A Randomized, Parallel-Arm, Double-Blind, Placebo-Controlled Study With Open-Label Extension to Assess the Efficacy and Safety of Vatiquinone for the Treatment of Friedreich Ataxia (MOVE-FA)
Phase: PHASE2
Conditions: Friedreich Ataxia
Sponsor: PTC Therapeutics

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CLINICAL PROTOCOL 
A RANDOMIZED, PARALLEL-ARM, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY WITH OPEN-LABEL EXTENSION 
TO ASSESS THE EFFICACY AND SAFETY OF VATIQUINONE FOR 
THE TREATMENT OF FRIEDREICH ATAXIA (MOVE-FA) 
PTC743-NEU-003-FA 
21 MAY 2021 
VERSION 5.0 
PTC THERAPEUTICS, INC. 
100 CORPORATE COURT 
SOUTH PLAINFIELD, NJ 07080 USA 
Notice of Proprietary Information: This document contains confidential information owned by or in the 
possession/control of PTC Therapeutics, Inc. Except as may otherwise be permitted in writing, by accepting or 
reviewing these materials, you agree that this information should not be disclosed to others (except where required by 
applicable law) and should not be used for unauthorized purposes. In the event of an actual or suspected breach of this 
obligation, PTC Therapeutics, Inc. should be notified promptly.
NCT #:  NCT04577352

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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC743-NEU 
International Nonproprietary Name 
Vatiquinone 
Therapeutic Area 
Friedreich Ataxia 
PTC Therapeutics Substance Identifier 
PTC743/Vatiquinone 
IND Number 
119220 
EudraCT Number 
2020-002812-36 
Protocol Number 
PTC743-NEU-003-FA 
Protocol Version 
5.0 
Protocol Version Date 
21 May 2021 
Protocol Phase 
2b/3 
Protocol Title 
A Randomized, Parallel-Arm, Double-Blind, Placebo-
Controlled Study with Open-Label Extension to Assess 
the Efficacy and Safety of Vatiquinone for the 
Treatment of Friedreich Ataxia (MOVE-FA) 
PTC Clinical Lead 
 
PTC Medical Monitor 
 
PTC Biostatistician 
 
PTC Study Manager 
 
 
 
 

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PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
PTC Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The eSignature page is located on the last page. 

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PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE 
 
I have read the protocol document and, on behalf of my institution, agree to comply with the protocol 
and all applicable regulations. 
 
 
 
 
Principal Investigator 
 
Date 
 
 
 
Institution: 
 
Address: 
 
City: 
 
State/Province: 
 
Country: 
 
Phone: 
 
Fax: 
 
E-mail: 
 
 
 
 
 

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SYNOPSIS 
Study Number 
PTC743-NEU-003-FA 
Name of Investigational 
Product 
Vatiquinone (PTC743) 
Title of Study 
A Randomized, Parallel-Arm, Double-Blind, Placebo-Controlled 
Study with Open-Label Extension to Assess the Efficacy and 
Safety of Vatiquinone for the Treatment of Friedreich Ataxia 
(MOVE-FA) 
Proposed Indication 
For the treatment of Friedreich ataxia 
Number of Study Sites 
Approximately ten sites globally 
Trial Phase 
Phase 2b/3 
Study Objectives 
Primary 
The primary objective of the study is to evaluate the efficacy (using 
the modified Friedreich Ataxia Rating Scale [mFARS]) and safety 
of vatiquinone in subjects with Friedreich ataxia (FA).  
Secondary 
• Demonstrate the effects of vatiquinone on activities of daily 
living as assessed by the FA Rating Scale Activities of Daily 
Living (FARS-ADL) scale 
• Demonstrate the effects of vatiquinone on ambulation as 
assessed by the 1-minute walk test (1MWT) 
• Demonstrate the effects of vatiquinone on falls as assessed by 
a fall log 
Exploratory 
• Demonstrate the effects of vatiquinone on speech using 
Redenlab protocol 
• Demonstrate the effects of vatiquinone on fatigue as assessed 
by the Modified Fatigue Impact Scale (MFIS) 
• Demonstrate the effects of vatiquinone on health status using 
the EQ-5D-5L 
• Demonstrate the effects of vatiquinone on the Upright 
Stability subscale of the mFARS 

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Study Endpoints 
Primary 
Change from baseline in the mFARS at Week 72 
Secondary 
Secondary endpoints will include change from baseline in the 
following assessments at Week 72: 
• FARS-ADL scale (key secondary endpoint) 
• 1MWT 
• Fall log 
Exploratory 
Exploratory endpoints will include change from baseline in the 
following assessments at Week 72: 
• Speech using Redenlab protocol 
• MFIS 
• EQ-5D-5L 
• Upright Stability subscale of the mFARS 
Study Population 
Subjects with FA aged 7 years and older 
Sample Size 
Based on the Phase 2 Study EPI-2010-006 data, vatiquinone 
demonstrated a change from baseline in mFARS score for 400 mg 
dose of -1.31 after 18 months of treatment, and natural history 
showed an estimated increase of 3.26 after 18 month of disease 
progression (Patel 2016). Assuming a common standard deviation 
of 6.76, with 1-sided type I error of 2.5% and 90% power, 
47 subjects per group are required to detect a treatment difference 
of -4.57 in mFARS score. Assuming a dropout rate of 10%, a total 
of 106 subjects between 7 and 21 years of age will be randomized. 
The primary efficacy analysis will be based on change from 
baseline in mFARS score of subjects between 7 and 21 years old. 
In order to explore the treatment efficacy and safety, approximately 
an additional 20 subjects >21 years of age will be randomized for a 
total of approximately 126 subjects.  

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Methodology/  
Study Design 
This study will be a stratified, randomized, parallel-arm, 
double-blind, placebo-controlled trial. Stratification factors include 
baseline mFARS score (<40 versus ≥40), age of disease onset 
(<14 years versus ≥14 years old), and age at screening (≤21 versus 
>21 years old). Subjects will be randomized 1:1 to receive either 
vatiquinone or placebo using interactive response technology 
(IRT). Following completion of the randomized, double-blind, 
placebo-controlled phase (72 weeks), subjects will enter into an 
open-label (24 weeks) extension phase during which they will 
receive open-label treatment with vatiquinone. For subjects 
entering the extension phase who initially received vatiquinone, 
they will continue to receive the same dose of vatiquinone (unless 
there has been a change in weight of ±5 kg from the 25 kg dosing 
determination threshold or the subject’s age changes from 11 to 
12 years). For subjects entering the extension phase who initially 
received placebo, the dose of vatiquinone will be determined based 
on age and weight as described in the Study Treatment description 
below. The maximum duration of subject treatment will be 
96 weeks (including the placebo-controlled phase and the extension 
phase). The overall study duration will be a maximum of 
approximately 106 weeks per subject. Subjects who complete the 
study may have the option to enter an open-label expanded access 
program to continue receiving vatiquinone. 

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Inclusion Criteria 
1. mFARS ≥20 to ≤70 at baseline 
2. Minimum age 7 years at the time of Screening Visit 
3. Must be able to ambulate at least 10 feet in one minute with 
or without assistance (non-wheelchair) 
4. Friedreich ataxia diagnosis (homozygous for 
guanine-adenine-adenine [GAA] repeat expansion in intron-1 
of frataxin gene), confirmed by clinical genetic testing 
(Note: size of GAA repeat is not required for eligibility) 
5. Consent to comply with study procedures. For subjects under 
the age of 18 (or age of consent), parent(s)/legal guardian(s) 
of the subject must agree to comply with the requirements of 
the study, including the need for frequent and prolonged 
follow-up; parent(s)/legal guardian(s) with custody of the 
subject must give their consent for subject to enroll in the 
study. 
6. Difference in the mFARS between Screening and Baseline of 
no more than 4 points 
7. Must be able to abstain from anticoagulants and any aspirin 
(including 81 mg) for 30 days prior to the Baseline Visit and 
for the duration of the study; any possible discontinuation of 
anticoagulants should be monitored and indicated by a 
specialist (eg, cardiologist, neurologist, or hematologist), and 
discontinuation will be noted by the prescribing physician 
(see Appendix 1). 
8. Must be able to abstain from potent cytochrome P450 (CYP) 
3A4 inducers/inhibitors (eg, ketoconazole, rifampin, 
St. John’s wort, grapefruit juice or any grapefruit product) for 
at least 30 days prior to enrollment (see Appendix 1) 
9. Must be able to swallow capsules 
10. Males and females of childbearing potential must be willing 
to use an effective method of contraception (eg, implants, 
injectables, transdermal patch, combined oral contraceptives, 
barrier methods, and intrauterine devices) from the time 
consent is signed until 30 days after last dose of study drug or 
early termination visit. Male subjects must agree not to donate 
sperm during the study and for at least 30 days after the last 
dose of study drug or early termination visit. Note: 
Double-barrier method (ie, condom with spermicide) is 
required if no other methods of contraception are in use.  

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Exclusion Criteria 
1. Individuals with clinical diagnosis of FA who have point 
mutations, deletions, or other non-GAA expansion mutations 
2. Previous treatment with vatiquinone  
3. Allergy to vatiquinone, sesame oil, gelatin (bovine and/or 
porcine), titanium dioxide, or red iron oxide 
4. Ejection fraction <50% 
5. Uncontrolled diabetes (HbA1c >7.0%) at the time of 
screening 
6. Has current suicidal ideation based on Columbia-Suicide 
Severity Rating Scale (C-SSRS) within 3 months prior to 
screening or between screening and baseline at the Baseline 
Visit or suicidal behavior within the last year at the Screening 
Visit or between screening and baseline at the Baseline Visit. 
7. Pregnant or lactating subjects or those sexually active subjects 
who are unwilling to comply with proper birth control 
methods; females of childbearing potential must have a 
negative pregnancy test at Screening and during the Baseline 
Visit 
8. Aspartate aminotransferase or alanine aminotransferase 
≥2×upper limit of normal (ULN) at time of screening 
9. International normalized ratio ≥1.5×ULN at time of screening 
or clinically significant bleeding, as determined by the 
investigator 
10. Serum creatinine ≥1.5×ULN at time of screening 
11. Comorbidities that may confound study results (eg, fat 
malabsorption syndrome, other mitochondrial disorder) in the 
opinion of the investigator 
12. Participation in any other interventional clinical trial or 
received any investigational drug in any other clinical trial 
within 60 days prior to the Baseline Visit. Subjects may be 
rescreened after the exclusionary period of 60 days has 
passed. 
13. Concomitant use of interventional CoQ10, vitamin E, or any 
approved or non-approved medication for FA within 30 days 
prior to the Screening Visit (see Appendix 1). These 
prohibited medications can be discontinued at the Screening 
Visit; if this is the case, the mFARS assessment must be 
repeated to confirm inclusion eligibility after a minimum of 
30 days post discontinuation, and there must be no more than 
a 4-point difference in mFARS assessed from the Post-
Discontinuation Visit to the Baseline Visit. 
14. Illicit drug use 30 days prior to screening and during the study 
is prohibited. 

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Study Treatment 
Subjects meeting eligibility criteria will be randomized 1:1 to 
receive either vatiquinone or matching placebo during the 
placebo-controlled phase of the study. 
• Subjects will receive vatiquinone at a dose of 200 or 400 mg 
three times daily (tid). If randomized to vatiquinone, subjects 
will receive a dose of either 200 mg orally (PO) tid if 
˂12 years of age and weighing ˂25 kg or 400 mg PO tid if 
≥12 years of age and/or ≥25 kg. If randomized to placebo, 
subjects will receive placebo PO tid. Drug dosing will occur 
according to the schedule described under the 
placebo-controlled and long-term phases. Food with at least 
25% fat (eg, yogurt, ice cream) is required for appropriate 
absorption of vatiquinone from the gastrointestinal tract.  
Study Drug Description:  
• Vatiquinone is manufactured as a 200 mg capsule (size 1 
Swedish orange) unit dose for oral administration and is 
packaged in 97 count white high-density polyethylene 
(HDPE) bottles with a child resistant closure. Each bottle of 
97 vatiquinone 200 mg capsules is enough for approximately 
one month when dosing 200 mg tid or approximately two 
weeks when dosing 400 mg tid. For this study, placebo will 
consist of a size 1 Swedish orange capsule containing sesame 
oil National Formulary (NF) and a colorant to match the 
appearance of both the capsule exterior and the contents of the 
vatiquinone 200 mg capsule. Blister packs may be approved 
for use in the open-label extension phase of the study.  
Treatment Duration 
Study duration will be approximately 106 weeks; 6 weeks at 
Screening; 72 weeks of double-blind, placebo-controlled treatment; 
24 weeks of open-label extension treatment; and approximately 
4 weeks posttreatment follow-up.  
Safety Monitoring 
Safety will be evaluated by physical examinations, vital signs 
assessments, echocardiograms, 12-lead electrocardiograms, routine 
clinical laboratory tests (including blood chemistry, hematology, 
and coagulation), and adverse event (AE) assessments from 
baseline through study completion. Suicide risk assessment will be 
performed throughout the study using the C-SSRS. 
Serious Adverse Event 
Reporting 
All serious adverse events (SAEs) should be reported via the SAE 
report form to PTC Therapeutics within 24 hours of becoming 
aware of the event(s). 
Pharmacokinetic 
Sampling 
Pharmacokinetic (PK) sampling will take place during each clinic 
visit from Baseline through the placebo-controlled phase just prior 
to the morning dose and >1 hour after the morning dose. 
PK sampling will take place just prior to the morning dose during 
all clinic visits in the open-label extension phase. 

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Statistical Methods 
The primary efficacy variable is change from baseline to Week 72 in 
mFARS neurological exam score. Baseline of mFARS is defined as 
the mFARS score recorded before subject has received randomized 
study medication.  
The primary estimand is the treatment difference between 
vatiquinone and placebo in change from baseline to Week 72 in 
mFARS score attributable to the initially randomized treatment for 
randomized subjects who received at least 1 dose of study 
medication and between 7 and 21 years of age at screening. Missing 
mFARS score will be imputed as described below to form a 
complete set for analysis.  
Intermittent missing mFARS scores will be imputed using Monte 
Carlo Markov Chain (MCMC) method with adjustment for 
covariates (for example, but not limited to, treatment group, age, 
region, gender) to produce 5 monotone missing pattern datasets first. 
Missing data after dropout will be imputed assuming missing not at 
random using pattern mixture complete case missing value pattern. 
Approximately 1000 complete data sets will be produced. The 
change from baseline at each visit will be calculated using the 
completed data sets for analysis. The primary efficacy analysis will 
be performed for subjects between 7 and 21 years of age at 
screening, and will compare change from baseline in mFARS 
neurological score to Week 72 between vatiquinone- and 
placebo-treated subjects using mixed model repeated measure 
(MMRM) stratified by baseline mFARS score (<40 and ≥40) and 
age of disease onset (<14 and ≥14 years), with treatment and region 
as the main effects and baseline mFARS and age as covariates using 
an unstructured variance-covariance matrix structure. If the model 
fails to converge, other variance-covariance structure will be 
explored. The test will be performed using one-sided type I error of 
2.5%. The results of MMRM analysis from each complete imputed 
dataset will be combined using Rubin’s rule (Little 2002). Detail of 
the imputation will be specified in the Statistical Analysis Plan 
(SAP). Analysis in mFARS change from baseline to Week 72 in all 
subjects will be considered secondary analysis and will be described 
in the SAP.  

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Timing of Assessments After subjects complete the baseline procedures on Day 1 and are 
eligible to be randomized, site staff will utilize an IRT to randomize 
each subject. Randomization will be 1:1 vatiquinone to placebo. 
During the Baseline Visit, subjects will be randomized to receive 
vatiquinone or matching placebo administered tid for 72 weeks 
(ie, the placebo-controlled phase). During the placebo-controlled 
phase, clinic visits will occur at Weeks 12, 24, 36, 48, 60, and 72 
(±1 week), and study site staff will perform telephone assessments 
for AEs/SAEs and concomitant medications on Weeks 4, 8, 16, 20, 
28, 32, 40, 44, 52, 56, 64, and 68. Following the 72-week 
placebo-controlled phase, subjects will enter into a 24-week 
open-label treatment phase with vatiquinone 200 mg or 400 mg tid. 
For subjects randomized to vatiquinone in the double-blind portion 
of the study, they will continue to receive the same dose of 
vatiquinone (unless there has been a change in weight of ±5 kg from 
the 25 kg dosing determination threshold or a change in age from 
11 to 12 years). For subjects entering the open-label extension phase 
who initially received placebo, the dose of vatiquinone will be 
determined based on age and weight as outlined in the 
Study Treatment section above. In the open-label extension phase, 
in-person visits will occur every 12 weeks (±2 weeks) and there will 
be every 6 week (±2 weeks) telephone contact with the subject in 
between the in-person visits as measured from Baseline Visit date. 

