dose of RTA 408 is 300 mg.  The dose level for each new cohort will not 
exceed the DSMB recommended dose level, and it will be selected by the Sponsor based on 
review of available safety, efficacy, PK, and PD data.  Prior to opening each cohort in Part 1 for 
enrollment, the Sponsor will evaluate all available data from doses studied in Part 1 to determine 
if enough information is available to select doses for Part 2 of the study.  Once enrollment begins 
in Part 2, no additional cohorts will be enrolled in Part 1.       
Part 2: The second part of this study will be a randomized, placebo-controlled, double-blind, 
parallel-group study to evaluate the safety and efficacy of RTA 408 150 mg in patients with 
Friedreich’s ataxia.  Patients enrolled in Part 2 will be randomized 1:1 to receive RTA 408 
150 mg, or placebo.  Randomization will be stratified by pes cavus status (pes cavus vs. no 
pes cavus).  Patients with pes cavus, a musculoskeletal foot deformity characterized by high arch 
of the foot that does not flatten with weight-bearing, will comprise no more than 20% of patients 
enrolled in Part 2.  The RTA 408 dose of 150 mg was selected for Part 2 based on DSMB and 
Sponsor review of available data from Part 1, including safety, efficacy, PK, and PD data. 
Following randomization on Day 1, patients will self-administer study treatment once daily for 
48 weeks.  A follow-up visit for safety will occur at Week 52 (4 weeks after last dose).  The 
DSMB will perform quarterly reviews of unblinded data for safety throughout Part 2. 

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Figure 1: 
Schema for Part 1 and Part 2 Evaluation of RTA 408 in Patients with 
Friedreich’s Ataxia 
 
 
Extension: The extension will assess long-term safety and tolerability of RTA 408 in qualified 
patients with Friedreich’s ataxia following completion of Part 1 or Part 2. Patients will not be 
unblinded to study treatment in Part 1 or Part 2 upon entering the extension study. 
Patients will receive open-label RTA 408 (150 mg) once daily until the drug is available through 
commercial channels, or until patient withdrawal, whichever is sooner.  All patients in the 
extension will follow the same visit and assessment schedule.  Extension Day 1 is defined as the 
first day treatment is dispensed to the patient for the extension, following completion of Part 1 or 
Part 2.  All other extension visits will be relative to extension Day 1.  Patients will be scheduled 
for in-person assessments during treatment in the extension at Day 1, Week 4, Week 24, and 
every 24 weeks thereafter.  Patients will also be assessed by telephone contact on Day 14.   
Since Part 2 patients will be followed continuously within the study, eligibility for the extension 
should be assessed at the Week 52 visit and a separate screening visit is not required.  After 
confirming eligibility for Part 2 patients, study treatment for extension Day 1 should be 
dispensed following the Week 52 assessments.  Part 1 patients will not have been followed 
continuously within this study, and therefore must complete a screening visit to confirm 
eligibility.  
The conduct of the extension phase, according to protocol specifications, was impacted by the 
Coronavirus Disease 2019 (COVID-19) pandemic. As a result, and as of Version 10 of the 
protocol, modifications intended to address access to and administration of investigational 

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product, and adherence to protocol-specified visits and laboratory assessments was implemented. 
These modifications are described in Appendix 13 (COVID-19 Mitigations). 
Figure 2: 
Schema for Open-Label Extension 
 
 
7.2. 
Number of Patients 
Up to approximately 172 patients will be enrolled in this study (up to 72 patients in Part 1 and 
approximately 100 patients in Part 2). 
The extension will only include qualified patients from Part 1 and Part 2, as outlined in  
Section 8.3. 
7.3. 
Treatment Assignment 
Part 1: Patients enrolled in the first cohort for Part 1 will be randomized 3:1 to receive RTA 408 
2.5 mg or placebo.  After the Week 2 visit, patients receiving RTA 408 2.5 mg will dose escalate 
to RTA 408 5 mg starting on Day 15 unless a DLT is observed.  Intra-patient dose-escalation 
will only be utilized in the first cohort for Part 1.  Starting with the second cohort for Part 1, 
patients will be randomized 3:1 to receive the cohort specific dose level of RTA 408 or placebo 
and will remain on the same treatment assignment throughout the study.   
Part 2: One dose level of RTA 408 within the dose-range evaluated in Part 1 will be used in 
Part 2.  Patients enrolled in Part 2 of the study will be randomized 1:1 to RTA 408 150 mg or 
placebo.  Part 2 randomization will be stratified by pes cavus status (pes cavus vs. no pes cavus).  
Patients with pes cavus, a musculoskeletal foot deformity characterized by high arch of the foot 
that does not flatten with weight-bearing, will not comprise more than 20% of patients enrolled 
in Part 2.  
All randomizations will be performed using an Interactive Web Response System (IWRS).   
Extension:  All patients in the extension will be assigned to RTA 408 150 mg. 
7.4. 
Dose Selection and Escalation Scheme 
7.4.1. 
Selection of Doses 
Part 1: The safety, efficacy, and PD of RTA 408 at multiple dose levels (2.5, 5, 10, 20, 40, 80, 
160, and 300 mg) will be evaluated in Part 1 to identify an appropriate dose for Part 2.    
Part 2 and Extension: No DLT was observed in Part 1 and a dose of 150 mg was selected for Part 
2 and Extension.  From the doses evaluated in Part 1, the 160-mg dose of RTA 408 was 
considered optimal based on DSMB and Sponsor assessment of available safety, efficacy, PK, 

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and PD data.  Available capsule strengths of RTA 408 (2.5-, 10-, and 50-mg capsules) require 
four capsules daily for a 160-mg dose and 3 capsules daily for a 150-mg dose.  Available PK 
data from Part 1 demonstrate that systemic exposure to RTA 408 is reasonably linear with dose, 
with modest inter-subject variability (e.g., AUC CV% of approximately 14 to 40%).  
Consequently, a 150-mg dose, is anticipated to provide similar drug exposure as the 160-mg 
dose.  Based on these considerations, an RTA 408 dose of 150 mg was selected for Part 2 and 
Extension because it differs by less than 10% from the 160-mg dose that was evaluated in Part 1 
and therefore is expected to provide similar systemic exposure while affording a reduction in the 
number and complexity of capsules that patients are required to swallow once each day for 
48 weeks during Part 2 and Extension.  
7.4.2. 
Dose-Escalation Scheme  
Part 1:  In Part 1 of the study, an initial cohort of 8 patients will be randomized 3:1 to RTA 408 
2.5 mg (n=6) or placebo (n=2).  Each patient in the first cohort will be evaluated for intra-patient 
dose-escalation by their investigator at the Week 2 visit.  If no DLTs are observed by Week 2 for 
that patient, the patient will dose escalate.  The patients receiving RTA 408 2.5 mg will begin 
receiving RTA 408 5 mg on Day 15 and the patients receiving placebo will remain on placebo in 
a blinded fashion.  If an investigator cannot come to a firm decision whether or not to dose 
escalate a patient, he or she should discuss the relevant safety information with the medical 
monitor.  Patients who are deemed inappropriate for dose escalation will continue on their 
originally randomized dose (i.e., 2.5 mg or placebo) throughout the remainder of the study.  
After the last patient in the initial cohort completes their Week 4 visit, the DSMB and Sponsor 
will review all available safety information from this cohort and make a recommendation 
regarding opening the next cohort to be randomized 3:1 to the cohort specific dose level of 
RTA 408 or placebo.  All subsequent cohorts in Part 1, beginning with the second 8-patient 
cohort, will be evaluated for safety of the cohort-specific dose level by the DSMB once the 
eighth patient enrolled completes their Week 2 visit.  The DSMB will recommend the dose of 
RTA 408 for the subsequent cohort.  The DSMB dose recommendation for each cohort must not 
exceed 100% more than the highest dose of RTA 408 previously evaluated in this study (not to 
exceed 300 mg).  The dose level for each new cohort will not exceed the DSMB recommended 
dose level, and it will be selected by the Sponsor based on review of available safety, efficacy, 
PK, and PD data.  
Part 2:  Dose-escalation or de-escalation will not be used in Part 2.  Patients randomized to 
RTA 408 will receive 150 mg of RTA 408 daily throughout the 48-week treatment period.   
Extension:  Dose-escalation or de-escalation will not be used in the extension portion of the 
study.  Patients will receive 150 mg of RTA 408 daily throughout participation in the extension.   
7.4.3. 
Criteria for Determining Dose-Limiting Toxicity 
Part 1: For the purpose of intra-patient dose escalation in Cohort 1, the assessment of a DLT 
(i.e., a side effect serious enough to prevent an increase in dose) will be based on the clinical 
judgment of the investigator.  Suspected DLTs should be discussed with the medical monitor.  If 
an investigator cannot come to a firm decision whether or not to dose escalate a patient, he or she 
should discuss the relevant safety information with the medical monitor.  All other patients 
enrolled in Part 1 will remain at a constant dose throughout the 12-week treatment period.   

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Part 2 and Extension:  Dose-escalation is not being used in Part 2 and side effects should be 
recorded as adverse events (AEs). 
7.4.4. 
Intra-patient Dose Escalation 
Intra-patient dose escalation will only occur for the first cohort of 8 patients randomized in Part 1 
of the study (i.e., those patients randomized to RTA 408 2.5 mg or placebo).  Investigators, and 
not the DSMB, will make intra-patient dose-escalation decisions during the first cohort of Part 1.  
Each patient will dose escalate starting on Day 15, unless a DLT is indicated by the investigator.  
Patients originally randomized to RTA 408 2.5 mg will dose escalate to RTA 408 5 mg, and 
those randomized to placebo will remain on placebo in a blinded fashion.  If the investigator 
cannot come to a firm decision whether or not to dose escalate a patient, he or she should discuss 
the relevant safety information with the medical monitor.  If the investigator determines the 
patient should not be dose escalated, that patient should continue on their originally randomized 
dose (i.e., 2.5 mg or placebo) throughout the remainder of the study visits. 
No other patients are eligible for intra-patient dose escalation.    
7.4.5. 
Additional Considerations for Dose Escalation Decisions in Part 1 
A maximum dose of 300 mg may be tested in Part 1 of this study; however, each dose escalation 
is limited to a 100% increase from the previous dose.  If the Sponsor or DSMB considers dose 
escalation not safe for any reason, no more dose escalation will be carried out.  The DSMB may 
recommend stopping dose escalation at any time, particularly if their review of AEs or laboratory 
data (e.g., AST, ALT, bilirubin, alkaline phosphatase (ALP), magnesium, creatinine, B-type 
natriuretic peptide [BNP], etc.), reveals any potential safety concern.  The Sponsor, in addition to 
reviewing all available safety and efficacy data, will also take into consideration the predicted 
systemic exposure to RTA 408 at the next proposed dose in comparison with the exposure vs 
adverse effect profile for RTA 408 in animals.  If systemic exposure is sufficiently high to 
warrant a potential concern based on animal toxicity data, dose escalation may be stopped or 
paused, if needed, to seek additional input from the DSMB or United States Food and Drug 
Administration (US FDA). 
7.5. 
Data Safety Monitoring Board  
A DSMB will review unblinded safety data throughout the study (i.e., Part 1, Part 2, and 
Extension) and make recommendations as appropriate.  The DSMB will begin monthly data 
reviews approximately 1 month after the first patient is enrolled in Part 1 through the last dose of 
the last patient enrolled in Part 1.  Part 2 and Extension data will be reviewed on a quarterly basis 
by the DSMB.  After the last patient completes Part 2, the DSMB will determine if regular 
meetings are necessary or may convert to less frequent reviews to align better with the extension 
schedule of every 24 week visits. 
The DSMB will consist of external clinical experts supported by an independent statistical group.  
The independent statistical group will prepare unblinded analyses for the DSMB and will not 
have a role in the statistical analysis plan (SAP) after Part 2 of the study has started enrolling 
patients.  A separate, blinded statistical group will be responsible for producing and finalizing the 
SAP and executing final data analysis for each part of the study.   

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The DSMB will be governed by a charter that will describe the following: 
• Roles and responsibilities of the DSMB members and the independent statistical 
group 
• Meeting format and frequency 
• Communication channels between the DSMB, the independent statistical group, the 
Sponsor, and the blinded study statisticians 
• Voting process and requirements (e.g., requirement of consensus for issuance of a 
termination recommendation) 
• Provisions governing conflict of interest and confidentiality  
 
Briefly, the DSMB will review the progress of the study and the accumulating unblinded data 
while the study is ongoing.  At each data review, the DSMB will assess safety, as evaluated by 
AEs, laboratory data (e.g., AST, ALT, bilirubin, ALP, magnesium, creatinine, BNP, etc.), 
limited functional assessment data (maximal exercise testing and mFARS score), and changes in 
other laboratory and vital sign parameters.  The DSMB will assess whether the study should be 
stopped for safety concerns or the informed consent updated to include new safety information.  
In addition, the DSMB will review serious adverse events (SAEs) from the safety database, 
including narratives.  The DSMB will make recommendations to Sponsor representatives 
following each meeting.  The DSMB may recommend that the study continue as is, be modified 
to protect patient safety, or be terminated.  In addition to the reviews of unblinded study data, the 
DSMB will participate with the Sponsor in the recommendation to open the 10-mg cohort and 
higher dosing cohorts for enrollment for Part 1 and opening Part 2 described in Section 7.4.2.  
However, investigators, and not the DSMB, will make intra-patient dose-escalation decisions 
during the first cohort of Part 1. 
7.6. 
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 have the responsibility to prescribe any additional therapy 
to be administered.  
7.7. 
Schedule of Assessments  
Table 3, Table 4, and Table 5 lists the overall schedule of assessments for the study. 

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k Study drug should be administered in the presence of study staff in the clinic on Day 1 after all Day 1 assessments have been completed.  Study drug should also be administered 
in the clinic on Day 14 (Visit 4), Day 84 (Visit 7), Day 168 (Visit 9), and Day 336 (Visit 13) after the blood collection for predose PK analysis.  All other doses can be 
administered at home.  Study drug should be administered once daily through Day 336 (Visit 13).  
l On study days where multiple assessments are to be completed, the maximal exercise test will be the first functional assessment performed.   
m The practice FARS assessment is not required for patients having completed a FARS assessment within 90 days prior to Screening. The practice FARS assessment must be 
performed prior to the screening maximal exercise test. 
n Other than the practice FARS, all FARS assessments must always be performed after the maximal exercise test. 
o Both Screening and Day 1 mFARS are required to determine patient eligibility.  
p Video of the 25-foot timed walk test is optional and will be collected only for those patients who provide consent to video.  
q Patients who consent to video collection of the 25-foot timed walk test will also have video collection during normal walking with a 25-foot (un-timed) walk using his/her 
normal gait.  The normal walk must be performed after the 25-foot timed walk test.  
r Patients and investigators must complete the patient global impression of change and clinical global impression of change following completion of the neurological FARS exam.  
s Patients will be provided the fall diary at Screening and must record fall incidents between Screening and Week 48. 
t Blood samples for PK analysis at Day 14 (Visit 4) should be collected prior to study drug administration as well as 1, 2, 4, and 8 hours after study drug administration.   
u A single blood sample for PK analysis at Day 84 (Visit 7), Day 168 (Visit 9), and Day 336 (Visit 13) should be collected prior to study drug administration. 
 
 

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g Blood samples should be collected for hepatitis B and C and HIV antibodies only in patients lacking evidence of a negative titer in the past year. 
h A serum pregnancy test will be performed at any point in time if a pregnancy is suspected.  All other pregnancy assessments will be urine pregnancy tests.  Additional pregnancy 
assessments will be performed more frequently if required by local law or requested by local health authorities or IRBs/ECs.   
i Patients and investigators must complete the patient global impression of change and clinical global impression of change following completion of the neurological FARS exam. 
j     Height will be performed at Week 4 for Part 2 patients enrolled in the Extension. 
 
 

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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria (Part 1 and Part 2) 
Patients must: 
1. Have genetically confirmed Friedreich’s ataxia  
2. Have an mFARS score ≥ 20 and ≤ 80.  The average of the two mFARS values collected 
at Screening and Day 1 visits must fall within the allowable range, and they must be 
within 4.5 points of each other 
3. Be male or female and ≥ 16 years of age and ≤ 40 years of age 
4. Have no changes to their exercise regimen within 30 days prior to Study Day 1 and be 
willing to remain on the same exercise regimen during the study period 
5. Have the ability to complete maximal exercise testing 
6. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥ 60 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 
4-variable formula  
7. Have a left ventricular ejection fraction ≥ 40% (based on echocardiogram performed at 
Screening Visit or within 90 days prior to Screening Visit) 
8. Be able to swallow capsules 
9. Be willing and able to cooperate with all aspects of the protocol 
10. Be willing to practice medically acceptable methods of birth control (Section 9.7.2)  
11. Provide written informed consent for study participation, approved by the appropriate 
Institutional Review Board (IRB) 
8.2. 
Patient Exclusion Criteria (Part 1 and Part 2) 
Patients must not: 
1. Have uncontrolled diabetes (HbA1c > 11.0%) 
2. Have a BNP level > 200 pg/mL 
3. Have a history of clinically significant left-sided heart disease and/or clinically 
significant cardiac disease, with the exception of mild to moderate cardiomyopathy 
associated with Friedreich’s ataxia, including but not limited to any of the following: 
a. Clinically significant congenital or acquired valvular disease 
b. Pericardial constriction (based on echocardiogram performed at Screening Visit 
or within 90 days prior to Screening Visit) 
c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at 
Screening Visit or within 90 days prior to Screening Visit) 

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d. Symptomatic coronary disease (prior myocardial infarction, percutaneous 
coronary intervention, coronary artery bypass graft surgery, or angina) 
e. History of hospitalization for heart failure in the last five years 
f. Cardiac insufficiency, defined as New York Heart Association Class > 2 
g. History of atrial fibrillation 
h. History of unstable arrhythmias 
4. Have known active fungal, bacterial, and/or viral infection, including human 
immunodeficiency virus (HIV) or hepatitis virus (B or C)  
5. Have known or suspected active drug or alcohol abuse, as per investigator judgment 
6. Have clinically significant abnormalities of clinical hematology or biochemistry, 
including but not limited to elevations greater than 1.5 times the upper limit of normal 
(ULN) of AST or ALT.  Levels above this threshold are allowable if attributable to 
muscle injury 
7. Have any abnormal laboratory test value or clinically significant pre-existing medical 
condition that, in the opinion of the investigator, would put the patient at risk by study 
enrollment 
8. Have taken any of the following drugs within 7 days prior to Study Day 1 or plan to take 
any of these drugs during the time of study participation: 
a. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, 
midazolam, sildenafil) 
b. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
c. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
9. Have a history of clinically significant liver disease (e.g., fibrosis, cirrhosis, hepatitis), or 
has, at screening, clinically relevant deviations in laboratory tests including any one of 
the following: 
a. ALT and/or AST > 1.5-fold ULN, 
b. bilirubin > 1.2-fold ULN, 
c. alkaline phosphatase (ALP) > 2-fold ULN, 
d. albumin < lower limit of normal (LLN) 
10. Have participated in any other interventional clinical study within 30 days prior to 
Study Day 1 
11. Have a cognitive impairment that may preclude ability to comply with study procedures 
12. Be unable to comply with the requirements of the study protocol or be unsuitable for the 
study for any reason, in the opinion of the investigator  
13. Have used antioxidant supplements, including but not limited to idebenone, coenzyme 
Q10, nicotinamide, and vitamin E above the recommended daily allowance, within 

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14 days prior to Study Day 1 or plan to take any of these supplements during the time of 
study participation 
14. Have previously documented mitochondrial respiratory chain disease 
15. Have a history of thromboembolic events within the past 5 years 
16. Have taken anticoagulant therapy within 30 days prior to Study Day 1  
17. Have scheduled surgical treatment for scoliosis or foot deformity during the study 
18. Have had significant current suicidal ideation within 1 month prior to Screening Visit as 
per investigator judgment or any history of suicide attempts 
19. Be pregnant or breastfeeding 
20. Prior participation in a trial with RTA 408 
8.3. 
Extension Eligibility 
Patients must complete 12 weeks of treatment in Part 1, or 48 weeks of treatment in Part 2, have 
no significant protocol deviations that would, in the opinion of the investigator, deem the patient 
unsuitable for enrollment in the Extension phase of the study, and continue to meet inclusion and 
exclusion criteria as specified in Appendix 1.  
8.4. 
Patient Rescreening 
Patients may repeat the screening procedures to qualify for the study if they have:  
• Used antioxidant supplements, including but not limited to idebenone, coenzyme 
Q10, nicotinamide, and vitamin E above the recommended daily allowance, within 14 
days prior to Study Day 1 (rescreening may be performed 14 days or more after 
discontinuation of supplement) 
• Used anticoagulant therapy within 30 days prior to Study Day 1 (rescreening may be 
performed 30 days or more after discontinuation of anticoagulant therapy) 
• Participated in any other interventional clinical study within 30 days prior to Study 
Day 1 (rescreening may be performed 30 days or more after completion of the clinical 
study) 
• An abnormal laboratory test value that may normalize, in the opinion of the 
investigator (rescreening may be performed once test value is within normal range) 
• Modified their exercise regimen within 30 days prior to Study Day 1 (rescreening 
may be performed 30 days or more after modification of exercise regimen) 
• Taken any of the following drugs within 7 days prior to Study Day 1 (rescreening 
may be performed 7 days or more after discontinuation of the drug): 
− Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, 
midazolam, sildenafil) 
− Moderate or strong inhibitors or inducers of cytochrome P450 2C8 or 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 

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− Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
• Failed screening because of operational challenges (rescreening may be performed no 
fewer than 2 weeks from the date of screen failure) 
• Failed screening because of mFARS (the absolute difference in mFARS was 
≥ 4.5 points between Screening and Day 1) 
Patients may repeat the screening procedures once to qualify for Parts 1 and 2 of the study. For 
the Extension, patients may be rescreened at the discretion of the Sponsor, following discussion 
with the investigator site. 
8.5. 
Patient Discontinuation and Termination 
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).  
8.5.1. 
Patient Discontinuation Criteria 
Discontinuation refers to a patient stopping administration of study drug.  Reasons for study drug 
discontinuation may include the following: 
• Occurrence of an AE or change in medical status that leads the investigator to be 
concerned about the patient’s welfare 
• Protocol violations 
• Administrative reasons (e.g., inability to continue) 
• Sponsor termination of the study 
• Voluntary withdrawal 
• Pregnancy during the study 
• Investigator unblinding 
Patients must permanently discontinue study drug if any of the following occur: 
• ALT or AST > 8X ULN; 
• ALT or AST > 5X ULN for more than 2 weeks; 
• ALT or AST > 3X ULN and TBL > 2X ULN 
• ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
Patients who are discontinued from study drug in Part 1 or Part 2 should still complete all study 
visits and undergo all scheduled study assessments, if possible.   