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TABLE OF CONTENTS 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ...........................................................2 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES..............................................3 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE............................................4 
SYNOPSIS  ......................................................................................................................................5 
TABLE OF CONTENTS ...............................................................................................................13 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................20 
1.1. 
Study Rationale ...........................................................................................................20 
1.2. 
Name and Description of Investigational Product ......................................................21 
1.3. 
Vatiquinone Mechanism of Action .............................................................................21 
1.4. 
Nonclinical Experience with Vatiquinone ..................................................................27 
1.5. 
Clinical Experience with Vatiquinone ........................................................................27 
1.6. 
Risk/Benefit Assessment ............................................................................................28 
2. 
STUDY OBJECTIVE AND ENDPOINTS ................................................................29 
2.1. 
Objectives ...................................................................................................................29 
2.1.1. 
Primary Objective .......................................................................................................29 
2.1.2. 
Secondary Objectives .................................................................................................29 
2.1.3. 
Exploratory Objectives ...............................................................................................29 
2.2. 
Endpoints ....................................................................................................................29 
2.2.1. 
Primary Endpoint ........................................................................................................29 
2.2.2. 
Secondary Endpoints ..................................................................................................29 
2.2.3. 
Exploratory Endpoints ................................................................................................30 
3. 
STUDY DESIGN .......................................................................................................30 
3.1. 
Overall Design ............................................................................................................30 
3.1.1. 
Screening ....................................................................................................................31 
3.1.2. 
Randomization ............................................................................................................31 
3.1.3. 
Placebo-controlled Phase ............................................................................................31 
3.1.4. 
Open-Label Extension Phase (Study Weeks 84 and 96 are in-Person Visits 
and Study Weeks 78 and 90 are Telephone Contacts ±2 weeks) ...............................31 
3.1.5. 
Follow-up Period ........................................................................................................32 

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3.1.6. 
Unscheduled Visits .....................................................................................................32 
3.1.7. 
End of Treatment Visits ..............................................................................................32 
3.1.8. 
Early Termination Study Visit ....................................................................................32 
3.2. 
Scientific Rationale for Study Design ........................................................................33 
3.3. 
Justification of Dose ...................................................................................................34 
3.4. 
End of Study Definition ..............................................................................................35 
4. 
STUDY POPULATION .............................................................................................35 
4.1. 
Overview .....................................................................................................................35 
4.2. 
Inclusion Criteria ........................................................................................................35 
4.3. 
Exclusion Criteria .......................................................................................................36 
4.4. 
Screen Failures ............................................................................................................37 
5. 
STUDY INTERVENTION ........................................................................................37 
5.1. 
Study Intervention(s) Administration .........................................................................37 
5.1.1. 
Study Intervention Description ...................................................................................37 
5.1.2. 
Dosing and Administration .........................................................................................37 
5.1.3. 
Treatment of Missed Doses and Overdose .................................................................37 
5.2. 
Preparation/Handling/Storage/Accountability ............................................................38 
5.2.1. 
Accountability .............................................................................................................38 
5.2.2. 
Formulation, Appearance, Packaging, and Labeling ..................................................38 
5.2.3. 
Preparation ..................................................................................................................38 
5.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................39 
5.3.1. 
Instructions for Unblinding .........................................................................................39 
5.4. 
Study Intervention and Compliance ...........................................................................39 
5.5. 
Concomitant Therapy .................................................................................................40 
5.6. 
Dose Modification and Stopping Rules ......................................................................40 
5.6.1. 
Procedure for Dose Modification ...............................................................................41 
6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................41 
6.1. 
Discontinuation of Study Intervention ........................................................................41 
6.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................42 
6.3. 
Lost to Follow-up .......................................................................................................42 
7. 
STUDY ASSESSMENT AND PROCEDURES ........................................................44 
7.1. 
Schedule of Events and Study Parameters ..................................................................44 

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7.2. 
Efficacy Assessments .................................................................................................47 
7.3. 
Pharmacokinetic and/or Other Assessments ...............................................................49 
7.4. 
Safety Assessments .....................................................................................................49 
7.4.1. 
Physical Examination, Height, Weight, and Vital Signs ............................................50 
7.4.2. 
Laboratory Evaluations ...............................................................................................50 
7.4.2.1. 
Hematology and Coagulation .....................................................................................50 
7.4.2.2. 
Serum Chemistry ........................................................................................................50 
7.4.2.3. 
Urine Drug Screen ......................................................................................................51 
7.4.3. 
Urine or Serum Pregnancy Test ..................................................................................51 
7.4.4. 
Abnormal Laboratory Findings ..................................................................................51 
7.5. 
Adverse Events and Serious Adverse Events .............................................................52 
7.5.1. 
Definition of Adverse Events .....................................................................................52 
7.5.2. 
Definition of Serious Adverse Events ........................................................................53 
7.5.3. 
Unexpected Adverse Events .......................................................................................54 
7.5.4. 
Eliciting Adverse Event Information ..........................................................................54 
7.5.5. 
Recording Non‑serious AEs and SAEs ......................................................................54 
7.5.6. 
Describing Adverse Event Relationship to Study Drug .............................................55 
7.5.7. 
Grading of Severity of Adverse Event ........................................................................55 
7.5.8. 
Adverse Event Reporting ............................................................................................56 
7.5.9. 
Serious Adverse Event Reporting ...............................................................................56 
7.5.10. 
Contraception ..............................................................................................................57 
7.5.11. 
Reporting Pregnancy ..................................................................................................58 
7.5.12. 
PTC Therapeutics Adverse Event Reporting Requirement ........................................59 
8. 
STATISTICAL CONSIDERATIONS .......................................................................59 
8.1. 
Statistical Hypotheses .................................................................................................59 
8.2. 
Sample Size Determination ........................................................................................59 
8.3. 
Population for Analyses ..............................................................................................60 
8.3.1. 
Randomized Analysis Set ...........................................................................................60 
8.3.2. 
Intent-to-Treat Set .......................................................................................................60 
8.3.3. 
Modified Intent-to-Treat Set .......................................................................................60 
8.3.4. 
Safety Analysis Set .....................................................................................................60 
8.3.5. 
Pharmacokinetic Analysis Set ....................................................................................60 
8.4. 
Statistical Analyses .....................................................................................................60 

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8.4.1. 
General Approach .......................................................................................................60 
8.4.2. 
Analysis of Primary Efficacy Endpoints ....................................................................61 
8.4.3. 
Analysis of Secondary and Exploratory Efficacy Endpoints .....................................62 
8.4.4. 
Safety Analyses ..........................................................................................................63 
8.4.4.1. 
Adverse Events ...........................................................................................................63 
8.4.4.2. 
Clinical Laboratory Evaluations .................................................................................64 
8.4.4.3. 
Vital Signs, Weight, and Oxygen Saturation ..............................................................64 
8.4.4.4. 
Electrocardiogram and Echocardiogram ....................................................................64 
8.4.4.5. 
Physical Examination .................................................................................................65 
8.4.4.6. 
Columbia-Suicide Severity Rating Scale ....................................................................65 
8.4.4.7. 
Concomitant Medication ............................................................................................65 
8.4.5. 
Baseline Descriptive Statistics ....................................................................................65 
8.4.5.1. 
Disposition of Subjects ...............................................................................................65 
8.4.5.2. 
Demographic and Baseline Characteristics ................................................................65 
8.4.6. 
Pharmacokinetic Analyses ..........................................................................................66 
8.4.7. 
Planned Interim Analyses ...........................................................................................66 
8.4.8. 
Subgroup Analyses .....................................................................................................66 
8.4.9. 
Sensitivity Analysis ....................................................................................................66 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................66 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................66 
9.1.1. 
Informed Consent Process ..........................................................................................66 
9.1.2. 
Study Discontinuation and Closure ............................................................................67 
9.1.3. 
Confidentiality and Privacy ........................................................................................67 
9.1.4. 
Future Use of Stored Specimens and Data .................................................................67 
9.1.5. 
Safety Oversight .........................................................................................................68 
9.1.6. 
Clinical Monitoring ....................................................................................................69 
9.1.7. 
Quality Assurance and Quality Control ......................................................................69 
9.1.8. 
Data Handling and Record Keeping ...........................................................................70 
9.1.9. 
Protocol Deviations ....................................................................................................70 
9.1.10. 
Publication and Data Sharing Policy ..........................................................................71 
9.2. 
Protocol Amendment History .....................................................................................72 
9.2.1. 
Amendment 2: 28 August 2020 (Version 3.0) ............................................................72 

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9.2.2. 
Amendment 3: 03 March 2021 (Version 3.1) .............................................................74 
9.2.3. 
Amendment 4: 15 April 2021 (Version 4.0) ...............................................................74 
9.2.4. 
Amendment 5: 21 May 2021 (Version 5.0) ................................................................76 
10. 
REFERENCES ...........................................................................................................78 
APPENDIX 1. PTC743-NEU-003-FA PROHIBITED MEDICATION LIST ...........................80 
 
LIST OF TABLES 
Table 1: 
Summary of Vatiquinone Ferroptosis Rescue in Friedreich Ataxia Patient 
Fibroblasts ...................................................................................................................25 
Table 2: 
Dose Modification and Stopping Rules for Vatiquinone ...........................................41 
Table 3: 
Relationship of Study Drug to Adverse Event Relationship ......................................55 
Table 4: 
Grading of Adverse Event Severity Grade .................................................................56 
Table 5: 
Investigator Site Requirements for Reporting Adverse Events ..................................56 
Table 6: 
PTC743-NEU-003-FA Prohibited Medication List ....................................................80 
 
LIST OF FIGURES 
Figure 1: 
Vatiquinone Dose-Dependent Inhibition of 15-Lipoxygenase ...................................21 
Figure 2: 
Overview of the Ferroptosis Pathway and Role of 15-Lipoxygenase as a 
Central Regulator of Lipid Oxidation, Inflammation, Glutathione Depletion, 
and Cell Death ............................................................................................................22 
Figure 3: 
Vatiquinone Rescues Friedreich Ataxia Patient Fibroblasts Following 
RSL3-Induced Ferroptosis Challenge .........................................................................23 
Figure 4: 
Vatiquinone Prevents Lipid Oxidation in Friedreich Ataxia Patient 
Fibroblasts Following RSL3-Induced Ferroptosis Challenge ....................................24 
Figure 5: 
Vatiquinone Potently Rescues Friedreich Ataxia Patient Fibroblasts 
Following Two Different Ferroptosis Challenges ......................................................25 
Figure 6: 
Long-Term Vatiquinone Treatment in Friedreich Ataxia Patients Led to a 
Significant Reduction in Disease Progression ............................................................26 
Figure 7: 
Study Design ...............................................................................................................30 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialized Term 
Explanation 
15-HpETE 
15-Hydroperoxyeicosatetraenoic acid 
15-LO 
15-Lipoxygenase 
1MWT 
1-Minute walk test 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC0-8h  
Area under the plasma concentration-time curve from time zero to 8 hours 
AUC0-24 
Area under the plasma concentration-time curve from time zero to 24 hours 
bid 
Twice daily 
BSO 
L-buthionine sulfoximine 
BUN 
Blood urea nitrogen 
Cmax 
Maximum observed (plasma) concentration 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
COVID-19 
Coronavirus disease 2019 
CS 
Clinically significant 
CTC 
Common Terminology Criteria 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP  
Cytochrome P450  
DSMB 
Data Safety Monitoring Board 
EC50 
Half maximal effective concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EQ-5D-5L 
A self-assessed, health-related, quality of life questionnaire developed by the 
EuroQol Research Foundation 
FA 
Friedreich ataxia 
FAC 
Ferric ammonium citrate 
FARS 
Friedreich Ataxia Rating Scale 
FARS-ADL 
Friedreich Ataxia Rating Scale Activities of Daily Living 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FXN 
Frataxin 
GAA 
Guanine-adenine-adenine 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLP  
Good Laboratory Practices  
Gpx4 
Glutathione peroxidase 4 
GSH 
Glutathione 
HCG  
Human chorionic gonadotropin  
HDPE 
High-density polyethylene 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Institutional Ethics Committee 
IND 
Investigational new drug application 

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Abbreviation or 
Specialized Term 
Explanation 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
MCMC 
Monte Carlo Markov Chain 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFARS 
Modified Friedreich Ataxia Rating Scale 
MFIS 
Modified Fatigue Impact Scale 
mITT 
Modified intent-to-treat 
MMRM 
Mixed model repeated measure 
NCS 
Not clinically significant 
NF 
National Formulary 
NOAEL 
No-observed-adverse-effect level 
Nrf2 
Nuclear factor erythroid 2–related factor 2 
OTC 
Over-the-counter 
PK 
Pharmacokinetic 
PO 
Orally 
PT 
Preferred Term 
PTC743 
Vatiquinone 
PTT 
Partial thromboplastin time 
PUFA 
Polyunsaturated fatty acid 
RBC 
Red blood cell 
RSI 
Reference Safety Information 
RSL3 
RAS-selective lethal 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SEM 
Standard error of the mean 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
tid 
Three times daily 
ULN 
Upper limit of normal 
USP  
United States Pharmacopeia 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
xCT 
Cystine/glutamate antiporter 
 
 

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1. 
INTRODUCTION 
PTC743 (vatiquinone) is a novel small molecule therapeutic in development for the treatment of 
mitochondrial disease and associated disorders of oxidative stress and inflammation. 
Vatiquinone targets oxidoreductase enzymes essential to inflammation, oxidation, and cell death. 
To date, vatiquinone has been evaluated for the treatment of mitochondrial diseases and has been 
demonstrated to improve long-term neurological and neuromuscular function in patients with 
Friedreich ataxia (FA). The purpose of this study is to evaluate the safety and efficacy of 
vatiquinone in patients with FA. 
1.1. 
Study Rationale 
Friedreich ataxia is an autosomal recessive, neurodegenerative disease that primarily affects the 
nervous system and heart. The disease was first described by Nicolaus Friedreich in the second 
half of the nineteenth century. In Western populations, the prevalence of FA varies between 
1:20000 and 1:725000. Epidemiological studies gave evidence of a west to east prevalence 
gradient in Europe with highest levels in the South of France, North of Spain, and Ireland and 
lowest levels in Scandinavia and Russia. Carrier frequencies vary between 1:55 (North Spain) 
and 1:336 (Russia). Friedreich ataxia is a debilitating disease that causes severe morbidity and 
mortality in affected patients. The condition is characterized by progressive gait and limb ataxia, 
dysarthria, lower limb areflexia, decreased vibration sense, muscular weakness in the legs, and 
vision loss as well as non-neurological sequelae including hypertrophic cardiomyopathy and 
diabetes mellitus. Nearly all patients become paraplegic and eventually require wheelchairs. 
Typical disease onset occurs during puberty; however, both early-onset and late-onset variants 
exist and median age of death is 36.5 years. Currently, there are no approved treatments for FA 
in the United States or Europe (Burk 2017, Cook 2017). 
More than 95 percent of patients are homozygous for a large expansion (60 to 1300) of a 
guanine-adenine-adenine (GAA) trinucleotide-repeat sequence located within the first intron of 
the gene for frataxin (FXN) on chromosome 9q21.21. The mutation causes a defect in 
transcription of the FXN protein, a 210-amino acid protein found in the mitochondria 
(Bencze 2006). Although there is a large body of literature on FXN, the precise mechanism of 
action underlying its function remains elusive. Because of the mitochondrial localization of FXN 
and significant role in mitochondrial enzyme integrity, the neurological and cardiac pathologies 
observed in FA result from mitochondrial dysfunction; hence, FA can be classified as a 
mitochondrial disease (Burk 2017). 
In common with other inherited disorders that affect mitochondrial function, FA patients 
demonstrate biochemistry consistent with high levels of oxidative stress and glutathione (GSH) 
depletion (Piemonte 2001).  
Recently, 15-lipoxygenase (15-LO) and ferroptosis, which regulate lipid oxidation and GSH 
levels, have been demonstrated to be important in the pathogenesis of FA (Seiler 2008, 
Cotticelli 2019). Ferroptosis was first described as a necrotic cell death pathway, triggered by 
iron and lipid peroxide accumulation, which causes morphologic and biochemical changes 
distinct from apoptosis and other necrotic pathways (Dixon 2012). By regulating the production 
of lipid peroxides, 15-LO is the key enzyme governor of ferroptosis (Shintoku 2017, Li 2018). 
Agents that target ferroptosis have been shown to be protective in various models of FA 
(Cotticelli 2019).  