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8.5.2. 
Patient Termination Criteria 
Termination refers to a patient stopping study drug and all study assessments and visits.  Reasons 
for study termination include the following: 
• Administrative reasons (e.g., inability to continue, lost to follow-up) 
• Death 
• Withdrawal of consent 
Patients who terminate the study for any reason may not re-initiate study drug or study 
assessments at any time.     

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9. 
TREATMENT OF PATIENTS 
9.1. 
Description of Study Drug 
Part 1: Depending on cohort dose level (or doses selected for part 2) patients will ingest up to 6 
capsules of study drug (1 from each bottle included in study treatment kit) daily throughout the 
study; study drug is described in Section 10.1.  Treatment kits containing up to 160 mg of 
RTA 408 or placebo will include 4 bottles, each containing 30 count of either active or placebo 
capsules.  Treatment kits containing greater than 160 mg of RTA 408 or placebo will be 
comprised of 6 bottles, each containing 30 count of either active or placebo capsules.  To 
maintain the study blind, treatment kits used in Part 2 will all include the same number of bottles.   
Part 2: Patients will ingest 3 capsules daily throughout the study; study drug is described in 
Section 10.1.  Treatment kits containing RTA 408 or placebo will include 3 bottles, each 
containing 30 count of either active (RTA 408 50 mg) or placebo capsules.  Patients may receive 
more than 1 treatment kit during dispensation to provide sufficient study drug until their next 
planned dispensation. 
Extension: Patients will ingest 3 capsules daily throughout the extension; study drug is described 
in Section 10.1.  Treatment kits containing RTA 408 will include 3 bottles, each containing 
30 count of active (RTA 408 50 mg) capsules.  Patients may receive more than 1 treatment kit 
during dispensation to provide sufficient study drug until their next planned dispensation. 
The Sponsor will provide sufficient quantities of study drug to allow for completion of the study. 
9.1.1. 
Management of Elevated Transaminase Levels (ALT and/or AST) 
In ongoing clinical trials with RTA 408, transient increases in transaminases and GGT levels 
have been observed in some patients (refer to the Investigator’s Brochure for additional 
information).  Transaminases should be monitored using data from the scheduled lab draws in 
Part 2 and the extension. Nearly all instances of elevated transaminases are expected to be 
asymptomatic.  Transaminase levels (as well as TBL, GGT, ALP) will be checked within 48 to 
72 hours during an unscheduled visit if the following occurs: 
• ALT or AST levels > 3X ULN. 
Testing will be repeated every 72 to 96 hours until transaminase levels are below 3X the ULN 
for at least one week or until the patient withdraws consent. 
Study drug administration will be permanently discontinued if any of the following occurs: 
• ALT or AST > 8X ULN; 
• ALT or AST > 5X ULN for more than 2 weeks; 
• ALT or AST > 3X ULN and (TBL > 2X ULN); 
• ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%).  
The hepatobiliary tree must be visualized (e.g., ultrasound, MRI) and assessed if a patient 
discontinues taking study drug secondary to elevated transaminase levels.  Additional 
tests/studies may be warranted depending on the clinical presentation. 

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9.2. 
Prior and Concomitant Medications 
9.2.1. 
Excluded Medications 
Patients who have taken any of the following drugs within 30 days prior to Study Day 1 will be 
excluded from the study: 
• Any other investigational drug 
• Anticoagulant therapy, with the exception of a daily baby aspirin (up to 81 mg) 
Patients who have taken any of the following drugs within 14 days prior to Study Day 1 will be 
excluded from Part 1 and Part 2: 
• Antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and dosages exceeding the recommended daily allowance of vitamin E  
• Anti-spasticity agents 
Patients who have taken any of the following drugs within 7 days prior to Study Day 1 will be 
excluded from the study: 
• Herbal preparations, minerals, or over-the-counter medication, except as identified in 
Section 9.2.2 
• Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, 
sildenafil) 
• Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
• Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
The following medications and medication classes are not permitted during Part 1 and Part 2, 
except as noted in Section 9.2.2: 
• Anticoagulant therapy, with the exception of daily baby aspirin (up to 81 mg) 
• Antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and dosages exceeding the recommended daily allowance of vitamin E  
• Herbal preparations, vitamins, minerals, or over-the-counter medication, except as 
identified in Section 9.2.2 
• Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, 
sildenafil) 
• Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
• Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
• Any interventional therapy intended to treat the Friedreich’s ataxia disease condition, 
with the exception of a constant exercise regimen 
• Anti-spasticity agents 

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The following medications and medication classes are not permitted during the extension study 
• Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, midazolam, 
sildenafil) 
• Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
• Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
9.2.2. 
Permitted Medications 
The following concomitant medications are permitted, as authorized by the treating physician: 
• Antibiotics, except as noted above (Section 9.2.1) 
• Daily multivitamin 
• Pain medication, except as noted above (Section 9.2.1) 
• Other medications intended to manage concurrent diseases, except as noted above 
(Section 9.2.1) 
• Oral, implantable, or injectable contraceptives 
The following concomitant medications are permitted only during the extension study: 
• Antioxidant supplements, including but not limited to idebenone, coenzyme Q10, 
nicotinamide, and dosages exceeding the recommended daily allowance of vitamin E  
• Anti-spasticity agents 
Patients taking medication chronically should be maintained on those same doses and dose 
schedules throughout the study period, as medically feasible.  Patients taking medications with 
intermittent or as-needed schedules should try to avoid taking the concomitant medication on 
days when PK samples will be collected, as medically feasible. 
9.3. 
Compliance with Study Drug 
The investigator or designee will only dispense study drug to patients randomized to study 
treatment in accordance with the protocol.  The study drug must not be used for reasons other 
than that described in the protocol. 
All patients will return all bottles and unused pills and will be dispensed a new kit of study drug 
at visits indicated in Table 3, Table 4, and Table 5.  In addition, patients in the first cohort of 
Part 1 will return all unused pills at the Week 2 visit and will be dispensed a new kit of study 
drug at that time.  Compliance will be measured by counting pills to determine the number of 
missed doses from one visit to the next.  Patients will also be provided a dosing diary to 
document that pills were taken as instructed as well as the date and time of dosing 
(Section 9.9.23).  To be considered compliant with study drug, patients can miss no more than 
25% of the total planned doses (i.e., 21 doses during Part 1, or 84 doses during Part 2) during the 
study.  Patients who exceed the number of allowed missed doses will be considered 
noncompliant with dosing.  Patients will not be discontinued from the study drug nor terminated 

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from the study for noncompliance, but protocol deviations should be recorded for dosing 
noncompliance. 
9.4. 
Randomization  
Patients enrolled in Part 1 cohorts will be randomized 3:1 to RTA 408 at the cohort-specific dose 
level or placebo.  Patients enrolled in Part 2 will be randomized 1:1 to RTA 408 150 mg or 
placebo.  Randomization in Part 2 will be stratified by pes cavus status (pes cavus vs. no 
pes cavus).  Patients with pes cavus, a musculoskeletal foot deformity characterized by high arch 
of the foot that does not flatten with weight-bearing, will not comprise more than 20% of patients 
enrolled in Part 2.  Randomization for both Part 1 and Part 2 will be generated using a 
centralized IWRS.   
Patients enrolled in the extension will be assigned to RTA 408 150 mg. 
9.5. 
Blinding 
To maintain the study blind, all study drug kits will be packaged with blinded labels.  
Investigators will distribute the blinded study drug kits by kit number to patients as assigned by 
the IWRS.  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 and 
appropriate measures will be taken to ensure the blind is maintained to reduce potential bias.  
Some Sponsor personnel may have access to treatment assignments during dose escalation 
(Part 1), but during Part 2, all Sponsor personnel will be blinded to treatment assignment. 
The only people with access to treatment assignments for Part 2 will be those individuals who 
maintain the IWRS, the DSMB, the unblinded statistical team providing data to and analyzing 
data for the DSMB, and safety personnel without direct involvement in the conduct of the study 
who are assigned to report unblinded data to regulatory authorities as required. 
The extension will be considered open-label.  All patients in the extension will be assigned 
RTA 408 150 mg. Patients will not be unblinded to study treatment in Part 1 or Part 2 upon 
entering the extension study. 
9.5.1. 
Patient Unblinding 
Although there is no known antidote to RTA 408, under rare circumstances, unblinding may be 
considered medically necessary for safety reasons.  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), but they should 
remain blinded and continue attending all study visits and should undergo all study assessments.  
Patient treatment assignments must not be unblinded in the case of an AE or SAE, except as 
described above. 

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9.5.2. 
Unblinding for Regulatory Submission 
In situations where a regulatory body requires unblinding and reporting of a particular SAE, 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 
the investigator, site personnel, or patient; therefore, this type of unblinding does not necessitate 
that the patient discontinue taking study drug.  
9.6. 
Unscheduled Visits 
Unscheduled visits are allowed for the following reasons: 
• Patient rescreening 
• Management of an AE or SAE 
• Performance of additional laboratory tests for clinically abnormal test values or to 
confirm a possible pregnancy 
• If 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, have not had reproductive potential terminated by 
radiation or chemotherapy, and are not postmenopausal for at least 1 year. 
9.7.2. 
Methods of Birth Control 
From the Screening Visit, while taking study drug, and until 3 months after taking the final dose 
of study drug, WOCBP must agree to practice one of the following methods of birth control: 
• Use of a 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 
with or without a diaphragm) 
• Use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for at least 
3 months prior to study drug administration 
• Use of an intrauterine device 
• Complete abstinence from sexual intercourse 
• Male sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate.)  The vasectomized partner should be the sole partner for 
that subject. 
From the Screening Visit, while taking study drug, and until 3 months after taking the final dose 
of study drug, males who have female partners of childbearing potential must agree to practice 
one of the following methods of birth control: 

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• Have had a vasectomy (at least 6 months earlier) 
• Use of a 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 
with or without a diaphragm) 
• Partner use of hormonal contraceptives (oral, parenteral, vaginal, or transdermal) for 
at least 3 months prior to study drug administration 
• Partner use of an intrauterine device 
• Complete abstinence from sexual intercourse 
Male patients must also agree to not donate sperm starting on the first day of treatment until 
approximately 3 months after last dose of study drug. 
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).  Male patients must be 
instructed to contact the investigator if a sexual partner suspects she may be pregnant. 
If a patient or investigator suspects that the patient may be pregnant, the study drug must be 
withheld until the results of a serum pregnancy test are available.  If pregnancy is confirmed with 
a serum pregnancy test, the patient must discontinue taking study drug but continue to attend all 
study visits and undergo all study assessments.  The investigator must immediately report a 
pregnancy associated with study drug exposure and record the event.   
Pregnancy is not considered an AE; however, the investigator must follow a pregnant patient or 
the pregnant female partner of a male patient (if consenting) and report follow-up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome.  Infants 
resulting from such pregnancies should be followed for a minimum of 8 weeks.  The Sponsor or 
its 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 case report form (CRF) and on an SAE form: 
• Congenital anomaly/birth defect 
• Stillbirth 
• Spontaneous miscarriage 
9.8. 
Treatment Interruption 
In the case of serious toxicities, the investigator may choose to interrupt treatment with study 
drug.  If study drug treatment interruption exceeds 21 total days, a protocol deviation should be 
noted.  Dose reductions are not permitted.  Patients who are permanently discontinued from 
study drug for any reason should still complete all Part 1 and Part 2 study visits and undergo all 
scheduled study assessments, if possible.  If the toxicity has resolved such that the investigator 
does not consider continued drug treatment to be an additional risk to the patient, the investigator 
may restart study drug treatment.  Patients who are permanently discontinued from study drug 

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during the extension should complete the end of study assessments, and be terminated from the 
study. 
9.9. 
Study Procedures  
To avoid inter-observer variability, every effort should be made to ensure that the same 
individual who made the initial baseline determination completes all subsequent assessments.  
All assessments occur in the study center clinic with the exception of those assessments for lab 
collection at Screening (all patients, Part 1 and Part 2) and Visit 3 (Part 1 only), which may be 
performed by a home health visit nurse (at appropriate locations and approved by Sponsor) and 
those assessments for Visits 6 and 8 in Part 1 and Visits 3, 6, 10 and 12 in Part 2, which will be 
performed via telephone contact.   During the extension every effort should be made to ensure 
patient assessments are performed on-site. If this is not possible home health visits are 
acceptable.  For more detail regarding use of home health services see Appendix 13 ( COVID-19 
Mitigations). 
9.9.1. 
Informed Consent 
Written informed consent (Section 17.3) must be obtained from the patient before any 
study-related procedures are performed, and if there is a change in the study procedures that 
could affect the patient’s willingness to participate.  Patients have the option to separately 
consent to have video recorded during the 25-foot timed walk and 25-foot normal walk tests at 
selected sites. 
9.9.2. 
Inclusion/Exclusion Criteria 
Inclusion and exclusion criteria should be reviewed at the times indicated in Table 3, Table 4, 
and Table 5.  Patients must meet all of the inclusion criteria and none of the exclusion criteria for 
entry into the study.  Investigators and/or study site personnel should contact the medical 
monitor for any questions regarding patient eligibility.  
9.9.3. 
Demographics and Baseline Disease Characteristics 
Demographic data, including sex, age, race, and ethnicity, and baseline disease characteristics, 
including, but not limited to, documentation of genetic confirmation of Friedreich’s ataxia and 
presence or absence of pes cavus, will be collected at the time indicated in Table 3 and Table 4.  
9.9.4. 
Pes Cavus Assessment 
The process for classifying pes cavus will be described in a separate study manual.  Pes cavus 
will be assessed at the times indicated in Table 4 and Table 5.  Patients who participated in Part 1 
of the study must complete a pes cavus assessment at the Extension Study Screening visit 
(Table 5).  
9.9.5. 
Foot X-Ray  
The foot x-ray assessment will be performed to quantify the foot structure of patients with and 
without pes cavus.  Specific radiological angles of the foot will be quantified by a central reader.  
Radiological angles assessed from a lateral image of the foot may include but are not limited 
to: tibia-talar angle, talo-calcaneal angle, tibia-calcaneal angle, talo-first metatarsal angle, 

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calcaneal pitch angle, and naviculocuboid overlap.  The x-ray of the lateral view of the right foot 
will be collected once per patient at the time indicated in Table 4.  Patients should complete the 
foot x-ray at Screening; however, if a patient was not able to complete the foot x-ray at 
Screening, it may be completed at any point during the first 52 weeks of the study.  
9.9.6. 
Prior and Concomitant Medications 
Information on prior and concomitant medications will be collected at the times indicated in 
Table 3, Table 4, and Table 5.  The name, dose, and frequency of all medications that the patient 
is taking or has taken within 30 days prior to Study Day 1 must be recorded during the study and 
until the final visit.  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 whenever possible.   
9.9.7. 
Medical History 
A complete medical history (e.g., per patient report) that includes all medical history within the 
past 5 years will be collected and recorded at the time indicated in Table 3, Table 4, and Table 5.  
9.9.8. 
Height 
Height should be measured without footwear, head coverings, or prosthetics at the time indicated 
in Table 3 and Table 4. 
9.9.9. 
Echocardiogram 
An echocardiogram will be recorded at the times indicated in Table 3, Table 4, and Table 5 after 
the patient has rested for approximately 10 minutes in a supine position.  For patients with 
echocardiograms collected within 90 days prior to Screening Visit, the most recent 
echocardiogram can be used to assess cardiac function and patient eligibility.  Patients are 
ineligible to participate in the study if they have pericardial constriction, restrictive or congestive 
cardiomyopathy, or left ventricular ejection fraction <40%.  However, patients with mild to 
moderate cardiomyopathy associated with Friedreich’s ataxia are not excluded. 
Patients from Part 1 of the study that want to participate in the Extension must have an 
echocardiogram collected within 90 days prior to Extension Day 1. 
9.9.10. 
Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be recorded at the times indicated in Table 3 and 
Table 4 after the patient has rested for approximately 10 minutes in a supine position.  The heart 
rate from the ECG machine should not be used as part of the vital sign measurements.  
An ECG is required for eligibility.  If a patient has had an ECG completed within 90 days prior 
to the Screening Visit, the most recent ECG can be used as the screening assessment for patient 
eligibility. 
9.9.11. 
Vital Sign Measurements  
Vital sign measurements should be taken at the times indicated in Table 3, Table 4, and Table 5 
and include the patient’s heart rate (beats/minute), blood pressure (mm Hg), and body 

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temperature (°C or °F).  Blood pressure should be taken after the patient has rested in a sitting 
position for approximately 5 minutes.  The same arm (usually the non-dominant arm) and the 
appropriate size cuff should be used for each measurement.   
9.9.12. 
Weight and Body Mass Index 
Weight should be measured at the times indicated in Table 3, Table 4, and Table 5.  Body mass 
index (BMI) will be calculated within the eCRF each time the weight is recorded.  If patients are 
weighed at the Screening Visit with additional leg braces, walkers, or shoes, all additional weight 
assessments must be conducted with the same appendages. 
9.9.13. 
Physical Examination 
A comprehensive physical examination must be performed by a physician, physician assistant, or 
registered nurse practitioner at the times indicated in Table 3, Table 4, and Table 5.  If possible, 
the same individual should perform each physical examination on a patient during the study.  
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.  Each body system finding must be assessed for clinical significance.  
Clinically significant findings at the Screening Visit must be included in the patient’s medical 
history.  New clinically significant findings after first dose must be included as AEs.  Subsequent 
assessments beyond screening should be characterized as new, worsening, improved, or 
unchanged relative to the previous assessment.      
9.9.14. 
Adverse Event Collection 
Patients should be observed for general appearance, presence of illness or injury, or signs 
indicative of a concurrent illness at the times indicated in Table 3, Table 4, and Table 5.  Patients 
should be instructed to volunteer any information regarding AEs at any time during the study.  
The study physician or the study staff should also query 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. 
9.9.15. 
Clinical Chemistry 
Blood samples will be collected for clinical chemistry analyses at the times indicated in Table 3, 
Table 4, and Table 5.  Clinical chemistry analyses are listed in Table 6.  Every effort should be 
made to collect laboratory data using the central lab.  Where use of the central lab is not possible, 
laboratory assessments should be collected through a local lab and reviewed by the investigator. 
For calculation of the eGFR, the 4-variable MDRD equation must be used.  The equation is as 
follows: 
eGFR = 175 x standardized serum creatinine –1 154 x age –0 203 x 1.212 [if black] x 0.742 [if female] 
 

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affected by recent exercise, patients must be allowed to rest for a minimum period of 1 hour 
following study-specific exercise testing prior to obtaining this blood sample.  This sample 
should be taken with the patient in the same position at all appropriate visits (e.g., sitting or semi-
recumbent).  
9.9.19. 
Hepatitis B and C and Human Immunodeficiency Virus 
Blood samples will be collected for hepatitis B and C and HIV antibody assessments only in 
patients lacking evidence of a negative titer in the past year at the time indicated in Table 3, 
Table 4, and Table 5.  
9.9.20. 
Pregnancy Test 
WOCBP (Section 9.7.1) will provide a blood or urine sample for a pregnancy test at the times 
indicated in Table 3, Table 4, and Table 5.  Negative serum test results are required at the 
Screening Visit before study enrollment, and negative urine test results are required at all other 
times indicated in Table 3, Table 4, and Table 5 for continued participation in the study.  Any 
patient who becomes pregnant during the study must discontinue taking study drug immediately.  
See Section 9.7.3 for a description of procedures to be followed in case of pregnancy. 
9.9.21. 
Exercise Regimen Reporting  
Exercise regimen will be recorded at baseline.  Patients will be asked about changes to their 
exercise regimen at the times indicated in Table 3 and Table 4.  Changes to the exercise regimen 
during Part 1 or Part 2 will be recorded as protocol deviations. 
9.9.22. 
Study Drug Dispensation  
Enough study drug will be dispensed to the patient at the times indicated in Table 3, Table 4, and 
Table 5 to last at least until the next study visit, along with instructions for use.   
9.9.23. 
Study Drug Return and Pill Count  
Study drug will be collected from the patient and pills will be counted by the principal 
investigator or the study staff at the times indicated in Table 3, Table 4, and Table 5 to determine 
treatment compliance.  Criteria for noncompliance and instructions for recording compliance on 
the CRF are included in Section 9.3.  
Patients will be provided a dosing diary in Part 1 and Part 2 to track all doses administered, 
including the date and time of each dose.  The patient will bring the dosing diary to the clinic to 
be reviewed by the site staff for study drug accountability. 
9.9.24. 
Study Drug Administration 
Part 1: As outlined in Section 9.1, study drug treatment kits will contain up to six 30-count 
bottles of RTA 408 or placebo capsules.  Patients should take 1 capsule from each bottle daily.  
Patients should self-administer study drug orally once daily in the morning on an empty stomach 
(approximately 1 hour before or 2 hours after eating).  Study drug should be taken with water at 
the times indicated in Table 3, except on Days 1, 14, 56 (Cohort 1; Part 1 only), and 84, when 
study staff will administer study drug at the clinic following all assessments on Day 1, and after 
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date and time of the 2 most recent doses of study medication prior to Days 14, 56 (Cohort 1; 
Part 1 only), and 84 will be recorded for PK analysis.  The date and time of the last study drug 
administration (Day 84) should be recorded.  A vomited dose should not be replaced.  Missed 
doses may be taken in the afternoon or evening of the same day approximately 1 hour before or 
2 hours after a meal.  A double dose (e.g., missed dose from previous day and dose for current 
day) should not be taken. 
Part 2: As outlined in Section 9.1, study drug treatment kits will contain three 30-count bottles of 
RTA 408 or placebo capsules. Patients should self-administer study drug orally once daily in the 
morning on an empty stomach (approximately 1 hour before or 2 hours after eating).  Study drug 
should be taken with water at the times indicated in Table 4, except on Days 1, 14, 84, 168, and 
336, when study staff will administer study drug at the clinic following all assessments on Day 1, 
and after the pre-dose blood sample for PK analysis on Days 14, 84, 168, and 336.  The date and 
time of the 2 most recent doses of study medication prior to Days 14, 84, and 168, will be 
recorded for PK analysis.  The date and time of the last study drug administration (Day 336) 
should be recorded.   
Extension: As outlined in Section 9.1, patients will ingest 3 capsules daily throughout the study. 
Study drug should be taken with water at the times indicated in Table 5.  Treatment kits 
containing RTA 408 will include 3 bottles, each containing 30 count of active (RTA 408 50 mg) 
capsules.  Patients may receive more than 1 treatment kit during dispensation to provide 
sufficient study drug until their next planned dispensation. 
A vomited dose should not be replaced.  Missed doses may be taken in the afternoon or evening 
of the same day approximately 1 hour before or 2 hours after a meal.  A double dose 
(e.g., missed dose from previous day and dose for current day) should not be taken. 
9.9.25. 
Telephone Contact 
Sites should complete a telephone visit contact with the patient to assess AEs and concomitant 
medications at the times indicated in Table 3, Table 4, and Table 5.  Sites should make at least 
3 attempts to contact the patient within the visit window if contact attempts are unsuccessful. 
9.9.26. 
Maximal Exercise Test 
Cycle ergometry using a recumbent stationary bicycle will be used to conduct maximal exercise 
testing at the times indicated in Table 3 and Table 4.  An example of the procedures for maximal 
exercise testing is provided in Appendix 2.  Maximal exercise testing assessments include but are 
not limited to peak work and peak oxygen utilization. On study days where multiple assessments 
are to be completed, the maximal exercise test must be the first functional assessment performed. 
9.9.27. 
Friedreich’s Ataxia Rating Scale 
The examiner will complete the full FARS neurological examination on the patient at the times 
indicated in Table 3, Table 4, and Table 5.  An example of the procedures for the FARS 
assessment is provided in Appendix 3. A practice FARS assessment is included in the schedule 
of assessments to familiarize those patients who have not recently completed a FARS assessment 
with the components of the neurological exam.  The practice FARS assessment is not required 
for patients having completed a FARS assessment within 90 days prior to Screening. The 
practice FARS assessment must be performed prior to the screening maximal exercise test.  