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Therefore, the development of vatiquinone for the treatment of FA is based on the following: 
• Vatiquinone mechanism of action: Vatiquinone targets 15-LO, a key regulator of 
ferroptosis and inflammation. 
• Ferroptosis and FA: Oxidative stress inflammation, and specifically the products of 
15-LO, have been demonstrated to be fundamental biochemical mechanisms 
underpinning FA pathogenesis. 
• Vatiquinone in vitro validation: Vatiquinone is a potent rescue agent of patient cells 
in an in vitro ferroptosis test system mimicking FA. 
• Clinical effect recorded in patients with FA 
1.2. 
Name and Description of Investigational Product 
Vatiquinone is 2-[(3R,6E,10E)-3-hydroxy-3,7,11,15-tetramethyl-6,10,14-hexadecatrienyl]-3,5,6-
trimethyl-2,5-cyclohexadiene-1,4-dione. Vatiquinone is the quinone oxidation product of 
alpha-tocotrienol, one of the eight naturally occurring forms of vitamin E. Vatiquinone is a 
viscous yellow oil and will be administered as a mixture with sesame oil National Formulary 
(NF)/ United States Pharmacopeia (USP) encapsulated in size 1 Swedish orange capsules. 
1.3. 
Vatiquinone Mechanism of Action 
Vatiquinone targets oxidoreductase enzymes critical to inflammation, oxidation, and cell death 
(ferroptosis) which have been shown to be associated with FA pathogenesis. 
1. In a cell-free enzymatic assay, it has been demonstrated that vatiquinone 
dose-dependently inhibits 15-LO enzyme activity (half maximal inhibitory concentration 
[IC50]=0.6 µM), as shown in Figure 1. 
Figure 1: 
Vatiquinone Dose-Dependent Inhibition of 15-Lipoxygenase 
 
Abbreviations: 15-LO, 15-lipoxygenase; IC50, half maximal inhibitory concentration  

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Cell-free 15-LO activity assay: Human 15-LO activity was determined by 
15-hydroperoxyeicosatetraenoic acid (15-HpETE) formation, measured by liquid 
chromatography tandem mass spectrometry (LC-MS/MS). Mean ± standard error of the mean 
(SEM) from three independent experiments are shown above in Figure 1.  
• 15-LO catalyzes the peroxidation of polyunsaturated fatty acids (PUFAs) to produce 
the lipid hydroperoxide 15-HpETE, a pro-inflammatory and pro-ferroptotic lipid 
signaling molecule. 
• 15-HpETE and downstream metabolites, such as hydroxy-eicosatetraenoic acids 
(HETEs) and 4-hydroxy-2-nonenal (4-HNE), are clinical biomarkers that have been 
associated with FA . 
Vatiquinone is an inhibitor for the enzyme 15-LO, a key governor of fatty acid oxidation and 
inflammation that underpin several neurological diseases, including FA. 
2. Ferroptosis, the biochemical process regulated by 15-LO, has been demonstrated to be a 
key mechanism, shown in Figure 2, underpinning FA. 
Figure 2: 
Overview of the Ferroptosis Pathway and Role of 15-Lipoxygenase as a Central 
Regulator of Lipid Oxidation, Inflammation, Glutathione Depletion, and Cell Death 
 
Abbreviations: BSO, L-buthionine sulfoximine; GSH, glutathione; GSSG, glutathione disulfide; GPX4, glutathione 
peroxidase 4; HpETE, hydroperoxyeicosatetraenoic acid; RSL3, RAS-selective lethal  
Ferroptosis pathway: Ferroptosis is regulated by 15-LO, and glutathione peroxidase 4 (Gpx4). 
Activation of 15-LO leads to the production of the lipid signaling molecule 15-OOH-
arachindonic acid [15(S)-HpETE]. Gpx4 reduces 15(S)-HpETE to 15-OOH-arachindonic acid 
preventing inflammation and ferroptosis. Ferroptosis is experimentally induced by inhibition of 
Gpx4 (RAS-selective lethal [RSL3]), depletion of GSH (erastin or L-buthionine sulfoximine 
[BSO]) or excess arachidonic acid. Vatiquinone inhibits 15-LO and prevents ferroptosis under 
the four pro-ferroptotic conditions described above. 
• Ferroptosis is a recently described form of regulated cell death (Dixon 2012, 
Stockwell 2017) mediated by lipid signaling molecules produced by 15-LO 
(Seiler 2008, Dixon 2012, Friedmann Angeli 2014). 

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• Under normal conditions, ferroptosis is prevented by the constitutive activity of the 
selenoenzyme, Gpx4, which utilizes GSH to reduce cellular lipid hydroperoxides 
(such as 15-HpETE) to their benign secondary alcohols . 
• Depletion of cellular GSH, as has been observed in mitochondrial disease 
(Milder 2012, Enns 2014), including FA patients (Piemonte 2001), or inhibition of 
Gpx4 leads to the accumulation of 15-HpETE and rapidly induces ferroptotic cell 
death (Seiler 2008, Yang 2014, Kagan 2017). 
• When patient fibroblasts or neuronal cells are depleted of endogenous GSH by an 
irreversible inhibitor of GSH synthesis (BSO), the result is rapid cell death that can be 
rescued by 15-LO inhibition (Seiler 2008). 
• In biochemical analyses of patients with FA, there is a significant increase in the 
substrates for 15-LO as well as a decrease in the level of reduced GSH 
(Piemonte 2001). 
3. In vitro validation: Vatiquinone is a potent rescue agent of FA patient cells in an in vitro 
test system mimicking ferroptosis-related disease pathology. 
• Fibroblasts collected from FA patients are more susceptible to a ferroptosis challenge 
compared to healthy control fibroblasts (Cotticelli 2019).  
• To determine the potential therapeutic benefit of vatiquinone and 15-LO inhibition, 
the sponsor developed an in vitro ferroptosis assay employing FA patient primary 
fibroblasts and Gpx4 inhibition. 
• Inhibition of cellular Gpx4 activity by RSL3, an irreversible small molecule inhibitor 
(Yang 2014), led to the rapid and nearly-complete death of FA patient fibroblasts. 
• Vatiquinone dose-dependently protected FA patient fibroblasts from RSL3-induced 
cell death, as shown in Figure 3. 
Figure 3: 
Vatiquinone Rescues Friedreich Ataxia Patient Fibroblasts Following 
RSL3-Induced Ferroptosis Challenge 
 
Abbreviations: EC50, half maximal effective concentration; RSL3, RAS-selective lethal 

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Cell viability assay: Friedreich ataxia fibroblasts from two donors (GM03816-GAA repeats 
380,330; GM04078-GAA repeats 541,420) were treated with RSL3 (2 µM) in combination with 
vatiquinone. Cell viability was assessed 18-hours later by CellTiter-Glo® 2.0 cell viability assay. 
Mean ± SEM (n=12 fields) from one experiment is shown above in Figure 3 and are 
representative of 3 independent experiments on two separate days. 
• To confirm the mechanism by which vatiquinone protected cells from ferroptosis, it 
was demonstrated that vatiquinone dose-dependently prevented RSL3-induced 
formation of oxidized lipid signaling molecules in fibroblasts from two FA patients 
(measured using the BODIPY 581/591 C11 oxidation-sensitive fluorescent lipid 
probe) (Figure 4). 
Figure 4: 
Vatiquinone Prevents Lipid Oxidation in Friedreich Ataxia Patient Fibroblasts 
Following RSL3-Induced Ferroptosis Challenge 
 
Abbreviations: EC50, half maximal effective concentration; RSL3, RAS-selective lethal 
Lipid oxidation assay: Friedreich ataxia fibroblasts from two donors (GM03816-GAA repeats 
380,330; GM04078-GAA repeats 541,420) were treated with RSL3 (2 µM) in combination with 
vatiquinone. The initial (0-5 h) cell lipid oxidation rate was assessed by monitoring green 
fluorescence of BODIPY C11-labeled cells by quantitative time-lapse microscopy (IncuCyte). 
Mean ± SEM (n=12 fields) from one experiment is shown above in Figure 4 and are 
representative of 3 independent experiments on two separate days. 
• To further confirm vatiquinone protected cells from ferroptosis, it was demonstrated 
that vatiquinone protected FA patient cells from ferroptosis induced using two 
additional approaches: 1) addition of ferric ammonium citrate plus the small molecule 
inhibitor of GSH synthesis - L-buthionine (S,R)-sulfoximine (BSO), and 2) 
preventing uptake of the GSH precursor cystine by the small molecule 
cystine/glutamate anti-porter (xCT) inhibitor erastin (Figure 5). 

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Figure 5: 
Vatiquinone Potently Rescues Friedreich Ataxia Patient Fibroblasts Following Two 
Different Ferroptosis Challenges 
 
Abbreviations: BSO, L-buthionine sulfoximine; FAC, ferric ammonium citrate 
Cell viability assay: Friedreich ataxia fibroblasts from a single donor (GM3665-GAA repeats 
1357,790) were treated with either ferric ammonium citrate (FAC) and BSO for 48 hours and 
24 hours respectively, or with erastin and vatiquinone added 2 hours later. Cell viability was 
assessed at 48 hours by the Promega® Cell-Glow. 
Table 1: 
Summary of Vatiquinone Ferroptosis Rescue in Friedreich Ataxia Patient 
Fibroblasts 
 
Vatiquinone Potency (nM) 
Condition 
Gene 
Cell ID 
GAA 
Repeats 
RSL3 
Survival 
RSL3 Lipid 
Oxidation 
FAC/BSO 
Survival 
Erastin 
Survival 
Friedreich ataxia 
FXN 
GM3816 
380,330 
12 
44 
- 
- 
Friedreich ataxia 
FXN 
GM4078 
541,420 
24 
31 
19 
 
Friedreich ataxia 
FXN 
GM3665 
790,1357 
- 
- 
10 
10 
Abbreviations: BSO, L-buthionine sulfoximine; FAC, ferric ammonium citrate; FXN, frataxin; 
GAA, guanine-adenine-adenine; ID, identification; RSL3, RAS-selective lethal 
Ferroptosis challenge summary: Friedreich ataxia fibroblasts from FA donors were treated 
with RSL3 (2 µM) in combination with vatiquinone and cell viability and lipid peroxidation 
were determined as described above. In the FAC/BSO assay, cells were treated with FAC and 
BSO for 48 hours and 24 hours, respectively, and vatiquinone was added 2 hours after BSO. Cell 
viability was assessed at 48 hours by the Promega Cell-Glow. In the erastin assay, cells were 
treated with erastin and vatiquinone was added 2 hours later. Cell viability was assessed at 
48 hours by the Promega Cell-Glow.  
• In addition to increased markers of oxidative stress and GSH depletion, fibroblasts 
from FA patients show an increased sensitivity to pro-oxidant agents, which is 
thought to result in reduced nuclear factor erythroid 2–related factor 2 (Nrf2) activity 
(Paupe 2009, Shan 2013). The Nrf2 pathway is one of the major reactive oxygen 
species scavenging pathways which defends the cells against oxidative stress and 
regulates mitochondrial metabolism and function (Esteras 2016). 
• It was demonstrated that vatiquinone increased the expression and activity of the 
antioxidant response master regulator Nrf2 in neural stem cells isolated from the 
embryonic cortex of the Frataxin knockin/knockout mouse.  
Collectively, these in vitro mechanism-of-action studies in FA primary fibroblasts establish that 
vatiquinone potently prevents lipid oxidation and ferroptotic cell death via inhibition of 15-LO, 
and provides supportive mechanistic rationale for the use of vatiquinone to treat FA patients.  

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4. Clinical effect: In compassionate use and a Phase 2b study, treatment with vatiquinone 
was associated with improvement in a number of disease symptoms and an improvement 
in overall disease progression as assessed by the validated Friedreich Ataxia Rating Scale 
(FARS).  
• In patients receiving vatiquinone as part of an expanded access protocol, it was 
demonstrated that vatiquinone treatment resulted in an increase in brain GSH levels in 
patients with FA (Blankenberg 2012). 
• Supporting the clinical relevance of the target and mechanism-of-action of 
vatiquinone, increases in brain GSH were linearly correlated to an improvement in 
disease severity scores in FA patients (Blankenberg 2012). 
• In a Phase 2b clinical trial, posthoc analysis showed that long-term vatiquinone 
treatment was associated with a significant improvement in neurological function as 
assessed by the validated FARS scale relative to natural history (Figure 6) 
(Zesiewicz 2018). 
Figure 6: 
Long-Term Vatiquinone Treatment in Friedreich Ataxia Patients Led to a Significant 
Reduction in Disease Progression 
 
Phase 2b clinical study: Patients receiving vatiquinone for 24 months demonstrated a 
significant improvement in the FARS compared to a natural history cohort group matched 2:1 for 
the following: age, sex, and disease severity. In this posthoc analysis, vatiquinone treatment was 
associated with a statistically significant improvement in disease severity as assessed by the 
FARS-Neuro score with evidence of reversal of disease progression (Zesiewicz 2018). 
Collectively, clinical studies in FA patients establish that vatiquinone increases brain GSH levels 
and positively affects disease progression supporting the further clinical development of 
vatiquinone for FA (Blankenberg 2012, Zesiewicz 2018).  

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Based on the vatiquinone mechanism of action, the understood biochemical mechanisms 
underpinning FA, the in vitro evidence of vatiquinone benefit, and clinical data collected to date, 
there is a valid rationale for the study of vatiquinone in patients with FA. 
1.4. 
Nonclinical Experience with Vatiquinone  
Vatiquinone has been evaluated in a comprehensive battery of nonclinical safety and toxicology 
studies. Vatiquinone is an orally available compound that has been demonstrated in vitro and in 
vivo to cross the blood-brain-barrier. In 6-month and 9-month repeat-dose toxicity studies in rat 
and dog, respectively, the no-observed-adverse-effect level (NOAEL) was 30 mg/kg/day, 
corresponding to Day 180 and Day 273 combined mean maximum observed plasma 
concentrations (Cmax) values of 8828 ng/mL (rat) and 12854 ng/mL (dog) and area under the 
plasma concentration-time curve from time zero to 24 hours (AUC0-24) values of 48786 (rat) and 
107426 ng×h/mL (dog). The dose-limiting adverse event (AE) in both rat and dog studies was 
anticoagulation as demonstrated by prolonged prothrombin time and activated partial 
thromboplastin time that most likely results from weak vitamin K antagonism exhibited by this 
class of compounds (Studies 1660-045 and 1660-046). 
Vatiquinone was negative in the Good Laboratory Practices (GLP) battery of genotoxicity assays 
including the bacterial reverse mutation Ames assay, the in vitro micronucleus assay in human 
peripheral blood lymphocytes, and the in vivo micronucleus assay in rat. 
Safety pharmacology data collected in the 28-day toxicity studies in rat and dog and during the 
6-month and 9-month toxicity studies in rat and dog, respectively, demonstrated that vatiquinone 
did not affect neurobehavioral or cardiovascular electrocardiogram (ECG) parameters (Studies 
1660-027, 1660-028, 1660-045, and 1660-046). In addition, vatiquinone is not a potent inhibitor 
of hERG (human ether-à-go-go-related gene) channel current (Study 130416.FEK). Vatiquinone 
did not influence respiratory function in the rat (Study 1660-032).  
Reproductive toxicity studies were conducted in rats and rabbits. A combined fertility study and 
embryo fetal development study in rat and embryofetal development study in rabbit 
demonstrated that vatiquinone did not induce reproductive or developmental toxicity at doses up 
to 100 mg/kg/day in rat and 1000 mg/kg/day in rabbit. There was no evidence of any teratogenic 
potential at the dose levels tested (Studies 1660-058 and 1660-061). 
An in vitro phototoxicity study (Study PTC743-2020-003) conducted in BALB/c 3T3 mouse 
fibroblasts to assess phototoxic potential demonstrated that vatiquinone had no phototoxic 
potential. 
1.5. 
Clinical Experience with Vatiquinone  
Over 500 patients have been treated with vatiquinone in clinical trials at doses ranging from 
50 mg daily to 400 mg tid. Subjects ranged in age from <1 year to 70 years old. The longest 
exposure has been over 10 years in a pediatric subject with Leigh syndrome (surfeit locus protein 
1 [SURF1] variant). There have been seven serious adverse events (SAEs) in 5 subjects deemed 
possibly related to vatiquinone. One subject experienced three SAEs (pneumonia, tachycardia, 
and increased unresponsiveness), and SAEs of hypoglycemia, depression, pancreatitis, and 
neutropenia were experienced by one subject each. Except for the event of neutropenia, these 
events were all assessed as unlikely related to vatiquinone by the sponsor.  

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In a 24-month Phase 2b randomized, double-blind and placebo-controlled trial of vatiquinone in 
adults with FA, 63 participants were enrolled and randomized to receive vatiquinone at a dose of 
400 mg tid (n=20), vatiquinone at a dose of 200 mg tid (n=22), or placebo (n=21). The study 
included a 6-month placebo-controlled phase followed by a 6-month open-label extension phase 
in which participants initially randomized to placebo were crossed over to vatiquinone treatment 
(either 200 mg or 400 mg), while participants originally taking the lower or higher dose of 
vatiquinone continued on those dosing levels. For the last 12 months of the study, all subjects 
received vatiquinone at a dose of 400 mg tid. There were no drug-related SAEs or dose-limiting 
toxicities reported. Increased triglycerides were noted in all 3 treatment groups and were 
assessed as related to the consumption of milk, which was ingested along with study medication 
to facilitate absorption. The most frequently reported AEs assessed as related to vatiquinone 
were dysgeusia, increased weight, and dyspepsia, which were reported in fewer than five 
participants in either treatment group for the entire 24-month study period (Zesiewicz 2018). 
No indications of adverse changes in laboratory liver function, renal function, or coagulation 
tests have been recorded in clinical studies that have been deemed associated with vatiquinone. 
1.6. 
Risk/Benefit Assessment 
At the dose levels selected for this study it is not foreseen that subjects will endure any risks 
greater than minimal. In order to further minimize potential risks, subjects will be frequently 
monitored for changes in coagulation parameters and other clinical pathology assessments. 
Administration of study drug will be adjusted or completely stopped if coagulation parameters 
(prothrombin time, international normalized ratio [INR], partial thromboplastin time [PTT]) are 
found to be increased to more than 1.5×ULN. 
There are no approved treatments available for patients with FA. In addition to improved 
neurological function, potential benefits may manifest in other specific aspects of disease 
morbidity such as functional ability.  
Based on the available information in Section 1.5, the foreseeable risks and burdens are expected 
to be low and comparable to those risks and burdens encountered in routine clinical care of 
pediatric and adult patients with FA. 
Subjects will be continually assessed at both in-person visits and by telephone. The frequency of 
visits and the type of procedures are considered no more burdensome than the standard of care 
for FA in the pediatric population. 
To minimize and oversee risks, investigators are properly trained and experienced in studying the 
pediatric FA population, including the evaluation and management of potential pediatric adverse 
events. The investigators are familiar with the background and requirements of the study and 
with the characteristics and properties of the study drug as described in the Investigator’s 
Brochure.  
The principal investigator will ensure the privacy, health, and welfare of the subjects during and 
after the clinical study, and must ensure that trained personnel are immediately available in case 
of a medical emergency. 