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Other than the practice FARS, all FARS neurological examinations must be performed following 
maximal exercise testing.   
The examiner will need a reflex hammer, tuning fork, and stopwatch.  Instructions will be 
provided in the study manual.  The FARS examination should be completed by one of the 
neurologists at the site delegated to complete this assessment.  The individual components of this 
examination will be recorded so that the mFARS score can be calculated as a subset of the full 
neurological FARS examination score, as required. 
The full neurologic FARS is divided into 5 sections: bulbar, upper limb coordination, lower limb 
coordination, peripheral nervous system, and upright stability.  This examination must be 
performed and ratings determined by a trained neurologist.  As the examiner proceeds through 
the items, he/she can call out scores to a coordinator or research assistant to record onto the CRF. 
For every item in the FARS exam, a higher score means that the patient is more severely 
affected.  A score of 0 for an item means that the patient has a normal score.  Not all of the items 
have the same possible scoring range.  Some of the items will range from 0 to 2, while others 
will range from 0 to 4.  Some items can be scored with 0.5 increments if the examiner feels that 
the patient falls between 2 defined scoring severities.  There are specific instructions for 
performing assessment of each item and scoring instructions on the CRF.   
The mFARS is not a separate assessment, but rather calculated as the full FARS neurological 
assessment minus section D (peripheral nervous system).  The mFARS includes 4 sections: 
bulbar, upper limb coordination, lower limb coordination, and upright stability.   
9.9.28. 
9-Hole Peg Test 
Patients will take the 9-HPT (Appendix 4) at the times indicated in Table 3, Table 4, and 
Table 5.  Instructions are provided in the study manual.   
9.9.29. 
25-Foot Timed Walk Test  
Ambulatory patients will complete the 25-foot timed walk test at the times indicated in Table 3, 
Table 4, and Table 5.  If a patient uses an assistive device for the 25-foot timed walk test on Day 
1, the same assistive device must be used for all 25-foot walk assessments.  Patients will have the 
option to consent to video recording during the 25-foot timed walk test at selected sites.  Video 
recording for the 25-foot timed walk test is optional.  Procedures for video collection will be 
described in a separate study-specific manual.  
9.9.30. 
Video Collection of Patients Walking 25-ft with Their Natural Gait 
Patients who consent to video collection of the 25-foot timed walk test will also have video 
collection during normal walking with a 25-foot (un-timed) walk using his/her normal gait, at the 
times indicated in Table 4.  The normal walk must be performed after the 25-foot timed walk 
test.  Procedures for video collection will be described in a separate study specific manual. 
9.9.31. 
SF-36 Health Survey Update  
Patients will be instructed to answer the 36 questions on the SF-36 survey (Jenkinson, 1999) 
according to how they have felt over the previous week, at the times indicated in Table 3 and 
Table 4.  The SF-36 (Appendix 5) assesses 8 health concepts: (1) limitations in physical 

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activities because of health problems; (2) limitations in social activities because of physical or 
emotional problems; (3) limitations in usual role activities because of physical health problems; 
(4) bodily pain; (5) general mental health (psychological distress and well-being); (6) limitations 
in usual role activities because of emotional problems; (7) vitality (energy and fatigue); and 
(8) general health perceptions.  
9.9.32. 
Activities of Daily Living  
Patients will be instructed to answer the 9 questions on the ADL survey at the times indicated in 
Table 4 and Table 5.  The ADL survey (Appendix 6) assesses 9 concepts: (1) speech; (2) 
swallowing; (3) cutting food and handling utensils; (4) dressing; (5) personal hygiene; (6) 
falling; (7) walking; (8) quality of sitting position; and (9) bladder function.  
9.9.33. 
Patient Global Impression of Change  
The Patient Global Impression of Change is a 7-point scale that requires the patient to assess how 
much the patient's illness has improved or worsened relative to a baseline state at the beginning 
of an intervention (Guy, 1976).  Patients will be instructed to complete the Patient Global 
Impression of Change survey at the times indicated in Table 4.  The patient global impression of 
change is assessed by completing the following statement “since I began trial treatment, my 
overall status is: very much improved (1), much improved (2), minimally improved (3), no 
change (4), minimally worse (5), much worse (6), very much worse (7).”  Patients must complete 
this assessment following completion of the FARS neurological assessment or the clinical global 
impression of change.  
9.9.34. 
Clinical Global Impression of Change  
The Clinical Global Impression of Change is a 7-point scale that requires the clinician to assess 
how much the patient's illness has improved or worsened relative to a baseline state at the 
beginning of an intervention (Guy, 1976).  Clinicians will be instructed to complete the Clinician 
Global Impression of Change survey at the times indicated in Table 4.  The clinician global 
impression of change is assessed by completing the following statement “Compared to the 
patient’s condition at the start of the trial, this patient’s overall status is: very much improved (1), 
much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse 
(6), very much worse (7).” Clinicians may take into account prior results of study assessments to 
influence their clinical judgement of the Clinician Global Impression of Change. Clinicians must 
complete this assessment following the patient’s completion of the FARS neurological 
assessment or the patient global impression of change. 
9.9.35. 
Falls Diary  
Throughout Part 2 of the study, patients will be instructed to record any instances of falls in a 
study diary (Table 4).  A fall is defined as “the patient unintentionally coming to rest on the 
ground or at a lower level.”  Items included on the falls diary may include but are not limited to 
the date and time of each fall, the location of the fall, the preceding activity prior to the fall, the 
perceived cause of the fall, and if an injury was sustained after the fall. Patients will be provided 
the fall diary at Screening and must record fall incidents between Screening and Week 48.  

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10.3. 
Study Drug Storage 
The stability of the drug product is being evaluated in ongoing studies. 
Investigative sites must store the investigational product in a secure location under controlled 
room temperature conditions of 20°C to 25°C (68°F to 77°F), with excursions allowed between 
15°C and 30°C (59°F to 86°F).  Sites must maintain a temperature log of the storage conditions.  
Temperature logs must be available for review at each monitor site visit.  If a temperature within 
the storage location at the site is noted to be outside the excursion range for 24 hours or more or 
exceeds 40°C, the Sponsor must be notified.  
10.4. 
Study Drug Administration 
Please refer to Section 9.9.24 for details on study drug administration.  Patients will receive 
enough capsules for continuous dosing once daily at least until the next study visit.  Clear 
instructions will be provided to the patient regarding study drug administration for each study 
drug administration time point listed in Table 3, Table 4, and Table 5. 
10.5. 
Study Drug Accountability 
The investigator or designee will maintain a record of all study drug received, dispensed, and 
returned to the Sponsor or its designee.  No study drug shall be destroyed by the clinical site 
unless directed to do so by the Sponsor or its designee.  Study drug bottles and any unused 
capsules should be returned by the patient to the study staff. 
10.6. 
Study Drug Handling and Disposal 
At the conclusion of the study, the Sponsor or its designee will direct the site regarding the final 
disposition of any remaining study drug. 

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11.2.2. 
Patient Global Impression of Change 
The proportion of patients who are a treatment success at Weeks 12, 24, 36, and 48, based on the 
Patient Global Impression of Change.  A treatment success is defined as “Much Improved” or 
“Very Much Improved” on the Patient Global Impression of Change. 
11.2.3. 
Clinical Global Impression of Change 
The proportion of patients who are a treatment success at Weeks 12, 24, 36, and 48, based on the 
Clinical Global Impression of Change.  A treatment success is defined as “Much Improved” or 
“Very Much Improved” on the Clinical Global Impression of Change. 
11.2.4. 
Maximal Exercise Test  
The changes in peak work and oxygen utilization during maximal exercise testing from Baseline 
to Weeks 4, 12, 18, 24, 36, and 48 will be analyzed. 
11.2.5. 
9-Hole Peg Test 
The change in performance on the 9-HPT from Baseline at Weeks 24 and 48 will be analyzed. 
11.2.6. 
25-Foot Timed Walk Test 
The change in performance on the 25-foot timed walk test from Baseline at Weeks 24 and 48 
will be analyzed 
11.2.7. 
SF-36 Health Survey Update 
The change in SF-36 patient-reported outcome scores from Baseline at Weeks 24 and 48 will be 
analyzed.   
11.2.8. 
Activities of Daily Living 
The change in ADL from Baseline at Weeks 24, 36, and 48 will be analyzed.   
11.2.9. 
Frequency of Falls 
The frequency of falls from Screening through Week 48 will be analyzed.   
11.2.10. 
Distribution of Change in mFARS Scores  
The proportion of patients at Week 48 with an mFARS change from baseline at or lower than 
specified cutoff values defined in the SAP (e.g., -2, -3, etc) will be analyzed.  