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The investigator will conduct a complete physical examination, oversee, and assess the results of 
the laboratory and further examinations and hold regular conversations with the subject to assess 
the subject’s condition and to collect information about any adverse events and relevant 
concomitant medication. 
2. 
STUDY OBJECTIVE AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy (using the modified Friedreich 
Ataxia Rating Scale [mFARS]) and safety of vatiquinone in subjects with FA.  
2.1.2. 
Secondary Objectives 
• Demonstrate the effects of vatiquinone on activities of daily living as assessed by the 
Friedreich Ataxia Rating Scale Activities of Daily Living (FARS-ADL) scale 
• Demonstrate the effects of vatiquinone on ambulation as assessed by the 1-minute 
walk test (1MWT) 
• Demonstrate the effects of vatiquinone on falls as assessed by a fall log 
2.1.3. 
Exploratory Objectives 
• Demonstrate the effects of vatiquinone on speech using Redenlab protocol 
• Demonstrate the effects of vatiquinone on fatigue as assessed by the Modified Fatigue 
Impact Scale (MFIS) 
• Demonstrate the effects of vatiquinone on health status using the EQ-5D-5L 
• Demonstrate the effects of vatiquinone on the Upright Stability subscale of the 
mFARS 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint  
The primary endpoint will be the change from baseline in the mFARS at Week 72. 
2.2.2. 
Secondary Endpoints 
Secondary endpoints will include change from baseline in the following assessments at Week 72. 
• FARS-ADL scale (key secondary endpoint) 
• 1MWT 
• Fall log  

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2.2.3. 
Exploratory Endpoints 
Exploratory endpoints will include change from baseline in the following assessments at 
Week 72. 
• Speech using Redenlab protocol 
• MFIS 
• EQ-5D-5L  
• Upright Stability subscale of the mFARS 
3. 
STUDY DESIGN 
3.1. 
Overall Design 
This study will be a parallel-arm, double-blind, placebo-controlled trial during which subjects 
will be randomized 1:1 to receive either vatiquinone or placebo using an interactive response 
technology (IRT) (Figure 7). Subjects will be stratified by mFARS (<40 versus ≥40), age at 
disease onset (˂14 years or ≥14 years), and age at Screening (≤21 years or >21 years). If 
randomized to vatiquinone, subjects will receive a dose of either 200 mg orally (PO) tid if 
˂12 years of age and weighing ˂25 kg or 400 mg PO tid if ≥12 years of age and/or ≥25 kg. 
Weight will be assessed during every clinic visit, and the dose of study drug will be adjusted to 
400 mg or down to 200 mg, as applicable, for any change in weight of ±5 kg from the 25 kg 
dosing determination threshold. The dose will also be adjusted if the subject’s age changes from 
11 to 12 years. If randomized to placebo, subjects will receive matching placebo tid PO. 
Following completion of the randomized placebo-controlled phase, subjects will enter into an 
open-label (24-week) extension phase during which they will receive open-label treatment with 
vatiquinone at the dose they received in the randomized phase of the study and then a safety 
follow-up. For subjects entering the extension phase who initially received vatiquinone, they will 
continue to receive the same dose of vatiquinone (unless there has been a change in weight or a 
change in age from 11 to 12 years [see Section 3.1.2 and Section 3.1.4]). For subjects entering 
the extension phase who initially received placebo, the dose of vatiquinone will be determined 
based on weight as described in Sections 3.1.2 and Section 3.1.4. Body weight will continue to 
be assessed at each visit during the extension phase and dose will be adjusted accordingly, as 
above. The maximum duration of subject treatment will be 96 weeks (including 
placebo-controlled phase and extension phase). The overall study duration will be a maximum of 
approximately 106 weeks per subject. See the Schedule of Events and Study Parameters in 
Section 7.1. Subjects who complete the study may have the option to enter an open-label 
expanded access program to continue receiving vatiquinone.  
Figure 7: 
Study Design 
 
Screening 
Up to Day 
-42
Baseline
Day 1
Placebo 
controlled 
phase
72 weeks
Open label 
extension 
phase
24 weeks
Follow-up
~30 days 
after last 
dose

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3.1.1. 
Screening 
Screening evaluations will be performed up to 42 days prior to the Baseline Visit. Concomitant 
use of interventional CoQ10, vitamin E, or any approved or non-approved medication for FA 
must be washed out for at least 30 days prior to the Screening Visit (see Appendix 1). These 
prohibited medications can be discontinued at the Screening Visit; if this is the case, the mFARS 
assessment must be repeated to confirm inclusion eligibility after a minimum of 30 days post 
discontinuation, and there must be no more than a 4-point difference in mFARS assessed from 
the Post-Discontinuation Visit to the Baseline Visit for eligibility. The time period between the 
screening (post-washout, if applicable) and baseline mFARS used for this inclusion criterion 
determination should occur at least 24 hours apart.  
The investigator should inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from (ICF) the subject or parent(s)/legal 
guardian(s) prior to performing any study-related screening procedures and prior to the 
administration of study drug. Subjects who are unable to adhere to the screening time window 
specified in the protocol due to unforeseen circumstances (eg, Coronavirus disease 2019 
[COVID-19]) may repeat the Screening Visit upon Sponsor approval. 
3.1.2. 
Randomization 
After subjects complete the baseline procedures on Day 1 and are eligible to be randomized, site 
staff will utilize IRT to randomize each subject. Randomization will be 1:1 vatiquinone to 
placebo. Subjects will be stratified by mFARS (<40 versus ≥40), age at disease onset (<14 years 
or ≥14 years), and age at Screening (≤21 years or >21 years). If randomized to vatiquinone, 
subjects will receive a dose of either 200 mg PO tid if ˂12 years of age and weighing ˂25 kg, or 
400 mg PO tid if ≥12 years of age and/or ≥25 kg. The database will be locked for a Week 72 
analysis.  
3.1.3. 
Placebo-controlled Phase 
Subjects will be randomized to receive vatiquinone at a dose 200 mg or 400 mg tid or matching 
placebo administered tid for 72 weeks (stratified by mFARS [<40 versus ≥40], age at disease 
onset [˂14 years or ≥14 years], and age at Screening [≤21 years or >21 years]).  
During the Baseline Visit, study medication will be dispensed to the subject according to the 
randomization and age and weight as discussed in Section 3.1. The first dose of study drug will 
be taken with food with at least 25% fat the same day as the Baseline Visit after all baseline 
assessments are completed. During the placebo-controlled phase, clinic visits will occur at 
Weeks 12, 24, 36, 48, 60, and 72; procedures to be performed during these visits are shown in 
Section 7.1. Study site staff will perform telephone assessments for AEs/SAEs and concomitant 
medications on Weeks 4, 8, 16, 20, 28, 32, 40, 44, 52, 56, 64, and 68. All visits and telephone 
assessments during this phase will have a window of ±1 week. 
3.1.4. 
Open-Label Extension Phase (Study Weeks 84 and 96 are in-Person Visits and 
Study Weeks 78 and 90 are Telephone Contacts ±2 weeks) 
Following the 72-week placebo-controlled phase, subjects will enter into a 24-week open-label 
treatment phase with vatiquinone at a dose of 200 mg or 400 mg tid, the dose level they were 
assigned in the randomized phase. For subjects entering the extension phase who initially 

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received vatiquinone, they will continue to receive the same dose of vatiquinone (unless there 
has been a change in weight as described below). For subjects entering the extension phase who 
initially received placebo, the dose of vatiquinone will be determined based on weight as 
described in Section 3.1.2. Weight will be assessed during every clinic visit, and the dose of 
study drug will be adjusted to 400 mg or down to 200 mg, as applicable, for any change in 
weight of ±5 kg from the 25 kg dosing determination threshold; the dose will also be adjusted if 
the subject’s age changes from 11 to 12 years. During this phase, subjects and investigators will 
remain blinded to the treatment received during the placebo-controlled phase. 
In-person visits will occur every 12 weeks (±2 weeks), and there will be every 6 weeks 
(±2 weeks) telephone contact with the subject in between the in-person visits as measured from 
Baseline Visit date. 
3.1.5. 
Follow-up Period 
The follow-up contact will be by telephone and should be completed approximately 30 days 
(±5 days) post last study drug administration or termination visit, whichever is later. AEs deemed 
study drug-related and any SAE, whether or not deemed study drug-related, will be followed 
until normalized or resolved. At the investigator’s discretion, an unscheduled office visit and 
additional tests may be conducted in order to ensure proper follow-up of an AE/SAE. If AEs that 
occurred during the study need to be followed up, blood samples should be taken per physician’s 
orders.  
3.1.6. 
Unscheduled Visits 
If a subject returns to the clinic outside of the normal study visit windows, assessments will be 
made at the investigator’s discretion. All study relevant unscheduled visit assessments will be 
recorded in the electronic case report form (eCRF) using the supplemental visit eCRF pages. 
3.1.7. 
End of Treatment Visits 
End of Treatment Visit takes place at Study Week 96 and includes the assessments listed in 
Section 7. Subjects who have an ongoing AE at the time of study completion will be followed for 
up to 30 days, until the event resolves, or until the sponsor and the investigator agree that further 
follow-up is not medically necessary. 
3.1.8. 
Early Termination Study Visit 
Subjects who terminate from the study after receiving first dose and prior to the completion of all 
scheduled visits should have the End of Treatment Visit assessments completed as soon as 
possible. The End of Treatment Visit will include the same assessments noted for the Week 96 
Visit, as listed in Section 7.1. In the event of early termination from study drug, and unless 
consent is withdrawn, all visits and safety and efficacy assessments should be continued 
according to the Schedule of Events and Study Parameters (Section 7.1). Subjects who have an 
ongoing AE at the time of study completion will be followed for up to 30 days, until the event 
resolves, or until the sponsor and the investigator agree that further follow-up is not medically 
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3.2. 
Scientific Rationale for Study Design  
Friedreich ataxia is a slowly progressive neurodegenerative disorder which affects multiple 
organ systems in addition to the central nervous system (CNS). Usual onset is during 
adolescence (mean 15.5 years, standard deviation 8 years) with a typical presenting symptom of 
unsteadiness of gait. Mean time to loss of independent gait is 8 years, with patients becoming 
wheelchair-bound after a mean disease duration of 11 to 15 years (Burk 2017). Currently, no 
medications are available to stop the relentless progression of this disease.  
Despite its known slow progression, the progression rate is more rapid in patients with earlier 
onset and with longer GAA repeat length; of these factors, the age of onset is the stronger 
predictor (Patel 2016). Despite the mean age of onset of 15.5 years, one-fifth of patients are 
younger than 5 years at onset (Burk 2017). Given this, and the knowledge that in a progressive 
neurodegenerative disorder, function that is lost is seldom able to be regained, it is important to 
intervene early in pediatric patients. The present study will enroll 106 subjects with an age of 7 
to 21, inclusive, and approximately 20 subjects over the age of 21 years. Subjects must be able to 
ambulate at least 10 feet in one minute with or without assistance (non-wheelchair), with an 
mFARS score of 20 to 70, inclusive. This mFARS range was chosen to avoid ceiling and floor 
effects, as the score on this scale is heavily determined by ambulatory factors. 
Randomized, double-blind, parallel group, placebo-controlled trials are the gold standard for the 
evaluation of the clinical benefit of an investigational agent. Parallel group design allows 
recruitment of patients for all treatment arms in the same timeframe. In a disease state that does 
not have an approved treatment option, such as Friedreich ataxia, the inclusion of a placebo arm 
does not pose any ethical concerns. In this study, at randomization, subjects will be stratified by 
3 factors, including baseline mFARS (<40 or ≥40), age at disease onset (<14 years or ≥14 years), 
and age at Screening (≤21 years or >21 years). The goal of stratifying by mFARS severity and 
age of disease onset is to achieve balance between disease severity and progression rate. 
Although the primary analysis is based on patient ages 7 to 21 years at screening in order to 
better assess efficacy (faster rate of progression in younger population), there is interest in 
understanding efficacy and safety of vatiquinone for the population older than 21 years. 
Therefore, approximately 20 subjects older than 21 years will be randomized. In order to 
maintain balance between number of subjects randomized to vatiquinone or placebo for both age 
groups, age at screening of ≤21 versus >21 years is also included as a stratification factor for 
randomization.  
The primary clinical outcome endpoint of mFARS is extensively validated in the FA 
investigative community. The mFARS may prove superior in more complex studies because it 
provides a more detailed evaluation of overall patient status and a more complex yet valid 
construct, with improved psychometric properties when compared to FARS (Rummey 2019).  
The present study includes secondary and exploratory clinical outcome endpoints to assess the 
effect of vatiquinone on subjects’ quality of life. Loss of ambulation and dysarthria are key 
features of this disorder and have a notable impact on quality of life. The 1MWT and fall log 
directly relate to a subject’s ability to ambulate during normal daily activities. The Redenlab 
speech assessment protocol is a sensitive measure of discrete components of speech ability.  

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Fatigue is another common finding in FA. Its impact is additive with any underlying 
neurological dysfunction, further limiting a patient’s ability to perform their daily activities. The 
MFIS is a validated instrument that has been utilized in many neurological disorders, particularly 
in multiple sclerosis (Meca-Lallana 2019). FARS-ADL and EQ-5D-5L are measurements of 
activities of daily living and general health status. FARS-ADL, as part of FARS, was specifically 
designed taking into account the unique challenges of the FA patient. The EQ-5D-5L has been 
broadly applied to many different patient groups (Devlin 2018). The Upright Stability subscale 
of the mFARS includes 6 stance-related items (stance with feet apart, stance with feet apart and 
eyes closed, stance with feet together, stance with feet together and eyes closed, tandem stance, 
and stance on the dominant foot) as well as sitting posture, tandem walk, and gait. This subscale 
is thought to quantify disease progression in the early phase of FA (Rummey 2019). 
The endpoints in this trial will be evaluated at 72 weeks. This treatment duration was chosen 
based upon the findings from other clinical trials, including the Phase 2b study of vatiquinone in 
subjects with FA (Zesiewicz 2018). In a slowly progressive neurodegenerative disorder such as 
FA, adequate time must be allowed to gauge any differences in progression between drug and 
placebo groups. Additionally, trials in FA with placebo arms have shown a considerable placebo 
effect which tends to peak at 12 weeks, and to diminish after approximately 6 months 
(Lynch 2010, Lynch 2019a). A 24-week open-label extension will follow the initial 72 weeks of 
treatment to evaluate the long-term safety and efficacy of vatiquinone in FA patients.  
In conclusion, PTC Therapeutics (PTC) believes that the design of this trial will allow for safe 
and robust assessment of vatiquinone in the FA population. 
3.3. 
Justification of Dose 
In a study in FA adult patients treated with vatiquinone 200 mg and 400 mg tid 
(Study EPI-2010-006), the mean Cmax and the area under the plasma concentration-time curve 
from time zero to 8 hours (AUC0-8h) at 200 mg were 465.6 ng/mL and 1026.2 ng*h/mL, 
respectively, whereas the mean Cmax and AUC0-8h at 400 mg tid were 1019.0 ng/mL and 
2428.4 ng*h/mL, respectively. At steady state (Day 91), AUC0-8h was 70% to 90% higher than 
that at Day 1. Following the second daily dose of 200 mg, mean Cmax reached 450 ng/mL and 
471 ng/mL for Day 1 and 91, respectively. Following the second daily dose of 400 mg, the 
plasma concentration increased substantially higher compared to the first daily dose, both on 
Days 1 and 91. The mean Cmax after the second daily dose of 400 mg was 1531 ng/mL and 
2109 ng/mL on Days 1 and 91, respectively. The plasma concentration-time profile at the steady 
state (Day 91) with the lower dose group (200 mg tid) showed that vatiquinone plasma 
concentration was largely maintained above 100 ng/mL (227 nM) after the morning dose, which 
exceeded the half maximal effective concentration (EC50) of cell-based assay of vatiquinone 
rescue of fibroblasts derived from patients with mitochondrial disorders and other disorders of 
oxidative stress including FA (EC50=24 nM).  

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In the same clinical study, there were no drug-related SAEs during the course of the study. 
In addition, there were no drug-related laboratory abnormalities and no dose-limiting toxicities 
of vatiquinone. The frequency of subjects who experienced any AE was similar by treatment 
group: 100% (200-mg cohort), 81.8% (200 mg crossed-over cohort), 95.0% (400 mg cohort) and 
90.0% (400-mg crossed-over cohort) and 90.5% (placebo). The most frequently reported events 
among subjects on active treatment were increased weight 32/63 (placebo 6/21), upper 
respiratory tract infection 23/63 (placebo 5/21), dysgeusia 13/63 (0 placebo), and headache 14/63 
(placebo 3/21). Posthoc analysis of the long-term effects of vatiquinone on FA disease 
progression showed that treatment with vatiquinone was associated with an overall improvement 
in FARS scores of 1.8, whereas a matched natural history cohort had an overall worsening of 
4.8 points over two years (p<0.01). These data suggest that long-term treatment with vatiquinone 
improved overall disease severity as well as slowed disease progression relative to disease 
natural history.  
Collectively, both doses of 200 mg and 400 mg tid were demonstrated to be safe and effective in 
adults in a Phase 2 study of FA subjects. Clinical studies in other patient populations also 
showed acceptable safety profile. Therefore, in this Phase 2b/3 study, we propose a dose of 
200 mg PO tid if ˂12 years of age and weighing ˂25 kg or 400 mg PO tid if ≥12 years of age 
and/or ≥25 kg. 
3.4. 
End of Study Definition 
The end of the study is defined as the last subject’s last visit. 
4. 
STUDY POPULATION  
4.1. 
Overview 
The study will be conducted at approximately 10 sites globally. Additional sites and investigators 
may be added as needed to complete the study. An estimated 126 subjects (106 subjects between 
ages 7 and 21 years and up to 20 subjects greater than 21 years) will be enrolled in the trial. 
4.2. 
Inclusion Criteria 
1. mFARS ≥20 to ≤70 at baseline 
2. Minimum age 7 years at the time of Screening Visit 
3. Must be able to ambulate at least 10 feet in one minute with or without assistance 
(non-wheelchair) 
4. Friedreich ataxia diagnosis (homozygous for GAA repeat expansion in intron-1 of FXN 
gene), confirmed by clinical testing (Note: size of GAA repeat is not required for 
eligibility) 
5. Consent to comply with study procedures. For subjects under the age of 18 (or age of 
consent), parent(s)/legal guardian(s) of the subject must agree to comply with the 
requirements of the study, including the need for frequent and prolonged follow-up; 
parent(s)/legal guardian(s) with custody of the subject must give their consent for subject 
to enroll in the study. 
6. Difference in the mFARS between screening and baseline of no more than 4 points 

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7. Must be able to abstain from anticoagulants and any aspirin (including 81 mg) for 
30 days prior to the Baseline Visit and for the duration of the study; any possible 
discontinuation of anticoagulants should be monitored and indicated by a specialist 
(eg, cardiologist, neurologist, or hematologist) and discontinuation will be noted by the 
prescribing physician (see Appendix 1). 
8. Must be able to abstain from potent cytochrome P450 (CYP) 3A4 inducers/inhibitors 
(eg, ketoconazole, rifampin, St. John’s wort, grapefruit juice or any grapefruit product) 
for at least 30 days prior to enrollment (see Appendix 1) 
9. Must be able to swallow capsules 
10. Males and females of childbearing potential must be willing to use an effective method of 
contraception as defined in protocol Section 7.5.10 from the time consent is signed until 
30 days after the last dose of study drug or early termination visit. Male subjects must 
agree not to donate sperm during the study and for at least 30 days after the last dose of 
study drug or early termination visit.   
4.3. 
Exclusion Criteria 
1. Individuals with clinical diagnosis of FA who have point mutations or deletions or other 
non-GAA expansion mutations 
2. Previous treatment with vatiquinone  
3. Allergy to vatiquinone, sesame oil, gelatin (bovine and/or porcine), titanium dioxide, or 
red iron oxide 
4. Ejection fraction <50% 
5. Uncontrolled diabetes (HbA1c >7.0%) at the time of screening  
6. Has current suicidal ideation based on Columbia-Suicide Severity Rating Scale (C-SSRS) 
within 3 months prior to screening or between screening and baseline at the Baseline 
Visit or suicidal behavior within the last year at the Screening Visit or between screening 
and baseline at the Baseline Visit 
7. Pregnant or lactating subjects or those sexually active subjects who are unwilling to 
comply with proper birth control methods; females of childbearing potential must have a 
negative pregnancy test at Screening and during the Baseline Visit  
8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2×ULN at time of 
screening 
9. INR ≥1.5×ULN at time of screening or clinically significant (CS) bleeding, as determined 
by the investigator 
10. Serum creatinine ≥1.5×ULN at time of screening 
11. Comorbidities that may confound study results (eg, fat malabsorption syndrome, other 
mitochondrial disorder) in the opinion of the investigator 
12. Participation in any other interventional clinical trial or received any investigational drug 
in any other clinical trial within 60 days prior to the Baseline Visit. Subjects may be 
rescreened after the exclusionary period of 60 days has passed. 

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13. Concomitant use of interventional CoQ10, vitamin E, or any approved or non-approved 
medication for FA within 30 days prior to the Screening Visit (Appendix 1). These 
prohibited medications can be discontinued at the Screening Visit; if this is the case, the 
mFARS assessment must be repeated to confirm inclusion eligibility after a minimum of 
30 days post-discontinuation and there must be no more than a 4-point difference in 
mFARS assessed from the Post-Discontinuation Visit to the Baseline Visit. 
14. Illicit drug use 30 days prior to screening and during the study is prohibited. 
4.4. 
Screen Failures 
Any subject that does not meet inclusion or exclusion criteria within the defined screening 
window prior to randomization, will be considered a screen failure.  
5. 
STUDY INTERVENTION 
5.1. 
Study Intervention(s) Administration 
5.1.1. 
Study Intervention Description 
Subjects meeting eligibility criteria will be randomized to receive either placebo or vatiquinone 
during the placebo-controlled phase of the study. 
5.1.2. 
Dosing and Administration 
Subjects will receive vatiquinone at a dose of 200 or 400 mg tid (at mealtimes [breakfast, lunch, 
and dinner]) with food with at least 25% fat. Vatiquinone (or placebo) dosing will occur 
according to the schedule described under Placebo-controlled and Open-label Extension Phase. 
A 25% fat meal is required for appropriate absorption of vatiquinone from the gastrointestinal 
tract. The study drug will be given orally and needs to be followed by eating yogurt, ice cream 
(no non-fat), or any other food with at least 25% calories from fat. Additional details on dosing 
can be found in the Pharmacy Manual. 
5.1.3. 
Treatment of Missed Doses and Overdose 
If a subject misses the breakfast or lunchtime dose of study drug, the dose may be “made up” up 
to 2 hours after scheduled. If more than 2 hours have elapsed from the time the missed dose was 
due, the subject will be required to skip that dose and wait until the next scheduled dose. If a 
subject misses the third dose (ie, the dinnertime dose), the dose may be made up anytime up until 
midnight and must be taken with a 25% fat meal requirement.  
For this study, any dose of vatiquinone greater than the scheduled daily dose taken within a 
24-hour time period (±1 hour) will be considered an overdose. PTC does not recommend specific 
treatment for an overdose of vatiquinone. The investigator will use clinical judgment to treat any 
overdose. Any overdose should be reported as an adverse event as described in Section 7.5.8. 

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5.2. 
Preparation/Handling/Storage/Accountability 
5.2.1. 
Accountability 
Adequate records of study drug receipt and disposition will be maintained by the (institution’s) 
pharmacy records of receipts, investigational drug orders, dispensing records, and disposition 
forms. The study monitor will also assess drug accountability and will request to review the 
pharmacy records and investigator study file to assure the study medication is prescribed by the 
investigator or designee for the purpose of this study.  
Subjects should return all used/unused study drug at each in person visit for proper study drug 
accountability. The Week 72 visit marks the end of the placebo-controlled period, and new study 
drug will be dispensed for the open-label phase at this visit. At study completion, all used/unused 
study drug should be returned to the drug depot or destroyed according to the study site’s 
standard operating procedures after site/monitor verifies accountability. 
Study medication will be reviewed to assess compliance on an ongoing basis. Subjects who take 
>80% of the prescribed doses and no more than 110% of the prescribed doses will be considered 
compliant. Subjects who fall outside of this threshold will be counseled and re-instructed on 
dosing procedures. Medication compliance will be recorded on the eCRF for each visit.  
Vatiquinone will be stored at room temperature below 30ºC. The investigator will ensure that all 
study drugs are stored and dispensed in accordance with the Food and Drug Administration 
(FDA) and local regulations concerning the storage and administration of investigational drugs. 
5.2.2. 
Formulation, Appearance, Packaging, and Labeling 
Vatiquinone is manufactured as a 200 mg capsule (size 1 Swedish orange) unit dose for oral 
administration and is packaged in 97 count white high-density polyethylene (HDPE) bottles with 
a child resistant closure. Each bottle of 97 vatiquinone 200 mg capsules is enough for one month 
when dosing 200 mg tid or for approximately 2 weeks when dosing 400 mg tid. Therefore, 
subjects receiving 200 mg tid will receive 3 bottles at each clinic visit, and subjects receiving 
400 mg tid will receive 6 bottles at each clinic visit.  
The placebo for vatiquinone 200 mg capsules is sesame oil with a colorant that is filled into hard 
gelatin Swedish orange opaque size 1 capsule shell and sealed with a gelatin banding solution 
seal identical in appearance to the active drug product. The composition of the placebo capsule 
excludes the active vatiquinone and includes carotene as a 20% suspension in olive oil 
(Betatene® 20% OLV) to match the color of the fill solution. During the phase of the study where 
subjects are to receive placebo, the number of placebo capsules provided to each subject will 
match those of active received when assigned to vatiquinone treatment. 
Each bottle is labeled with the following but not limited to the product name, product lot number, 
recommended storage conditions, expiration date, and a caution limiting it for Clinical Trial Use 
Only. Blister packs may be approved for use in the open-label extension phase later in the study. 
5.2.3. 
Preparation 
Not applicable 

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5.3. 
Measures to Minimize Bias: Randomization and Blinding 
Subjects meeting the eligibility criteria for the study will be stratified by baseline mFARS 
(<40 versus ≥40), age at disease onset (<14 years or ≥14 years), and age at Screening (≤21 years 
or >21 years) and randomized 1:1 during the Baseline Visit (after completing the Baseline Visit 
procedures) to either vatiquinone treatment or placebo group associated with the assigned 
randomization number via IRT, according to a pre-generated randomization schedule that was 
prepared by an independent third party company. Based on subject’s age at Screening and body 
weight, dose of vatiquinone or placebo will be determined as follows: Subjects ˂12 years of age 
and weighing ˂25 kg will receive vatiquinone 200 mg or matching placebo tid; 
Subjects ≥12 years of age and/or ≥25 kg will receive vatiquinone 400 mg or matching placebo 
tid.  
The investigators, study subjects, and sponsor will be blinded as follows: the sponsor will be 
blinded to the randomized treatment until the study is unblinded after all subjects complete the 
placebo-controlled phase; subjects and investigators remain blinded to the treatment received 
during both the placebo-controlled and open-label phases. 
The appearance of vatiquinone and placebo are the same and the quantity of drug dispensed are 
the same as well to keep all parties blinded. Vatiquinone is manufactured as a 200 mg capsule 
(size 1 Swedish orange) unit dose for oral administration and is packaged in 97 count white 
HDPE bottles with a child resistant closure. For this study, placebo will consist of a size 
1 Swedish orange capsule containing sesame oil NF and a colorant to match vatiquinone 200 mg 
capsule appearance of both the capsule exterior and contents. During the phase of the study 
where subjects are to receive placebo, the number of placebo capsules provided to each subject 
will match the number of capsules of vatiquinone provided to those assigned to vatiquinone 
treatment.  
Under normal circumstances, the blind will not be broken. The appearance of vatiquinone and 
placebo are the same, as described in Section 5.2.2. The blind may be broken by the principal 
investigator if specific emergency treatment would be dictated by knowing the medication. In 
such cases, the Principal Investigator should contact the PTC medical monitor; however, in 
emergency the investigator may do so and notify the medical monitor.  
5.3.1. 
Instructions for Unblinding 
Investigators have the ability to unblind via the IRT. Additional details are provided in the IRT 
Site User Training presentation. 
5.4. 
Study Intervention and Compliance 
This study will be conducted in full accordance with all applicable Federal and local laws and 
regulations, including 45 Code of Federal Regulations (CFR) 46, 21 CFR Parts 50, 54, 56, 312, 
and 314 and the Good Clinical Practice: Consolidated Guideline approved by the International 
Council for Harmonisation (ICH). Any episode of noncompliance will be documented.  
The investigators will perform the study in accordance with this protocol, will obtain consent and 
will report adverse events in accordance with site Institutional Review Board (IRB)/Institutional 
Ethics Committee (IEC) Policies and Procedures and all Federal requirements. Collection, 
recording, and reporting of data will be accurate and will ensure the privacy, health, and welfare 
of research subjects during and after the study. 

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5.5. 
Concomitant Therapy 
Any medication taken by a subject 60 days prior to Baseline Visit and during the course of the 
study and the reason for use of the medication will be recorded on the eCRF. During screening, 
each subject will be instructed to report the use of any medication to the investigator. Subjects 
will also be instructed about the importance of not taking any other medication throughout the 
study (including over-the-counter [OTC] medications) without consulting the investigator. 
Subjects should abstain from anticoagulants (eg, enoxaparin, heparin, warfarin, any aspirin 
[including 81 mg]) for at least 30 days prior to the Baseline Visit and throughout study 
participation (see Appendix 1). Any possible discontinuation of anticoagulants should be 
monitored and indicated by a specialist (eg, cardiologist, neurologist, or hematologist), and 
discontinuation will be noted by the prescribing physician. Ongoing treatment with CYP 
inhibitors such as ketoconazole or CYP inducers such as rifampin, along with use of St. John’s 
wort extract and/or grapefruit juice or any grapefruit product (see Appendix 1), must be 
completed at least 30 days prior to enrollment. Concomitant use of interventional CoQ10, 
vitamin E, or any approved or non-approved medication for FA within 30 days prior to 
Screening Visit will not be permitted (see Appendix 1). These prohibited medications can be 
discontinued at the Screening Visit; if this is the case, the mFARS must be repeated to confirm 
inclusion eligibility after a minimum of 30 days post-discontinuation, and there must be no more 
than a 4-point difference in mFARS assessed from the Post-Discontinuation Visit to the Baseline 
Visit. Participation in any other interventional clinical trial or use of any investigational drug in 
any other clinical trial within 60 days prior to the Baseline Visit will not be permitted. Subjects 
may repeat the Screening Visit once after the exclusionary period of 60 days has passed.  
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any other drug(s) should consider the subject’s safety, the medical need, the 
potential for drug interactions, the possibility for masking symptoms of a more relevant 
underlying event, and whether use of a concomitant medication will compromise the outcome or 
integrity of the study. Illicit drug use 30 days prior to screening and during the study is 
prohibited. 
Subjects and parents/caregivers or legal guardian should be instructed about the importance of 
the need to inform the clinic staff of the use of any drugs or remedies (whether prescribed, OTC, 
or illicit) before and during the course of the study. 
The investigator is encouraged to consult the PTC medical monitor or designee with questions 
relating to specific drugs and their potential for interactions with PTC743. 
5.6. 
Dose Modification and Stopping Rules 
In the event that any subject develops any AE ≥Grade 3 per Common Terminology Criteria for 
Adverse Events (CTCAE) criteria version 5.0 in severity that is deemed related to treatment with 
study drug and not related to the underlying disease, the principal investigator should contact 
PTC’s medical monitor to discuss dose modification options up to and including discontinuation 
of the administration of study drug. 
In the event that any subject develops or is diagnosed with an allergy to vatiquinone sesame oil, 
gelatin (bovine and/or porcine), titanium dioxide, or red iron oxide after initiating treatment with 
study drug, administration of study drug will be discontinued. 

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In the event that any subject develops elevated INR ≥Grade 2 in severity (>1.5×ULN) per 
CTCAE criteria version 5.0 thought to be related to treatment with study drug, administration of 
study drug will be reduced according to Table 2. Should the INR toxicity not resolve to at least 
Grade 1 in severity within two weeks of the initial dose reduction, administration of study drug 
may either be further reduced or discontinued. 
Once a subject’s dose is reduced due to elevated INR thought to be related to study drug 
administration, their dose should not be re-escalated. 
The investigator is responsible for decisions on dose holds, reductions, or interruptions for any 
CS AE. The Data Safety Monitoring Board (DSMB) is responsible for determining dose 
modification or stopping actions for any other safety event. 
Table 2: 
Dose Modification and Stopping Rules for Vatiquinone 
Qualifying Event 
Example Guidelines for Management 
Recommendation 
If Resolved To ≤ Grade 1 
If Not Resolved To 
≤Grade 2 After 14 Days 
INR ≥ Grade 2 or 
>1.5×ULN 
If subject on 200 mg 
tid: 
Reduce dose by 1/3 
from 200 mg tid to 
200 mg bid. 
Re-evaluate 7 days 
after dose reduction. 
Continue on study at 
2/3 dose. 
 
*Once a subject is dose 
reduced, do not re-escalate 
for the duration of study 
participation. 
Consider withdrawing the 
subject after consultation 
with the study medical 
monitor. 
If subject on 400 mg 
tid: 
Reduce dose by 1/2 
to 200 mg tid. 
Re-evaluate 7 days 
after dose reduction. 
Continue on study at 
½ dose. 
 