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
Safety parameters in Part 1 and Part 2 include results of echocardiogram, ECG, vital sign 
measurements, weight, BMI, physical examination, AEs, SAEs, concomitant medications, and 
laboratory tests (clinical chemistry, hematology, urinalysis, microscopy, assessment of BNP and 
NT-proBNP, and pregnancy tests [as indicated]).  Safety parameters in the extension study 
include vital sign measurements, physical examination results, AEs, SAEs, weight, and 
laboratory tests (clinical chemistry, hematology, urinalysis, microscopy, assessment of BNP and 
NT-proBNP, and pregnancy tests [as indicated]). 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An 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 is any newly occurring event or previous condition that has increased 
in severity or frequency since the administration of study drug.   
Pre-planned elective procedures (surgeries or therapies) that are performed to manage/treat 
conditions that existed prior to the patient’s enrolling in the trial (e.g., elective periodontal 
surgery, elective hernia repair) should not be recorded as AEs, but should be documented in the 
patient’s source documents.  If a pre-planned procedure is performed early (e.g., as an 
emergency) because the pre-existing condition worsens, the worsening condition should be 
captured as an AE. 
All AEs that are observed or reported by the patient during the study (from the time of the first 
dose of study drug until the final visit or 30 days following final study dose for patients who 
terminate early) must be reported, regardless of their relationship to study drug or their clinical 
significance. 
12.2.1.2. Serious Adverse Event 
An SAE is any AE occurring at any dose and regardless of causality that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect in an offspring of a patient taking study drug 

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• Is an important medical event  
The term "life-threatening" refers to an event in which the patient was at immediate risk of death 
at the time of the event.  It does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Important medical events are those that may not meet any of the criteria defined above; however, 
they may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
other outcomes listed in the SAE definition. 
Pregnancy is not considered an AE; however, information will be collected for any pregnancies 
that occur during the study (from the time of first dose of study drug until the final visit).  Certain 
pregnancy outcomes will require submission as an SAE (Section 9.7.3). 
The investigator is responsible for reporting to the Sponsor or its designee all AEs and SAEs that 
are observed or reported by the patient during the study (from the time of first dose of study drug 
until the final visit), 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.  The Sponsor or its 
designee may contact the investigator to obtain additional information on any SAE that 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 will 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 should be recorded 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, ECG 
abnormalities, or 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 

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from the time of study drug administration and/or follows a known response pattern 
to the study drug but could have been produced by other factors. 
• Probable: This relationship suggests that a reasonable temporal sequence of the event 
with study drug administration exists and, based upon the known pharmacological 
action of the drug, known or previously reported adverse reactions to the drug or class 
of drugs, or judgment based on the investigator’s clinical experience, the association 
of the event with study drug administration seems likely. 
12.5. 
Assessment of Severity 
The investigator will grade the severity of the AEs as mild, moderate, or severe using the 
following definitions: 
• Mild: Symptoms causing no or minimal interference with usual social and functional 
activities 
• Moderate: Symptoms causing greater than minimal interference with usual social and 
functional activities 
• Severe: Symptoms causing inability to perform usual social and functional activities 
12.6. 
Recording Adverse Events 
All conditions present prior to the first dose of study drug should be documented as medical 
history.  All drug-related (characterized as possibly or probably related; 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 or non‒drug-related 
abnormal laboratory results will be followed through the final visit (i.e., end of study or early 
termination).  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 or 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 CRF.  AEs characterized as intermittent require documentation 
of onset and duration. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent 
medications, or progression of disease states must also be reported.  Pre-existing conditions 
(present before the start of the AE collection period) are considered concurrent medical 
conditions and should NOT be recorded as AEs.  However, if the patient experiences a 
worsening or complication of such a concurrent condition, the worsening or complication 
(except disease progression) should be recorded as an AE.  Investigators should ensure that the 
AE term recorded captures the change in the condition (e.g., “worsening of…”). 
Each AE should be recorded to represent a single diagnosis.  Accompanying signs (including 
abnormal laboratory test values or ECG findings) or symptoms should NOT be recorded as 
additional AEs.  If a diagnosis is unknown, sign(s) or symptom(s) should be recorded as an 
AE(s).  Changes in laboratory test values or ECG parameters are only considered to be AEs if 
they are judged to be clinically significant (i.e., if some action or intervention is required or if the 

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provide copies of any reports to regulatory agencies regarding serious and unexpected SAEs to 
the investigators for their information and submission to their IRB, as appropriate.  
Principal investigators are responsible for informing their IRB of any SAEs at their site, as 
appropriate.  The DSMB will review all safety data in an unblinded manner throughout the study 
and make recommendations as appropriate.  SAE correspondence with regulatory authorities or 
IRBs must be submitted to the Sponsor or its designee for recording in the study file. 

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9-HPT scores, low-contrast letter visual acuity test scores, Fatigue Severity Scale scores, and 
SF-36 scores. 
Part 2: Efficacy variables are mFARS scores, full FARS scores, peak work during maximal 
exercise testing, parameters collected during maximal exercise testing (other than peak work), 
9-HPT scores, 25-foot timed walk test distance, ADL, Patient Global Impression of Change, 
Clinical Global Impression of Change, and SF-36 scores. 
14.2.4. 
Safety Variables 
The safety variables in Part 1 and Part 2 include results of echocardiogram, ECGs, weight and 
BMI, vital sign measurements, physical examinations, laboratory test results (clinical chemistry, 
hematology, urinalysis, microscopy, and pregnancy tests [as indicated]), concomitant 
medications, AEs, and SAEs.  Safety parameters in the extension study include vital sign 
measurements, physical examination results, AEs, SAEs, weight, and laboratory tests (clinical 
chemistry, hematology, urinalysis, microscopy, assessment of BNP and NT-proBNP, and 
pregnancy tests [as indicated]). All AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) and analyses of the AE data will be detailed in the SAP. 
14.3. 
Statistical Analyses 
Separate SAPs will be written for each study part.  The SAPs will detail the analyses to be 
performed for each study part and will be developed prior to the database lock of each study part.  
The SAPs, which will describe in detail the methods used for the primary and secondary 
endpoints, will serve as the final arbiter of all statistical analyses.   
Data will be summarized using descriptive statistics.  Continuous data will be summarized with 
number of patients (n), mean, median, minimum, maximum, standard deviation, coefficient of 
variation, and geometric mean (where applicable).  Categorical data will be summarized using 
frequency counts and percentages.   
14.3.1. 
Analysis Sets 
Part 1 and Part 2 will be analyzed separately.  For Part 1 and Part 2, the following analysis sets 
will be defined: 
• The intent-to-treat (ITT) population includes all enrolled patients categorized by their 
assigned treatment group (whether or not they received study drug).   
• The safety population includes all patients who received at least 1 dose of study drug.  
Patients who receive at least 1 dose of RTA 408 will be classified in the RTA 408 
group at the highest dose level received. 
• Additional analysis sets may be defined in the SAP as appropriate. 
Extension: All patients who received at least 1 dose of study drug in the extension will be 
included in the extension safety population.   
14.3.2. 
Primary Efficacy Analysis 
Primary analysis of the efficacy data will be based on the ITT population.  Mixed-model 
repeated measures (MMRM) analysis will be used to analyze the Part 1 and Part 2 primary and 

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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
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 its designee will monitor all aspects of the study for compliance with applicable 
government regulation with respect to the International Council for Harmonisation Harmonised 
Tripartite Guideline for Good Clinical Practice (GCP) E6(R2), abbreviated as ICH E6(R2), and 
current standard operating procedures. 
Each principal 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 study-related 
monitoring and to the internet during the visit. 
15.2. 
Audits and Inspections 
Principal investigators and institutions involved in the study will permit study-related 
monitoring, audits, 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 FDA, or other relevant regulatory authorities, access to all 
study records. 
The principal investigator or designee 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 its designee. 

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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may 
conduct a quality assurance audit.  Please see Section 15.2 for more details regarding the audit 
process. 
16.2. 
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 its designee with updated information, if any 
relevant changes occur during the course of the investigation and for 1 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. 
16.3. 
Sponsor Obligations  
The Sponsor or its 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 its designee is not financially responsible for treatment 
of non–study-related fatalities, physical injuries, or damage to health that may occur during the 
clinical study, as well as the patient’s underlying disease. 
16.4. 
Investigator Documentation 
Before beginning the study, the principal investigator will be asked to comply with ICH E6(R1), 
Section 8.2 and Title 21 of the US Code of Federal Regulations (CFR), abbreviated as US CFR 
Title 21, by providing the essential documents to the Sponsor or its 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 
• Curriculum vitae for the principal investigator and each sub-investigator listed on 
Form FDA 1572.  A curriculum vitae and current licensure, as applicable, must be 
provided.  The curriculum vitae must have been signed and dated by the principal 
investigators and sub-investigators within 2 years before study start-up to indicate the 
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• Completed financial disclosure forms (Section 16.2) to allow the Sponsor or its 
designee to submit complete and accurate certification or disclosure statements 
required under US CFR Title 21, Part 54.  In addition, the investigators must provide 
to the Sponsor or its 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 
16.5. 
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 study-related fatalities, physical injuries, or damage to health that may occur during the 
clinical study. 
16.6. 
Use of Information  
All information regarding RTA 408 supplied by the Sponsor to the investigator is privileged and 
confidential.  The investigator agrees to use this information to accomplish the study and will not 
use it for other purposes without consent from the Sponsor.  Furthermore, the investigator is 
obligated to provide the Sponsor with complete data obtained during the study.  The information 
obtained from the clinical study will be used towards the development of RTA 408 Capsules and 
may be disclosed to regulatory authority(ies), other investigators, corporate partners, or 
consultants, as required. 

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17. 
ETHICS 
17.1. 
Institutional Review Board Review 
The protocol and the proposed informed consent form (ICF) 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 ICF 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 its designee with written documentation of reviews of the clinical research. 
17.2. 
Ethical Conduct of the Study 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH E6(R1), with applicable local regulations (e.g., US CFR Title 21), and with the ethical 
principles of the Declaration of Helsinki.  
The principal investigator agrees to conduct the study in accordance with the International 
Council for Harmonisation (ICH) for Guidance for Industry on GCP ICH E6(R1) 
[http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_
Guideline.pdf] and the principles of the Declaration of Helsinki [https://www.wma.net/policies-
post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-
subjects/.  The principal investigator must conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. 
17.3. 
Written Informed Consent 
Because the study will be conducted under a US Investigational New Drug Application, a signed 
ICF, in compliance with US CFR Title 21, 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 its 
designee to the investigators.  The consent must be reviewed by the Sponsor or its 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 ICF is 
revised during the course of the study, all participants affected by the revision must sign the 
revised IRB-approved consent form in order to continue on the study. 
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 (US FDA, 2014).  Before enrollment, each prospective 
patient will be given a full explanation of the study and be allowed to read the approved ICF.  
Once the principal investigator or designee is assured that the patient understands the 

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implications of participating in the study, the patient will be asked to give consent to participate 
in the study by signing the ICF.  
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 ICF (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. 
17.4. 
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 its designee must be obtained for the disclosure of any 
said confidential information to other parties. 
17.5. 
Modification of the Protocol 
Any changes that 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 principal investigator, and the IRB.  In cases 
where the protocol is modified to enhance patient safety, changes may be implemented and the 
amendment must be immediately submitted to the IRB. 
The principal 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 US CFR Title 21, Part 312, Section 32. 
17.6. 
Protocol Deviations 
The principal investigator or designee must document any protocol deviations.  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 site personnel and reviewed 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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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Retention of Records 
The investigator will maintain all study records according to ICH E6(R1) and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last marketing 
application is approved 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.  
18.2. 
Case Report Forms 
All CRF data will be entered in electronic forms at the investigational site.  The electronic data 
capture system used to capture data electronically for all patients who signed informed consent 
will be US CFR Title 21, Part 11 compliant. 