*Once a subject is dose 
reduced, do not re-escalate 
for the duration of study 
participation. 
Abbreviations: bid, twice daily; INR, international normalized ratio; tid, three times daily; ULN, upper limit of normal 
5.6.1. 
Procedure for Dose Modification 
In order to determine that there is an INR (or other laboratory related AE) requiring dose 
modification, laboratory results classified by the investigator as clinically significant must be 
provided. In the case of other laboratory related AEs, the investigator will consult with the 
medical monitor since the protocol does not specify dosing parameters for this. Instructions on 
reducing the dose in IRT can be found in the IRT manual.  
6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
6.1. 
Discontinuation of Study Intervention 
Subjects will receive study treatment until protocol specified study completion or treatment 
discontinuation for one of the reasons listed below. However, subjects may discontinue study 
treatment or withdraw their consent to participate in the study at any time without prejudice. In 
the event that a subject discontinues from the study drug prematurely, and unless consent is 
withdrawn, all efforts must be made to collect efficacy and safety data by completing all study 
visits according to the Schedule of Events and Study Parameters (Section 7.1).  

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The following conditions require subject discontinuation from all study treatment: 
• At their own request or at the request of their legally authorized representative 
• If a subject experiences an AE that is deemed related to treatment with study drug and 
in the investigator’s or the sponsor’s medical judgment continuation of treatment 
would be detrimental to the subject 
• At the specific request of a regulatory agency for termination of treatment of an 
individual subject or all subjects under the protocol  
• Subject participation in another clinical study using an investigational agent or 
investigational medical device 
• Refusal of sexually active fertile subjects (excluding subjects who have been 
sterilized) to use medically accepted methods of contraception 
• If a subject becomes pregnant  
• Significant noncompliance with the protocol in the opinion of the investigator or the 
sponsor 
The date vatiquinone is discontinued and the reason for discontinuation will be recorded in the 
source documents and in the eCRF. The PTC medical monitor (and designee) should be 
informed via e-mail when a subject discontinues study drug.  
When vatiquinone is discontinued, the investigator is expected to perform all of the evaluations 
according to the subject’s original schedule and as required at the End of Study Visit and any 
additional evaluations that may be necessary to ensure that the subject is free of untoward 
effects. 
6.2. 
Participant Discontinuation/Withdrawal from the Study 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject’s medical 
records. If the reason is not known, the subject must be followed to establish whether the reason 
was due to an AE, and, if so, this must be reported in accordance with the procedures in the 
section entitled Adverse Event Reporting (Section 7.5.8). 
Evaluations should be performed on all subjects who participate but do not complete the study 
according to protocol. Dropouts may be replaced at the request of the sponsor. Subjects who 
have an ongoing AE at the time of study completion will be followed until the event resolves, or 
until the sponsor and the investigator agree that further follow-up is not medically necessary. 
6.3. 
Lost to Follow-up 
A subject who repeatedly fails to return for scheduled visits and is unable to be contacted by the 
study site will be considered lost to follow-up. 
The investigator will make every effort to contact subjects lost to follow-up. 
The following actions should be taken if a subject fails to return to the clinic for a required study 
visit: 

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• Attempt to contact the subject and reschedule the missed visit as soon as possible and 
counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study. 
Before a subject is deemed lost to follow-up, the investigator or designee must make every effort 
to contact the subject. These contact attempts should be documented in the subject’s medical 
record. A minimum of 3 documented telephone contact attempts and 1 certified letter within 
6 weeks of the most recent planned study visit must be sent in efforts to contact the 
subject/caregiver/legal guardian. After being considered lost to follow-up, a subject’s status may 
be changed if the subject/caregiver/legal guardian makes contact at a later time provided the trial 
is ongoing. 

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7. 
STUDY ASSESSMENT AND PROCEDURES 
7.1. 
Schedule of Events and Study Parameters 
Study Period 
Screening1 
(Up to 42 
days prior 
to Baseline) 
Screening visit  
(for post-
discontinuation 
mFARS) 
Baseline 
(Day 1) 
Placebo-controlled 
(All visits/contacts ± 1 week) 
Open-label extension 
(All visits/contacts 
± 2 weeks) 
Follow-up 
(approximately 
30 days 
[±5 days] after 
last dose or 
early 
termination 
visit) 
Study Week 
 
 
 
Weeks 4, 8, 16, 
20, 28, 32, 40, 44, 
52, 56, 64, & 68 
Telephone calls 
Weeks 12, 
24, 36, 48, 60 
In-person 
visits 
Week 72 
In-person 
visit 
Weeks 78 
and 90 
Telephone 
calls 
Weeks 84 
and 962 
In-person 
visits 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Eligibility assessment 
and Inclusion/ 
exclusion criteria 
X 
 
X 
 
 
 
 
 
 
Chart review-previous 
medical history3 and 
demographics 
X 
 
 
 
 
 
 
 
 
Genetic confirmation 
of Friedreich ataxia 
diagnosis4 
X 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
X 
 
X 
X 
 
X 
 
Echocardiogram5 
X 
 
 
 
X 
X 
 
X 
 
Height, weight, oxygen 
saturation 
X6 
 
X 
 
X 
X 
 
X 
 
Physical exam7 and 
vital signs 
(Temp, HR, RR, BP) 
X 
 
X 
 
X 
X 
 
X 
 
Pregnancy test8 
X 
 
X 
 
X 
X 
 
X 
X 
Fasting hematology 
including CBC with 
differential and 
coagulation panel9 
X 
 
X 
 
X 
X 
 
X 
 
Fasting serum 
chemistry9, 10 
X 
 
X 
 
X 
X 
 
X 
 
HbA1c 
X 
 
 
 
X 
X 
 
X 
 
Urine drug screen 
(10 panel) 
X 
 
 
 
 
 
 
 
 

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Study Period 
Screening1 
(Up to 42 
days prior 
to Baseline) 
Screening visit  
(for post-
discontinuation 
mFARS) 
Baseline 
(Day 1) 
Placebo-controlled 
(All visits/contacts ± 1 week) 
Open-label extension 
(All visits/contacts 
± 2 weeks) 
Follow-up 
(approximately 
30 days 
[±5 days] after 
last dose or 
early 
termination 
visit) 
Study Week 
 
 
 
Weeks 4, 8, 16, 
20, 28, 32, 40, 44, 
52, 56, 64, & 68 
Telephone calls 
Weeks 12, 
24, 36, 48, 60 
In-person 
visits 
Week 72 
In-person 
visit 
Weeks 78 
and 90 
Telephone 
calls 
Weeks 84 
and 962 
In-person 
visits 
 
PK samples11 
 
 
X 
 
X 
X 
 
X 
 
AE/SAE assessment 
SAEs only 
 
X 
X 
X 
X 
X 
X 
X12 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X13 
 
 
 
 
 
 
Modified Friedreich 
Ataxia Rating Scale 
X14 
X14 
X14 
 
X 
X 
 
X 
 
One-minute walk test 
X 
 
X 
 
X 
X 
 
X 
 
Modified Fatigue 
Impact Scale 
 
 
X 
 
X 
X 
 
X 
 
FARS-ADL 
 
 
X 
 
X 
X 
 
X 
 
EQ-5D-5L 
 
 
X 
 
X 
X 
 
X 
 
Fall log review 
 
 
 
 
X 
X 
 
X 
 
Speech assessment 
X 
 
X 
 
X 
X 
 
X 
 
C-SSRS15 
X 
 
X 
 
X 
X 
 
X 
 
Train subject/caregiver 
on fall log completion 
 
 
X16, 17 
 
 
 
 
 
 
Fall log entry16. 17 
 
 
X——————————————————————————————————— 
 
Vatiquinone (200 mg 
or 400 mg) or placebo 
dose PO tid with 25% 
fat meal 
 
 
X18 —————————————————————————————————— 
 
Dispense study drug 
 
 
X18 
 
X 
X19 
 
X 
 
Drug reconciliation  
 
 
 
 
X 
X 
 
X 
 
Abbreviations: AE, adverse event; BP, blood pressure; CBC, complete blood count; COVID-19, Coronavirus disease 2019; C-SSRS, Columbia-Suicide Severity 
Rating Scale; ECG, electrocardiogram; FARS-ADL, Friedreich Ataxia Rating Scale Activities of Daily Living; GAA, guanine-adenine-adenine; 
GGT, gamma-glutamyl transferase; HR, heart rate; ICF, informed consent form; INR, international normalized ratio; LDH, lactate dehydrogenase; mFARS, 
modified Friedreich Ataxia Rating Scale; PK, pharmacokinetic; PO, by mouth; RR, respiratory rate; SAE, serious adverse event; Temp, temperature; tid, three 
times daily; wk, week 
Note: Clinical lab samples should be collected with pre-dose PK samples to avoid multiple needle sticks. Dosing may occur prior to laboratory results being 
available.  

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1 Screening will be conducted and completed up to 42 days prior to the Baseline Visit for those requiring a washout. Subjects who are unable to adhere to the 
screening time window specified in the protocol due to unforeseen circumstances (eg, COVID-19) may be rescreened upon Sponsor approval. 
2 The End of Treatment Visit will take place at Week 96. 
3 Fall history will be collected as part of the medical history. A fall log will be maintained as described in Footnote 17. 
4 If previous genetic testing is available, it does not have to be repeated. The size of GAA repeat is not required for eligibility (Section 4.2). 
5 Echocardiogram will take place after completion of all other assessments/procedures on the same day, as applicable, for primary and secondary endpoints. 
Echocardiogram will be performed at Screening and at the Week 36, Week 72, and Week 96 visits. Unscheduled echocardiograms may be performed at the 
investigator’s discretion; any unscheduled echocardiogram is considered relevant at the investigator’s discretion. 
6 Height will only be collected at the Screening Visit. All subsequent visits will collect weight and oxygen saturation. 
7 Physical examinations will include a neurologic assessment. Full physical examination will be performed at Screening, and a targeted examination (including 
neurologic assessment) may be performed at all subsequent visits. 
8 Female subjects of childbearing potential must have a negative serum pregnancy test at screening; urine pregnancy testing may be performed at all subsequent 
visits. At-home urine pregnancy test kits will be provided; subjects will be required to perform the test at home ~30 days post last dose of study drug and self-report 
the results via telephone. 
9 Since subjects may sign the ICF then have screening labs obtained immediately after, subjects may obtain screening hematology and serum chemistry 
laboratory samples under non-fasting conditions. All subsequent laboratory samples should be obtained under fasting conditions (ie, following an 8-hour fast). 
Screening laboratory samples will be used for inclusion/exclusion; baseline labs do not need to be resulted prior to the first dose of study drug. Local laboratories 
may be utilized sparingly for screening laboratory values or for INR follow-up for INR AE. 
10 Serum chemistry will include complete metabolic panel, magnesium, phosphorous, LDH, GGT, and lipid panel. 
11 Pharmacokinetic samples will be collected at each clinic visit starting at the Baseline Visit at 0 hour (immediately prior to the morning dose) and >1 hour following 
the dose for placebo-controlled visits only. Pre-dose PK samples will be collected at each visit during the open-label extension phase. 
12 The follow-up contact will be by telephone and should be completed approximately 30 days (±5 days) after last study drug administration or termination visit, 
whichever is later. Data to be followed will be limited to AEs that were deemed study drug-related or any SAE and will be followed until resolution or until they have 
normalized. At the investigator’s discretion, an office visit and additional tests may be conducted in order to ensure proper follow-up of an AE/SAE. 
13 Randomization will occur on the same day as the Baseline Visit. 
14 The Screening and the Baseline mFARS must occur at least 24 hours apart. Subjects may have an additional Screening Visit for mFARS assessment after a 
minimum of 30-days post-discontinuation of interventional CoQ10, vitamin E, or any approved or non-approved medication for FA. If the subject has already been 
off of these medications for 30 days at the time of the Screening Visit, then an additional Screening Visit for mFARS will not be required. 
15 C-SSRS will be collected at Screening, Baseline, and during every in-person visit while on study treatment.  
16 During the Baseline Visit, the subject and/or caregiver will be trained on how to capture information in the fall log. 
17 The fall log will capture the date and time of each fall. Falls should be recorded daily by the patient or a live-in caregiver. The daily log should capture how often 
the patient falls during the day, whether the fall resulted in an injury, any other consequences from the fall (eg, went to the hospital, loss of consciousness), what 
the person was doing prior to the fall, and who reported the fall (ie, patient, caregiver, or another witness who reported it to the caregiver). Outcomes should 
assess both frequency of falls and fall severity (eg, falls leading to injury). All falls resulting in injury should be reported as an AE. 
18 First dose for the placebo-controlled phase of the study will be taken in the clinic on the same day as the Baseline Visit after all baseline assessments are 
completed. Study drug will be dispensed during the Baseline Visit and at each subsequent in-person visit (except for the Week 96 visit). Drug may be delivered via 
delivery service if needed. 
19 The Week 72 visit marks the end of the placebo-controlled phase; open-label study drug is dispensed at the Week 72 visit. Please remember that subjects are to 
bring back all used/unused study drug to each in person visit for accountability throughout the study. 
 

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7.2. 
Efficacy Assessments 
Primary efficacy will be assessed by the change from baseline to 72 weeks in the mFARS score. 
Secondary endpoint assessments will include the FARS-ADL scale (key secondary endpoint), 
1MWT, and fall log. Exploratory endpoints will include speech fluency, fatigue scale, 
EQ-5D-5L, and Upright Stability subscale of the mFARS. 
The FARS is a disease-specific scale that measures progression of neurological effects of FA, 
specifically designed for this patient population and used as an outcome measure in several FA 
clinical trials. The FARS specially assesses FA disease progression when used at 1 and 2 years, 
following initial evaluation as seen in FA natural history studies (Zesiewicz 2018, Lynch 2019b). 
The mFARS is a validated and reliable 93-point scale with a Cronbach α=0.92; comprised of the 
neurologic component of the FARS, evaluating bulbar, upper limb, lower limb, and upright 
stability/gait function. For each item, responses categorize the corresponding neurological 
finding, and the findings are assigned a score ranging from 0 to 3, 4, or 5 with 0 being normal 
and higher numbers indicative of greater impairment. The FARS was converted to the mFARS 
by removing the peripheral nervous system component and 2 items of the bulbar subscore to 
improve overall construct and interrater reliability. As a result, subscale correlations and 
reliability of the mFARS score are improved and the items assessing functional ability are more 
psychometrically robust . 
The FARS-ADL is a subsection of the FARS questionnaire that assesses activities of daily 
living, including speech, personal hygiene, feeding, and mobility. Subjects rank each category 
using a scale of 0 to 4, with lower scores indicative of “normal” function/activity. 
The 1MWT is a timed performance test used to measure functional ability, walking endurance, 
balance, and muscle performance by measuring maximal walking speed in 1 minute. Patients are 
instructed to walk as quickly as possible for 1 minute without running. Maximal walking speed is 
measured upon completion of the walk and recorded. It has been validated for use in patients 
with cerebral palsy with similar functional limitations. It exhibits good test-retest reliability and 
may be a more useful measure of functional mobility, given its shorter length as compared to 
other tests, such as the 6-minute walk test, in this population (McDowell 2005).  
Loss of ambulation is a key feature of FA and has a notable impact on quality of life. The 1MWT 
and fall log directly relate to a subject’s ability to ambulate during normal daily activities. Thus, 
each subject will be required to maintain a fall log, which will include the date and time of each 
fall. Falls as defined by World Health Organization, “inadvertently coming to rest on the ground, 
floor or other lower level, excluding intentional change in position to rest in furniture, wall or 
other objects,” will be reported (WHO 2007). Fall history will be assessed at baseline as part of 
the medical history and will be recorded daily during the study by the patient or a live-in 
caregiver. The daily log should capture how often the patient falls during the day, whether the 
fall resulted in an injury, any other consequences from the fall (eg, went to the hospital, loss of 
consciousness), what the person was doing prior to the fall, and who reported the fall (ie, patient, 
caregiver, or another witness who reported it to the caregiver). Outcomes should assess both 
frequency of falls and fall severity (eg, falls leading to injury). All falls that result in injury 
should be reported as AEs. 

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Speech measures may be sensitive to disease progression through the late stages of FA when arm 
and leg function have declined on the performance tests. Speech evaluations will be performed 
per the Redenlab protocol, which is described below. 
• Speech Agility (syllable repetition): Measures speed and consistency of speech. 
Participants are required to rapidly and clearly produce repeating consonant-vowel 
syllabic strings. Testing commences with participants playing an example of the 
stimuli. On-screen instructions will ask: “Repeat the syllables /pataka/ as quickly and 
as clearly as possible for 10 seconds”. The participant will produce the same task 
twice. A timer appears on-screen next to the voice meter confirming the recording 
process. The tester or participant must tap the record and stop button on the screen 
before and after the task. This test takes approximately 45 seconds for both iterations. 
• Prosody Tests (reading, days of the week): Measures vocal control and timing. Tasks 
vary in linguistic complexity allowing for differentiation of motor/cognitive 
contribution to speech timing. Participants are asked to complete two speech tasks, 
including saying the days of the week and reading a standardized passage. All tasks 
are elicited via on-screen instructions. The days of the week task is repeated twice. 
This test takes approximately 3 minutes to complete. 
• Voice Performance (long vowel): Measures voice quality and phonatory-respiratory 
support. A picture appears on-screen prior to the task prompting participants to sit up 
straight, thereby standardizing posture. Participants are prompted to produce two 
tasks. The first requires participants to complete a maximum phonation task. On-
screen instructions ask: “Take a deep breath and say /ah/ for as long as you can”. 
Participants then repeat the task. On-screen instructions then ask: “Say ‘ah’ for 
5 seconds using your best and clearest voice”. A timer appears on-screen next to the 
voice meter confirming the recording process. This test takes approximately 1 minute 
to complete for all iterations.  
• Articulation and timing (picture description, monologue): Measures language 
performance, speech clarity and timing. Participants are asked to complete one speech 
task: 1. Unprepared monologue (describing happy story, memory, friends, family 
etc.). All tasks are elicited via on-screen instructions. The task is elicited once. This 
test takes approximately 1 to 2 minutes to complete. 
Fatigue is another common finding in FA. Its impact is additive with any underlying 
neurological dysfunction, further limiting a patient’s ability to perform their daily activities. The 
MFIS is a 21-item, reliable, validated instrument that has been utilized in many neurological 
disorders. It is a modified form of the Fatigue Impact Scale, a component of the Multiple 
Sclerosis Quality of Life Inventory, with a Cronbach’s α=0.90. It assesses fatigue in three 
Modules as it relates to physical, cognitive, and psychosocial functioning. Higher scores indicate 
greater impact of fatigue on participant function (Meca-Lallana 2019). 

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The EQ-5D-5L is a standardized measure of health status. It is comprised of 2 parts. 
The descriptive portion examines mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression and asks the subject to rank each category on a scale of 1, indicating no 
problem, to 5, indicating extreme problems, with higher values indicating greater problems. The 
second part of the EQ-5D-5L includes a visual analogue scale, which records the subject’s self-
rated health on a vertical visual analogue scale with response options including “The best health 
you can imagine” (score of 100) and “the worst health you can imagine” (score of 0) 
(Herdman 2011, Devlin 2018). The EQ-5D-5L is the most appropriate utility instrument for FA 
patients in children aged 7 and above.  
The Upright Stability subscale of the mFARS demonstrates a Cronbach α of 0.87 and includes 
6 stance-related items (stance with feet apart, stance with feet apart and eyes closed, stance with 
feet together, stance with feet together and eyes closed, tandem stance, and stance on the 
dominant foot) as well as sitting posture, tandem walk, and gait. This subscale is thought to 
quantify disease progression in the early phase of FA (Rummey 2019).  
7.3. 
Pharmacokinetic and/or Other Assessments 
Pharmacokinetic (PK) samples will be collected in the placebo-controlled phase at each clinic 
visit starting at the Baseline Visit at 0 hour (trough; just prior to the morning dose) and >1 hour 
following the dose. During the open-label extension phase of the study, pre-dose PK samples 
will be collected at each visit. Subjects will be instructed to refrain from taking their morning 
dose on clinic visit days; the dose on these days will be taken immediately following pre-dose 
PK and clinical laboratory collection. The time of dose administration at the night before and in 
the morning will be recorded (none will be recorded at the Baseline Visit since the first dose of 
study drug will be taken at this visit). Each dose will be taken with a 25% fat meal requirement.  
7.4. 
Safety Assessments 
Safety will be evaluated by physical examinations, vital signs assessments, echocardiograms, 
12-lead ECGs, routine clinical laboratory tests (including blood chemistry, hematology, 
coagulation as described below), and AE assessments from baseline through study completion. 
SAEs will be collected from the time of obtaining informed consent through the end of the 
extension phase. Suicide risk assessment will be performed throughout the study using the 
C-SSRS. The C-SSRS is a semi-structured clinician-rated interview to assess severity of suicidal 
behavior and ideation in the pediatric, adolescent population in community, clinical, and research 
settings . The C-SSRS can be administered by any research personnel regardless of degree, as 
long as they view the C-SSRS training and are issued a training certificate. Sites will follow their 
internal processes for referrals, if a patient is found to have suicidal ideation based on the results 
of the C-SSRS throughout the study. There is no indication that the investigational product leads 
to increased suicidality; however, per FDA guidelines, suicidality should be assessed in studies 
of drugs with CNS activity (FDA 2012). 
If at any time during the treatment phase of the study, in the opinion of the investigator, a finding 
of an AE precludes continuation of treatment with study drug at the dose level at which the AE 
was observed, the dose and/or dose regimen for the study drug may be reduced or terminated 
altogether at the discretion of the investigator. The investigator will consult with sponsor prior to 
discontinuation of treatment with vatiquinone and the DSMB will be notified of all AEs and 
SAEs. 

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7.4.1. 
Physical Examination, Height, Weight, and Vital Signs 
A complete physical examination will be conducted (excluding genital/rectal exam) at the 
Screening Visit. The physical examination will consist of an examination of the following: 
neurological assessment and assessments of general appearance, skin, head, eyes, ears, nose, 
throat, neck (including thyroid), lymph nodes, chest, heart, abdomen, and extremities. Targeted 
physical examinations, including a neurological assessment, will be conducted at all subsequent 
visits. 
Medical history and demographics including age, gender, and race, will be collected at the 
Screening Visit. Weight (kg) will be measured in ordinary indoor clothing (ie, street clothes, 
scrubs, etc.) with shoes off. Height will be recorded in centimeters (cm). 
If clinically significant findings, as determined by the investigator, are recorded for a particular 
symptom, sign, or abnormal measurement, that measurement will be repeated at medically 
appropriate intervals until the value returns to an acceptable range, a specific diagnosis is 
established, or the condition is otherwise explained. 
Vital sign measurements (temperature, pulse rate, blood pressure, and respiration rate) will be 
obtained in the sitting position (after the subject has been sitting for 5 minutes if the subject is 
capable of sitting for 5 minutes). Oxygen saturation will be obtained along with all vital sign 
assessments. 
7.4.2. 
Laboratory Evaluations 
Subjects will have approximately 169 mL of blood drawn over the course of the study. This 
blood volume estimate is based on draw values of approximately 2 mL each for hematology and 
HbA1c, about 4 mL for chemistries, about 2.7 mL for coagulation panels, and about 4 mL for 
drug concentrations per sampling; there are 10 scheduled samplings for hematology, coagulation, 
and chemistry; 9 scheduled samplings for HbA1c; and 16 samplings for PK. The variables 
discussed below will be collected at various times (according to the Schedule of Events and 
Study Parameters) to assess safety. 
7.4.2.1. 
Hematology and Coagulation 
The following hematology and coagulation values will be collected according to the Schedule of 
Events and Study Parameters shown in Section 7.1. 
• Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
volume (MCV) 
• Leukocytes: white blood cell count and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) 
• Platelets: platelet count 
• Coagulation: prothrombin time with INR, and PTT 
7.4.2.2. 
Serum Chemistry 
The following chemistry values will be collected according to the Schedule of Events and Study 
Parameters shown in Section 7.1. 

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• Liver: alkaline phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total, 
direct), gamma-glutamyl transferase (GGT), and lactic dehydrogenase (LDH) 
• Renal: blood urea nitrogen (BUN), and creatinine 
• Electrolytes: sodium, potassium, chloride, and carbon dioxide (CO2), calcium, 
magnesium, phosphorous 
• General: total protein, albumin, glucose 
• Lipids: cholesterol (total) and triglycerides 
• HbA1c 
7.4.2.3. 
Urine Drug Screen 
A 10-panel urine drug test will be collected at the Screening Visit (see the Schedule of Events 
and Study Parameters shown in Section 7.1). 
7.4.3. 
Urine or Serum Pregnancy Test 
Both men and women should be counseled to abstain from sexual activity or use an acceptable 
method of birth control while participating in this clinical research study and for approximately 
30 days after the last dose. Subjects will be required to use effective method of contraception 
(hormonal or double-barrier method). Female subjects who become pregnant should be 
immediately discontinued from the study if they have not yet received study drug. If a subject is 
found to be pregnant after she has received study drug, she should discontinue dosing, complete 
all end of study procedures, and be followed to determine the outcome of the pregnancy. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
See Section 7.5.11 for rules regarding reporting pregnancies. 
Human chorionic gonadotropin (HCG) beta will be measured on all female subjects of 
childbearing potential at Screening (serum), Baseline (urine), every 12 weeks (urine) throughout 
the study, and 30 days after the last administration of study drug (urine). 
7.4.4. 
Abnormal Laboratory Findings 
Laboratory values will be collected throughout the study to assess for safety. The investigator 
must review and assess all laboratory results in a timely manner, and determine whether the 
abnormal laboratory values, if any, are CS or not clinically significant (NCS), and whether there 
are associated signs and symptoms. Laboratory abnormalities that require clinical intervention or 
further investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event will be recorded as AEs.  
An abnormal laboratory finding in absence of any other signs or symptoms is not necessarily an 
AE. If the abnormal laboratory finding is accompanied by signs or symptoms, report the signs 
and symptoms as the AE in lieu of the abnormal laboratory value. If a diagnosis is available, 
report the diagnosis. Clinically significant laboratory abnormalities after taking study medication 
that reflect a meaningful change from the screening value(s) and that require active management 
are to be considered by the investigator as AEs (eg, abnormalities that require study treatment 
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Laboratory tests that result in significantly abnormal values should be repeated for verification. 
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, or to monitor the course of an AE, should be obtained when clinically indicated. 
In particular, if a CS abnormal result is observed that is not resolved by the final study visit, 
repeat tests should be performed to document resolution or stability of the abnormality. 
Diagnoses associated with any National Institutes of Health Common Terminology Criteria 
(CTC) v5.0 Grade 3 or 4 laboratory abnormalities will be recorded as AEs on the eCRF. 
Repeated and verified laboratory tests that meet at least Grade 3 AE requirements will be 
reported to the IRB/IEC per institutional requirements. The recorded AEs should indicate the 
underlying abnormality or diagnosis (eg, renal insufficiency) if known, as opposed to the 
observed deviation in laboratory results (eg, elevated creatinine). Any additional relevant 
laboratory results obtained by the investigator during the study will be supplied to the sponsor. 
7.5. 
Adverse Events and Serious Adverse Events 
7.5.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered related to the drug. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease in a study 
subject who is administered study drug in this study. 
For this protocol, untoward medical occurrences that should be reported as AEs include the 
following: 
• All AEs during the course of treatment with study drug administration 
• All AEs resulting from medication misuse, abuse, withdrawal, or overdose, of study 
drug 
• All AEs resulting from medication errors such as dispensing or administration error 
outside of what is described in the protocol 
• Apparently unrelated illnesses, including worsening of a preexisting illness 
• Injury or accidents. Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as 2 separate AEs. The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test) 
• Laboratory or ECG abnormalities that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event. Laboratory abnormalities associated with a 
clinical event should be captured in the source documents. Laboratory abnormalities 
not requiring clinical intervention or further investigation will be captured as part of 
overall laboratory monitoring, and should not be reported as AEs. 

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• A preexisting condition (eg, allergic rhinitis) must be noted on the appropriate eCRF 
for Visit 1, but should not be reported as an AE unless the condition worsens, or 
episodes increase in frequency during the AE reporting period. Diagnostic and 
therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE. For example, an 
acute appendicitis that occurs during the treatment with study drug should be reported 
as the AE and the resulting appendectomy should be recorded in the source 
documents and eCRF. If a surgical procedure was planned prior to entry into the 
study, and the surgery is not performed because of a worsening of a baseline 
condition, this should not be reported as an AE. Note that, as described in 
Section 7.5.2 any hospitalization occurring as the consequence of an AE during the 
study period should be reported as an SAE. 
Each AE is to be classified as serious or non-serious by the investigator using medical and 
scientific judgment. 
7.5.2. 
Definition of Serious Adverse Events  
An SAE is an untoward medical occurrence or effect associated with the use of a study drug at 
any dose, regardless of whether it is considered to be related to the study drug, which results in 
one of the following: 
• Results in death. This includes all deaths on treatment or within 30 days after last 
study drug administration, including deaths due to disease progression. Any death 
occurring later than 30 days following the last dose need not be reported as an SAE 
unless it is a result of an event that started within the period covered by the on-study 
definition. The reported AE should be the event that caused the death. In addition, 
any AE resulting in death that occurs subsequent to the AE reporting period and that 
the investigator assesses as possibly related to the study drug should also be reported 
as serious. 
• Is life-threatening. This refers to an event in which the subject was at risk of death at 
the time of the event. It does not include an event that, had it occurred in a more 
severe form, hypothetically might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for administration of the study drug, procedures required by the study 
protocol, or treatment-related diagnostic procedures; other planned hospitalizations; 
or hospitalizations related only to progression of disease). Treatments in the 
emergency room for procedures such as hydration that do not require admitting the 
subject to the hospital and observational durations in the emergency room for less 
than 24 hours do not fall into this category but the event may be serious due to 
another seriousness criterion. 
• Results in persistent or significant disability or incapacity or substantial disruption of 
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• Any other medically important event that the investigator or the sponsor judges to be 
serious or which is defined as serious by the regulatory agency in the local country. 
These are AEs that might not be immediately life-threatening or result in death or 
hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. Medical judgment should be 
exercised in deciding whether an AE is serious based on above definition. Examples 
of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
• A pregnancy resulting in spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly (including that in an aborted fetus). 
An event need not be reported as an SAE if it exclusively represents an expected change or 
progression of the disease under study. 
Note that any SAEs occurring from the time of informed consent through 30 days following the 
last dose of study drug should be reported to the sponsor if the investigator becomes aware of 
them. 
7.5.3. 
Unexpected Adverse Events 
The Investigator Brochure contains the Reference Safety Information (RSI) which will be used 
for assessing expectedness. If an event is not listed in the RSI, it should be considered 
unexpected or if the AE occurs at a greater severity, specificity, or frequency, it should be 
considered unexpected. 
7.5.4. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject/parent(s)/legal guardian/legally acceptable representative. In addition, each study 
subject/parent(s)/legal guardian/legally acceptable representative will be questioned about AEs at 
each scheduled clinic visit after study drug administration or during any telephone contact with 
the subject/parent(s)/legal guardian/legally acceptable representative. The type of question asked 
should be open-ended, for example, “How have you been feeling?” or a similar type of query. 
7.5.5. 
Recording Non‑serious AEs and SAEs 
All AEs (both serious and non-serious) that occur in subjects during the AE reporting period 
must be recorded, whether or not the event is considered drug -related. In addition, any known 
untoward event that occurs subsequent to the AE reporting period that the investigator assesses 
as possibly related to the investigational drug/product should also be recorded as an AE. 
All AEs are to be recorded in the source documents and on the eCRF using concise medical 
terminology; whenever possible, terms contained in the Medical Dictionary for Regulatory 
Activities (MedDRA) should be employed. In addition, the following information should be 
recorded: 
• Indication of whether the event is serious or non-serious (see Section 7.5.2) 
• Relationship to study drug (see Section 7.5.6) 