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19. 
PUBLICATION POLICY 
The Sponsor reserves the right to review all planned communications and manuscripts based on 
the results of this study.  This reservation of the right is not intended to restrict or hinder 
publication or any other dissemination of study results, but to allow the Sponsor to confirm the 
accuracy of the data, to protect proprietary information, and to provide comments based on 
information that may not yet be available to the study investigators.  The Sponsor supports 
communication and publication of study results whatever the findings of the study.  The Sponsor 
also encourages disclosure of any conflict of interest from all authors or investigators when 
manuscripts are submitted for publication.  
Those individuals who have contributed greatly to this study, as determined by the Sponsor, may 
serve on any publications committee for the study. 

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20. 
LIST OF REFERENCES 
Di Prospero NA, Baker A, Jeffries N, et al. Neurological effects of high-dose idebenone in 
patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol 
2007;6:878-886. 
D’Oria V, Petrini S, Travaglini L, et al. Frataxin deficiency leads to reduced expression and 
impaired translocation of NF-E2-Related Factor (Nrf2) in cultured motor neurons. Int J Mol Sci 
2013;14:7853-7865.  
Dürr A. Friedreich’s ataxia: treatment within reach. Lancet Neurol 2002;1:370-374. 
Guy, W. ECDEU Assessment Manual For Psychopharmacology, DHEW Publication No. ADM 
76–338, US Government Printing Office, Washington, DC, USA, 1976. 
Holmström KM, Baird L, Zhang Y, et al. Nrf2 impacts cellular bioenergetics by controlling 
substrate availability for mitochondrial respiration. Biol Open 2013;2;761-770.  
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. 
Jenkinson C, Stewart-Brown S, Petersen S, Paice C. Assessment of the SF-36 version 2 in the 
United Kingdom. J Epidemiol Community Health 1999;53:36-50. 
Klockgether T, Ludtke R, Kramer B, et al. The natural history of degenerative ataxia: a 
retrospective study in 466 patients. Brain 1998;121:589-600.  
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The Fatigue Severity Scale: Application to 
patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121-
1123. 
Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol 1995;49:57-68. 
Ludtmann MHR, Angelova PR, Zhang Y, et al. Nrf2 impacts the efficiency of mitochondrial 
fatty acid oxidation. Biochem J 2014;457:415-424.  
Marmolino D. Friedreich’s ataxia: past, present and future. Brain Res Rev 2011;67:311-330.  
Neymotin A, Calingasan NY, Wille E, et al. Neuroprotective effect of Nrf2/ARE activators, 
CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral 
sclerosis. Free Rad Biol Med 2011;51:88-96.  
Paupe V, Dassa EP, Goncalves S, et al. Impaired nuclear Nrf2 translocation undermines the 
oxidative stress response in Friedreich ataxia. PLoS One 2009;4:4253-4264.  
Saha PK, Reddy VT, Konopleva M, et al. The triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-
28-oic-acid methyl ester has potent anti-diabetic effects in diet-induced diabetic mice and 
Lepr(db/db) mice. J Biol Chem 2010;285:40581-40592.  
Shin S, Wakabayashi J, Yates MS, Wakabayashi N, et al. Role of Nrf2 in prevention of high-fat 
diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmcol 2009; 
620:138-144. 

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Uruno A, Furusawa Y, Yagishita Y, et al. The Keap1-Nrf2 system prevents onset of diabetes 
mellitus. Mol Cell Biol 2013;33:2996-3010.  
United States Food and Drug Administration [Web site]. Screening Tests Prior to Study 
Enrollment - Information Sheet. Guidance for Institutional Review Boards and Clinical 
Investigators. Available at: 
http://www.fda.gov/RegulatoryInformation/Guidances/ucm126430.htm. Accessed July 21, 2014. 

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21. 
APPENDICES 

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APPENDIX 1. EXTENSION ELIGIBILITY CRITERIA 
Extension Inclusion Criteria 
Patients must: 
1. Have adequate kidney function defined as an estimated glomerular filtration rate (eGFR) 
≥ 60 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) 
4-variable formula  
2. Have a left ventricular ejection fraction ≥ 40% (based on echocardiogram performed at 
Screening Visit or within 90 days prior to Screening Visit) 
3. Be able to swallow capsules 
4. Be willing and able to cooperate with all aspects of the extension 
5. Be willing to practice medically acceptable methods of birth control (Section 9.7.2)  
6. Provide written informed consent for study participation, approved by the appropriate 
Institutional Review Board (IRB) 
7. Have been enrolled in Part 1 or Part 2 and completed assessments through the follow-up 
visit with no major protocol deviations that would, in the opinion of the investigator, 
deem the patient unsuitable for enrollment in the Extension phase of the study. 
Extension Exclusion Criteria 
Patients must not: 
1. Have uncontrolled diabetes (HbA1c > 11.0%) 
2. Have B-type natriuretic peptide (BNP) level > 200 pg/mL 
3. Have a history of clinically significant left-sided heart disease and/or clinically 
significant cardiac disease, with the exception of mild to moderate cardiomyopathy 
associated with Friedreich’s ataxia, including but not limited to any of the following: 
a. Clinically significant congenital or acquired valvular disease 
b. Pericardial constriction (based on echocardiogram performed at Screening Visit 
or within 90 days prior to Screening Visit) 
c. Restrictive or congestive cardiomyopathy (based on echocardiogram performed at 
Screening Visit or within 90 days prior to Screening Visit) 
d. Symptomatic coronary disease (prior myocardial infarction, percutaneous 
coronary intervention, coronary artery bypass graft surgery, or angina) 
e. History of hospitalization for heart failure in the last five years 
f. Cardiac insufficiency, defined as New York Heart Association Class > 2 
g. History of atrial fibrillation 
h. History of unstable arrhythmias 

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4. Have known active fungal, bacterial, and/or viral infection, including human 
immunodeficiency virus (HIV) or hepatitis virus (B or C)  
5. Have known or suspected active drug or alcohol abuse, as per investigator judgment 
6. Have clinically significant abnormalities of clinical hematology or biochemistry, 
including but not limited to elevations greater than 1.5 times the upper limit of normal of 
AST or ALT.  Levels above this threshold are allowable if attributable to muscle injury 
7. Have any abnormal laboratory test value or clinically significant pre-existing medical 
condition that, in the opinion of the investigator, would put the patient at risk by study 
enrollment 
8. Have taken any of the following drugs within 7 days prior to Extension Day 1 or plan to 
take any of these drugs during the time of study participation: 
a. Sensitive substrates for cytochrome P450 2C8 or 3A4 (e.g., repaglinide, 
midazolam, sildenafil) 
b. Moderate or strong inhibitors or inducers of cytochrome P450 3A4 
(e.g., carbamazepine, phenytoin, ciprofloxacin, grapefruit juice) 
c. Substrates for p-glycoprotein transporter (e.g., ambrisentan, digoxin) 
9. Have a history of clinically significant liver disease (e.g., fibrosis, cirrhosis, hepatitis), or 
has, at screening, clinically relevant deviations in laboratory tests including any one of 
the following: 
a. alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
> 1.5-fold ULN, 
b. bilirubin > 1.2-fold ULN, 
c. alkaline phosphatase (ALP) > 2-fold ULN, 
d. albumin < lower limit of normal (LLN) 
10. Have participated in any other interventional clinical study within 30 days prior to 
Extension Day 1 
11. Have a cognitive impairment that may preclude ability to comply with study procedures 
12. Be unable to comply with the requirements of the study protocol or be unsuitable for the 
study for any reason, in the opinion of the investigator  
13. Have a history of thromboembolic events within the past 5 years 
14. Have taken anticoagulant therapy within 30 days prior to Extension Day 1  
15. Have had significant current suicidal ideation within 1 month prior to Extension Day 1 as 
per investigator judgment or any history of suicide attempts 
16. Be pregnant or breastfeeding 
17. Have an ongoing SAE from a clinical study that is assessed by the investigator as related 
to RTA 408 
18. Have discontinued treatment early in Part 1 or Part 2. 

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APPENDIX 2. MAXIMAL EXERCISE TEST 
 
 

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APPENDIX 3. FARS ASSESSMENT 
 
 

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APPENDIX 4. 9-HOLE PEG TEST 
The 9-HPT is a quantitative measure of upper extremity (arm and hand) function.  Both the 
dominant and non-dominant hands are tested twice (2 consecutive trials of the dominant hand, 
followed immediately by 2 consecutive trials of the non-dominant hand).  It is important that the 
9-HPT be administered on a solid table (not a rolling hospital bedside table) and that the 9-HPT 
apparatus be anchored (e.g., with Dycem).  Instructions on completing the 9-HPT are provided in 
the study manual. 
 

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APPENDIX 5. SF-36 HEALTH SURVEY UPDATE 
This survey asks for your views about your health.  This information will help keep track of how 
you feel and how well you are able to do your usual activities. Thank you for completing this 
survey! 
For each of the following questions, please mark an 
 in the one box that best describes your 
answer. 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 


 


  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
2. Compared to one year ago, how would you rate your health in general 
now? 
Much better 
now than one 
year ago 
Somewhat 
better  
now than one 
year ago 
About the 
same as  
one year ago 
Somewhat 
worse  
now than one 
year ago 
Much worse 
now than one 
year ago 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 

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3. The following questions are about activities you might do during a typical 
day.  Does your health now limit you in these activities?  If so, how much?  
 
Yes,  
limited  
a lot 
Yes, 
limited  
a little 
No, not 
limited  
at all 
 
 
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports .................. 
 1 .............
 2 ............. 
 3 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf......................... 
 1 .............  2 ............. 
 3 
c Lifting or carrying groceries ................................................ 
 1 .............  2 ............. 
 3 
d Climbing several flights of stairs ......................................... 
 1 .............  2 ............. 
 3 
e Climbing one flight of stairs ................................................ 
 1 .............  2 ............. 
 3 
f Bending, kneeling, or stooping ............................................ 
 1 .............  2 ............. 
 3 
g Walking more than a mile .................................................... 
 1 .............  2 ............. 
 3 
h Walking several hundred yards ........................................... 
 1 .............  2 ............. 
 3 
i Walking one hundred yards ................................................. 
 1 .............  2 ............. 
 3 
j Bathing or dressing yourself ................................................ 
 1 .............  2 ............. 
 3 

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4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of 
the time 
None of  
the time 


a Cut down on the amount of  
time you spent on work or  
other activities ............................... 
 1 ............ 
 2 ............. 
 3.............. 
 4 ............ 
 5 
b Accomplished less than you  
would like ..................................... 
 1 ............ 
 2 ............. 
 3.............. 
 4 ............ 
 5 
c Were limited in the kind of  
work or other activities ................. 
 1 ............ 
 2 ............. 
 3.............. 
 4 ............ 
 5 
d Had difficulty performing the  
work or other activities (for  
example, it took extra effort) ........ 
 1 ............ 
 2 ............. 
 3.............. 
 4 ............ 
 5 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of 
the time 
None of  
the time 


a Cut down on the amount of  
time you spent on work or  
other activities ............................... 
 1 ............ 
 2 ............. 
 3.............. 
 4 ............ 
 5 
b Accomplished less than you  
would like ..................................... 
 1 ............ 
 2 ............. 
 3.............. 
 4 ............ 
 5 
c Did work or other activities  
less carefully than usual ................ 
 1 ............ 
 2 ............. 
 3.............. 
 4 ............ 
 5 

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6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 






  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
  
 6 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 

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9. These questions are about how you feel and how things have been with 
you during the past 4 weeks.  For each question, please give the one 
answer that comes closest to the way you have been feeling.  How much of 
the time during the past 4 weeks… 
10. During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of  
the time 





  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of the 
time 
None of  
the time 

a Did you feel full of life? ............... 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
b Have you been very nervous? ....... 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? ................................ 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
d Have you felt calm and   
peaceful? ....................................... 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
e Did you have a lot of energy? ....... 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
f Have you felt downhearted  
and depressed? .............................. 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
g Did you feel worn out? ................. 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
h Have you been happy? .................. 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 
i Did you feel tired? ........................ 
 1 ............. 
 2 ............ 
 3 ............. 
 4 .............
 5 

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11.  How TRUE or FALSE is each of the following statements for you? 
Definitely 
true 
Mostly  
true 
Don’t  
know 
Mostly  
false 
Definitely 
false 


a I seem to get sick a little 
easier than other people ................ 
 1 ............. 
 2 ............ 
 3 ............. 
 4 ............. 
 5 
b I am as healthy as  
anybody I know ............................ 
 1 ............. 
 2 ............ 
 3 ............. 
 4 ............. 
 5 
c I expect my health to  
get worse ....................................... 
 1 ............. 
 2 ............ 
 3 ............. 
 4 ............. 
 5 
d My health is excellent ................... 
 1 ............. 
 2 ............ 
 3 ............. 
 4 ............. 
 5 
Thank you for completing these questions! 

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APPENDIX 6. ACTIVITIES OF DAILY LIVING 
 
 
 
 
 
 

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APPENDIX 7. PATIENT GLOBAL IMPRESSION OF CHANGE 
The Patient Global Impression of Change is a 7-point scale that requires patients to assess how 
much their illness has improved or worsened relative to their baseline state at the beginning of 
the trial.  Patients will self-rate their perceived change by completing the following statement: 
“Since I began trial treatment, my overall status is:” 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
 

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APPENDIX 8. CLINICAL GLOBAL IMPRESSION OF CHANGE 
The Clinical Global Impression of Change is a 7-point scale that requires the clinician to assess 
how much the patient's illness has improved or worsened relative to a baseline state at the 
beginning of an intervention (Guy, 1976).  The Clinician Global Impression of Change is 
assessed by completing the following statement “Compared to the patient’s condition at the start 
of the trial, this patient’s overall status is…” 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse  
 

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APPENDIX 9. LOW-CONTRAST LETTER VISUAL ACUITY TEST 
(PART 1 ONLY) 
Due to the frequency of visual deficits in Friedreich’s ataxia, assessment of visual function plays 
an important role in clinical trials and clinical practice. Vision testing is done using a portable 
retro-illuminated vision board.  A pre-measured yellow vision string (full length is 3.2 meters, 
red mark denotes 2 meters) is used to measure the distance from the patient’s forehead to the 
vision board.  A pointer is also used to orient the patient to the specific line they are being asked 
to read.  
Additional details regarding administration of the low-contrast visual acuity test will be provided 
in a study specific manual. 
 

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APPENDIX 10. FATIGUE SEVERITY SCALE (PART 1 ONLY) 
 
 
 

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APPENDIX 13. COVID-19 MITIGATIONS 
This appendix outlines the mitigation strategies adopted to protect the health of participants in 
Study 408-C-1402, while maintaining compliance with good clinical practice (GCP) and 
minimizing the risk to trial integrity during the COVID-19 (Coronavirus Disease 2019) 
pandemic. At the time of the pandemic, Parts 1 and 2 of Study 408-C-1402 were already 
completed, therefore, this appendix applies to the Extension phase of the study. 
The mitigations specified below will be in place as long as COVID-19 related local government 
restrictions impact trial conduct, according to protocol specifications. 
1. 
SITE OPERATIONS & PATIENT MANAGEMENT 
If study sites are closed or restrict access to study teams during the COVID-19 pandemic, study 
teams must maintain open lines of communication with active study participants. Additionally, 
the Sponsor is to be regularly updated on changes to sites’ status regarding closures, access 
limitations, contact information or other important information. Sites are encouraged to provide 
alternate contact information to their patients and the Sponsor. Updates are to be sent to the 
Sponsor study team
. 
2. 
COVID-19 TESTING AND INVESTIGATIONAL PRODUCT USE 
If a patient enrolled in the Extension phase of Study 408-C-1402 tests positive for severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, the 
investigational product (IP) RTA-408 (omaveloxolone) must be temporarily discontinued until 
the patient no longer presents an active infection, as assessed by the Investigator and/or the 
patient’s physician(s). The Sponsor must be notified immediately for additional guidance. 
2.1. 
Resumption of Investigational Product after Recovery from COVID-19 Infection 
When the investigator deems that the patient can safely return to the site for an in-person visit, 
the investigator should conduct an unscheduled visit and perform all assessments as in Week 4. 
If there are no changes in clinical status that would preclude resuming IP, IP may be resumed. A 
follow-up telephone visit should be conducted 2 weeks after this unscheduled visit to collect 
adverse events and prior and concomitant medications. Four weeks after the unscheduled visit, 
the patient should return for repeat assessments as in the Week 4 visit.  The usual visit schedule 
may resume thereafter. 
3. 
INVESTIGATIONAL PRODUCT (IP) ACCESS 
In order to maintain dosing continuity during the COVID-19 pandemic, IP may be directly 
shipped to the patient, using couriered tracking services, in cases where the patient becomes 
unable to travel to his/her study site.  Stability information for IP shipments are contained in the 
“Guidance for Direct-to-Patient Shipping of RTA-408 Drug Product Capsules during the 
Coronavirus (COVID-19) Pandemic” (Attachment 1). All shipments must be sent via overnight 
express shipping (where possible) and include a temperature monitoring device. Sites will be 
supplied with temperature monitors upon request.  For shipments that show temperature 
excursions below 20C or above 25C during transit, the Sponsor should be notified immediately 
via the COVID-19 Investigational Product Temperature Excursion form. The Sponsor will assess 
whether the product is deemed fit for use. During the assessment period, the patient should be 
informed to not take the IP until further notice from the site. IP dispensation should be recorded 

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in the appropriate drug accountability logs and all IP receipts of delivery should be filed in the 
Investigative Site File. If a patient is located in a country different from that of the site, the site 
will also provide information for customs on the shipped package.    
4. 
STUDY VISIT 
Where in-person clinic visits are not possible, in-home visits and/or telemedicine visits (e.g. 
phone or video) may be conducted to complete study assessments not limited to:  
• Adverse event assessment. 
• Prior and concomitant medication assessment. 
• Pregnancy testing for women of childbearing potential (WOCBP): patients must 
complete scheduled urine pregnancy tests at home. Pregnancy test(s) should be 
provided to patients where relevant. The site should obtain verbal confirmation from 
the patients that the test is negative prior to instructing the patients to start the shipped 
RTA-408 IP. Additionally, the site will specifically remind patients of the need to 
adhere to appropriate protocol required contraceptive measures where necessary. 
• Vital signs. 
• Safety labs:  Every effort should be made to collect laboratory data using the central 
lab.  Where use of the central lab is not possible, laboratory assessments should be 
collected through a local lab and reviewed by the investigator. 
4.1. 
United Kingdom Site 
Per regulatory authority requirements, every effort should be made to obtain safety laboratory 
assessments every 24 weeks (Table 5) using either the central laboratory, local laboratories, or 
home health services (if available). In cases when laboratory assessments cannot be performed as 
a result of COVID-19 related restrictions, alternative proportionate mechanisms of oversight 
should be followed to ensure patient safety and well-being. 
Specifically, alternative mechanisms of oversight to liver function and BNP tests were employed 
based on benefit/risk assessment in the context of the guidance for Investigators provided in the 
Investigator Brochure version 6.1, sections 6.2.1 – Transaminases and GGT Elevations, 6.6.2 – 
Transient Elevation of Serum Transaminases, and 6.6.1 – Fluid Overload. 
For the six-monthly visits, the following alternative proportionate oversight approach should be 
followed: 
• Telephone Questionnaire 
Hepatic questions 
− Have you noticed any yellowing of your skin or eyes? 
− Have you noticed any usual swelling of your abdomen or feet? 
− Are you bruising very easily or had any cuts that kept bleeding? 
− Has your skin become itchy? 
− Have you had any changes in the color of your urine or stool? 

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− Have you had any pain in the right upper quadrant of your abdomen? 
− Have you felt particularly nauseous? 
Fluid overload/Cardiac questions 
− Have you had any pain in your chest? 
− Have you become more short of breath? 
− Can you lie flat in bed without getting short of breath? 
− Have you noticed your heart racing or going into a funny rhythm? 
− Have you felt like you are going to faint? Or fainted? 
• Additional hepatic recommendations 
− Continue site education regarding concomitant medication, particularly 
medications and/or supplements that are associated with hepatic injury including 
paracetamol. 
− Include urine bilirubin (if possible) with home urine dipstick. 
• Home weight for fluid overload/cardiac assessments 
− Weight gain will be used to monitor fluid status. 
− Last home weight is used as baseline. 
− Patient(s) who experience a five-pound (2.3 kilograms) or greater increase in 
weight compared to the last home weight will be instructed to contact the site to 
assess the need to hold RTA-408 IP by the Investigator. IP should be discontinued 
if clinically important fluid retention is suspected. 
Importantly, the alternative proportionate oversight measures outlined above can only be used 
for a certain period before safety laboratory assessments must be collected to conclusively 
measure relevant safety parameters. The maximum medically accepted delay in performing 
laboratory assessments (either local or on study) is 12 weeks post a six-monthly visit, assuming 
alternative proportionate oversight is ongoing and no concerns arise from this oversight. 
If safety laboratory assessments cannot be completed within the maximum medically accepted 
delay, study drug must be temporarily discontinued until safety laboratory assessments can be 
obtained and it is deemed appropriate to restart IP dosing.  
 

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ATTACHMENT 1 
 
 
 

Signature Page for Study 408-C-1402 - Protocol Version 11.0
VV-CLIN-006039 (v1.0)
Signature Page for Study 408-C-1402 - Protocol Version 11.0
VV-CLIN-006039 (v1.0)
Approval
14-Jul-2021 15:58:16 GMT+0000
Approval
14-Jul-2021 16:04:48 GMT+0000
Approval
14-Jul-2021 16:30:27 GMT+0000
Approval
am Operations
14-Jul-2021 18:35:49 GMT+0000
Approval
airs
15-Jul-2021 15:43:17 GMT+0000
Approval
ment
15-Jul-2021 19:19:57 GMT+0000