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• Severity of the event (see Section 7.5.7) 
• Onset date 
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 
Classification of the event as serious or non-serious determines the reporting procedures to be 
followed. 
7.5.6. 
Describing Adverse Event Relationship to Study Drug 
The investigator should provide an assessment of the relationship of the AE to the study drug, ie, 
whether there is a reasonable possibility that the study drug caused the AE, using the 
considerations outlined in Table 3. 
Table 3: 
Relationship of Study Drug to Adverse Event Relationship 
Relationship 
Description  
Probable  
A clinical event in which a relationship to the study drug seems probable because of 
such factors as consistency with known effects of the drug; a clear temporal 
association with the use of the drug; improvement upon withdrawal of the drug; 
recurrence upon rechallenge with the drug; lack of alternative explanations for the 
event.  
Possible  
A clinical event occurring coincident with administration of the study drug and which 
may or may not be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal or rechallenge may be lacking.  
Unlikely  
A clinical event with a temporal relationship to the study drug exposure that does not 
preclude causality but for which there is a clear alternate cause that is more likely to 
have caused the adverse event than study drug. Such alternatives include a 
concomitantly administered drug, the subject’s disease state, other medical conditions, 
or environmental factors.  
Unrelated  
A clinical event, for which a relationship to the study drug seems improbable because 
of factors such as inconsistency with known effects of the study drug, lack of a 
temporal association with study drug administration, lack of association of the event 
with study drug withdrawal or rechallenge, and/or presence of alternative explanations 
for the event. Alternative explanations might include a known relationship of the 
adverse event to a concomitant drug, medical history of a similar event, the subject’s 
disease state, other medical conditions, or environmental factors.  
7.5.7. 
Grading of Severity of Adverse Event 
The severity of AE will be graded using the CTCAE Version 5.0 (refer to the Study Manual). 
For each episode, the highest severity grade attained should be reported. 
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the AE. For purposes of consistency with the CTCAE, these 
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Table 4: 
Grading of Adverse Event Severity Grade 
Grade 
Adjective 
Description  
Grade 1  
Mild  
Sign or symptom is present, but it is easily tolerated, is not expected to 
have a clinically significant effect on the subject’s overall health and 
well-being, does not interfere with the subject’s usual function, and is 
not likely to require medical attention  
Grade 2  
Moderate  
Sign or symptom causes interference with usual activity or affects 
clinical status, and may require medical intervention  
Grade 3  
Severe  
Sign or symptom is incapacitating or significantly affects clinical status 
and likely requires medical intervention and/or close follow-up  
Grade 4  
Life-threatening 
Sign or symptom results in a potential threat to life  
Grade 5  
Fatal  
Sign or symptom results in death  
7.5.8. 
Adverse Event Reporting 
Investigator site reporting requirements for AEs are summarized in Table 5. 
Table 5: 
Investigator Site Requirements for Reporting Adverse Events 
Event 
Recorded on the eCRF 
Reported on the SAE or Pregnancy Report (as 
applicable) Form to PTC Pharmacovigilance 
Within 24 Hours of Awareness  
Serious AE 
All  
All  
Non-Serious AE 
All  
None  
Exposure to the study 
drug during pregnancy 
or breastfeeding, and 
occupational exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure 
Exposure during pregnancy, exposure via 
breastfeeding, occupational exposure 
(regardless of whether associated with an AE) 
Abbreviations: AE, adverse event; eCRF, electronic case report form; SAE, serious adverse event 
All AEs should be followed up by the investigator until they are resolved, or the investigator 
assesses them as chronic or stable. The investigator should consider protocol guidelines and use 
his/her discretion in ordering additional tests as necessary to monitor the resolution of such 
events. In the event of additional investigations, the PTC Pharmacovigilance Department or 
designee should be informed via e-mail or fax. A subject withdrawn from the study because of 
an AE must be followed by the investigator until clinical recovery is complete and laboratory 
results have returned to normal, or until progression has been stabilized. Follow-up may need to 
continue after the subject has discontinued from the study, and additional investigations may be 
requested by the PTC medical monitoring team. 
The first day of AE reporting will coincide with the date of signing of informed consent and 
including a minimum of 30 calendar days after the last administration of study drug. 
7.5.9. 
Serious Adverse Event Reporting 
All SAEs occurring from the time of informed consent through 30 days following the last dose of 
study drug should be reported via the SAE report form to PTC within 24 hours of becoming 
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The SAE report form should be signed by the investigator; however, if the investigator is unable 
to sign at the time of the event or within 24 hours, the form should be signed by the clinical staff 
member reporting the SAE (eg, the study coordinator). The SAE report form must be faxed or 
e-mailed to the PTC Pharmacovigilance Department or designee and to the site IRB/IEC 
(if required by local regulations) within 24 hours. 
Follow-up information to the SAE should be clearly documented as “follow-up” in the SAE 
report form and must also be faxed or e-mailed to the same party. All follow-up SAE report 
forms for the event must be signed by the investigator. Any source documents (eg, progress 
notes, nurses’ notes, laboratory and diagnostic test results, discharge summaries) provided to the 
sponsor should be redacted so that the subject’s name, address, and other personal identity 
information are obscured. Only the subject’s study number and initials are to be provided 
(in regions where the provision of such information is permitted). The information in the AE 
portion of the eCRF and the SAE report form(s) must match or be reconciled. Where the same 
data are collected, the forms must be completed in a consistent manner. For example, the same 
AE term should be used on both forms. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (for example, if a subject initially seeks treatment elsewhere), the investigator is to 
report the event within 24 hours after learning of it and to document his/her first awareness of the 
AE. 
The PTC Pharmacovigilance Department contact information for reporting SAEs is provided 
below. This information is also provided in the Study Manual and in the SAE report form. 
PTC Therapeutics Safety Department 
Attention: Pharmacovigilance 
E-mail: Pharmacovigilance@ptcbio.com 
Facsimile: 1 (908) 325-0355 
7.5.10. 
Contraception 
Women of childbearing potential (WOCBP) includes any female who has experienced menarche 
and who has not undergone successful surgical sterilization (eg, hysterectomy, bilateral tubal 
ligation, bilateral oophorectomy) or is not postmenopausal. Postmenopausal is defined as 
≥12 months with no menses without an alternative medical cause. Women who are using an 
active method of birth control, are practicing abstinence or where the partner is sterile 
(eg, vasectomy), are considered to be WOCBP. 
WOCBP must use 2 forms of effective contraception simultaneously for the duration of study 
participation and through approximately 30 days after the last dose or early termination in a 
manner such that risk of failure is minimized. Periodic and/or temporary abstinence such as 
declaration of abstinence during study participation or fertility awareness-based methods to 
prevent pregnancy (including but not limited to symptothermal and ovulation estimation by 
either calendar day or salivary/cervical secretions) are not considered effective methods of birth 
control; however, true (absolute) sexual abstinence (ie, in line with the preferred and usual 
lifestyle of the subject) may be permitted. Effective methods of birth control approved for use in 
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• Implants (eg, Norplant® system) 
• Injectable (eg, Depo-Provera®) 
• Transdermal patch 
• Combined oral contraceptives 
• Barrier methods (condoms and diaphragm with spermicide) - note: double-barrier 
method is required if no other methods of birth control are in use. 
• Intrauterine devices (eg, ParaGard®, Mirena®) 
Prior to trial enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during trial participation and through approximately 30 days after the last dose or early 
termination. During the trial, all WOCBP will be instructed to contact the investigator 
immediately if they suspect they might be pregnant (eg, missed or late menstrual period). 
Male subjects must agree not to donate sperm during the study and for at least 30 days after 
treatment discontinuation or early termination. 
7.5.11. 
Reporting Pregnancy 
PTC should be notified in the event that a female subject in the study, or a female partner of a 
male subject in the study, becomes pregnant on-study or within 30 days of the last administration 
of study drug must be reported on a Pregnancy Notification Form (see the Study Manual for 
details). 
This must be done whether or not an AE has occurred and within 24 hours of awareness of the 
pregnancy. The information submitted should include the anticipated date of birth or pregnancy 
termination. 
Written consent is required prior to collecting and reporting any information on a female partner 
of a male subject in the study. 
If possible, the investigator should follow the subject, or the pregnant female partner of a male 
subject, until completion of the pregnancy and notify the PTC medical monitor of the outcome 
within 5 days or as specified below. The investigator will provide this information as a follow-up 
to the initial Pregnancy Notification Form via the Pregnancy Outcome Form (see the Study 
Manual for details). 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus]), the investigator should follow the procedures for reporting SAEs, ie, report the 
event to the PTC Safety Department or designee and follow-up by submission of appropriate AE 
eCRFs (see Section 7.5.9). 

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7.5.12. 
PTC Therapeutics Adverse Event Reporting Requirement 
As the sponsor of the study, PTC is responsible for reporting certain safety information, such as 
suspected unexpected serious adverse reactions (SUSARs) and other significant safety findings, 
per local reporting requirements, to each investigator in an expedited manner. If notification of a 
SUSAR requiring expedited reporting to investigators is received, PTC or its designated 
representative will contact each investigational site participating in this study by e-mail, fax, 
and/or overnight mail such that the investigator can promptly notify the site IRB/IEC per their 
local requirements. The initial expedited safety report will be provided as required according to 
local regulations (eg, within 15 days) after the earliest date PTC or an agent of PTC (eg, a site 
monitor) becomes aware of the event. This awareness date is the date the regulatory reporting 
clock begins and the date is considered Day 0. 
8. 
STATISTICAL CONSIDERATIONS 
The primary objective of this study is to evaluate the efficacy (using the mFARS) and safety of 
vatiquinone on subjects with Friedreich ataxia. 
After the last subject completes the double-blind Week 72 visit or follow-up visit (in case of 
subject withdrawal), database will be cleaned, locked, and unblinded. Statistical analysis of 
double-blind portion of the study will be conducted while subjects continue to participate in the 
open-label extension portion of the study. Open-label extension portion of the data will be 
cleaned and locked after the last subject has completed the follow-up procedures.  
8.1. 
Statistical Hypotheses 
The primary efficacy hypotheses are: 
H0:  µv = µP  vs  H1:  µv > µP, where µv is the treatment effect of vatiquinone in change from 
baseline in mFARS score and µP is the treatment effect of placebo in change from baseline in 
mFARS score at Week 72. A larger numerical decrease from baseline in mFARS represents a 
larger treatment effect. 
8.2. 
Sample Size Determination 
Based on Phase 2 Study EPI-2010-006 data, vatiquinone 400 mg tid dose demonstrated a change 
from baseline in mFARS score for 400 mg dose of -1.31 after 18 months of treatment, and 
natural history showed an estimated increase of 3.26 after 18 months of disease progression 
(Patel 2016). Assuming a common standard deviation of 6.76, with 1-sided type I error of 2.5% 
and 90% power, 47 subjects per group is required to detect a treatment difference of -4.57 in 
mFARS score. Assuming a dropout rate of 10%, a total of 106 subjects between 7 and 21 years 
of age will be randomized. The primary efficacy analysis will be based on change from baseline 
in mFARS score of subjects between 7 and 21 years old.  
In order to explore the treatment efficacy and safety, approximately 20 subjects >21 years of age 
will be randomized for a total of approximately 126 subjects. 

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8.3. 
Population for Analyses 
8.3.1. 
Randomized Analysis Set 
The Randomized Analysis Set will include all subjects who are randomized for the study. 
8.3.2. 
Intent-to-Treat Set 
The intent-to-treat (ITT) set will include all subjects who are randomized, have received at least 
one dose of study drug (vatiquinone or placebo), and have baseline and at least one post-baseline 
measurement of the primary endpoint.  
Analysis in mFARS change from baseline to Week 72 based on the ITT set will be considered as 
secondary analysis. 
8.3.3. 
Modified Intent-to-Treat Set 
The modified intent-to-treat (mITT) set will include all subjects who are randomized, between 
age of 7 and 21 years, inclusive, at Screening, have received at least one dose of study drug 
(vatiquinone or placebo), have baseline and at least one post-baseline measurement of the 
primary endpoint.  
Analysis in mFARS change from baseline to Week 72 performed based on the mITT set will be 
considered as primary efficacy analysis.  
8.3.4. 
Safety Analysis Set 
The safety analysis set will include all subjects who receive at least one dose of study drug. This 
will be the primary analysis set for summarizing safety data. Subjects will be summarized by the 
treatment they received. 
8.3.5. 
Pharmacokinetic Analysis Set 
The PK analysis set will include all subjects who have any evaluable plasma concentration. 
8.4. 
Statistical Analyses 
8.4.1. 
General Approach 
Descriptive statistics will be provided for demographic, safety, and efficacy. Descriptive 
statistics on continuous data will include number of subjects, mean, median, standard deviation, 
minimum, and maximum while categorical data will be summarized using frequency counts and 
percentages.  
Subjects randomized to vatiquinone will be treated as one group regardless of the dose (200 mg 
tid or 400 mg tid). 
Assessments of change from baseline to posttreatment or the ratio of posttreatment to baseline 
will include only those subjects with both baseline and posttreatment measurements. The last 
non-missing value of a variable taken before the first dose of study drug will be used as the study 
baseline value, unless otherwise specified. In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified. 

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Efficacy variables will be summarized and analyzed for the double-blind phase based on 
treatment assigned at randomization. Analyses and summaries will be performed for both the 
mITT set and the ITT set unless specified otherwise. Analysis results based on the mITT set will 
be considered primary support of efficacy and those based on ITT set will be considered 
secondary.  
Safety summaries will be presented by treatment received and will be performed based on the 
safety analysis set.  
All statistical summaries and analyses will be performed using SAS® software (SAS Institute, 
Cary, North Carolina, USA). 
A detailed Statistical Analysis Plan (SAP) describing the methodology to be used in the final 
analysis will be prepared and finalized before the study is unblinded after all subjects complete 
the placebo-controlled phase.  
8.4.2. 
Analysis of Primary Efficacy Endpoints 
The primary estimand is the treatment difference between vatiquinone and placebo in change 
from baseline to Week 72 in mFARS score attributable to the initially randomized treatment for 
randomized subjects who received at least 1 dose of study medication and between 7 and 
21 years of age at screening. Missing mFARS score will be imputed as described below to form 
a complete set for analysis.  
Intermittent missing mFARS scores will be imputed using Monte Carlo Markov Chain (MCMC) 
method with adjustment for covariates (for example, but not limited to, treatment group, age, 
region, gender) to produce 5 monotone missing pattern datasets first. Missing data after dropout 
will be imputed assuming missing not at random using pattern mixture complete case missing 
value pattern. Approximately 1000 complete data sets will be produced. The change from 
baseline at each visit will be calculated using the completed data sets for analysis. The primary 
efficacy analysis will be performed for subjects between 7 and 21 years of age at screening, and 
will compare change from baseline in mFARS neurological score to Week 72 between 
vatiquinone- and placebo-treated subjects using mixed model repeated measure (MMRM) 
stratified by baseline mFARS score (<40 and ≥40) and age of onset (<14 and ≥14 years ) with 
treatment and region as the main effects and baseline mFARS and age as covariates using an 
unstructured variance-covariance matrix structure. If the model failed to converge, other 
variance-covariance structure will be explored. The test will be performed using one-sided type I 
error of 2.5%. The results of MMRM analysis from each complete imputed dataset will be 
combined using Rubin’s rule (Little 2002). Detail of the imputation will be specified in the SAP.  
A completer analysis will be performed for all subjects who took medication till the end of 
double-blind period as specified by the protocol and have mFARS score at Week 72 visit.  
The overall Neurological section score (sum of the Bulbar [except for tongue and facial atrophy], 
Upper Limb Coordination, Lower Limb Coordination and Upright Stability), total score from 
each subsection, and Stance from Upright Stability will be summarized at baseline and each time 
point along with the change from baseline by treatment. For the subsections containing the 
measurements from the left and the right, the sum of the two scores will be used in the 
calculation for the total section score. For Upright Stability subsections (2a, 2b, 3a, 3b, 4, and 5), 
the average score from the 3 trials will be used in the calculation for the total section score. 
Higher score reflects greater Friedreich ataxia disease severity thus, a negative change from 

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baseline suggests an improvement. Summaries will present observed values and no imputation 
will be performed for missing values. 
Open-label Extension Period 
After all subjects complete long-term follow-up, subjects’ mFARS score from double-blind and 
long-term follow-up will be summarized in the following way: 
• For subjects randomized to vatiquinone, the change from study baseline (also their 
vatiquinone treatment baseline) will be presented for each visit from Week 12 to the 
end of the follow-up to show long-term treatment effect of vatiquinone.  
• For subjects randomized to placebo, their last mFARS score will be used as 
vatiquinone treatment baseline. Change from vatiquinone treatment baseline to each 
long-term follow-up visit will be calculated. In this fashion, change to Week 84 
shows change from treatment baseline after 12 weeks of vatiquinone treatment, and 
Week 96 shows changes after 24 weeks of treatment.  
• The above two sets of summary statistics for changes from treatment baseline will be 
presented in one table to show the treatment effect of vatiquinone by treatment group, 
and overall (combine the 12, 24, 36, 48, 60, and 72 weeks vatiquinone-treated change 
from baseline for the placebo group with originally vatiquinone-treated group’s week 
12 and 24 weeks change from baseline) to show the overall change from vatiquinone 
treatment baseline. 
Listings will be provided to show the observed efficacy variables by visit. 
8.4.3. 
Analysis of Secondary and Exploratory Efficacy Endpoints 
Secondary efficacy variables include the following: 
• Change from baseline in FARS-ADL scale to Week 72 
• Change from baseline in 1MWT to Week 72 
• Number of falls through Week 72 
Exploratory efficacy variables include the following: 
• Change from baseline in Speech evaluation to Week 72 
• Change from baseline in MFIS to Week 72 
• Change from baseline in EQ-5D-5L score to Week 72  
• Change from baseline in Upright Stability subscale of mFARS score to Week 72 
Comparisons between treatment groups for change from baseline in FARS-ADL scale, 
one minute timed walk, MFIS score, EQ-5D-5L, and Upright Stability subscale of the mFARS to 
Week 72 will be analyzed using the same model as the primary efficacy variable by using its 
respective baseline and age as covariates. Summary statistics will be provided for total score at 
each visit as well as change from baseline at each visit. 
A summary of the number of falls will be presented, and the number of falls over time will be 
compared between the two treatment groups.  

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Handling and comparison between treatment groups for change from baseline in speech will be 
provided by Redenlab and will be described in a separate document. 
Long-term Follow-Up Extension 
For long-term follow-up data, the change from vatiquinone treatment baseline will be presented 
in the same fashion as mFARS described above for FARS-ADL, 1MWT, MFIS, EQ-5D-5L, and 
Upright Stability scale of the mFARS. The observed number of falls will be presented in similar 
fashion. 
8.4.4. 
Safety Analyses 
Safety data (including AEs, vital signs, physical examinations, laboratory data, C-SSRS, 
echocardiogram, and ECG data) will be listed and summarized by treatment group for subjects in 
the safety analysis set. All safety data collected on or after the date of the first dose of study drug 
through completion of the study will be summarized by treatment. The last measurements taken 
prior to first dose will be used as study baseline. The last measurements taken during 
double-blind period for subjects originally treated with placebo will be the vatiquinone treatment 
baseline. For subjects originally treated with vatiquinone, their study baseline is also their 
vatiquinone treatment baseline. This definition will be used for all the numerical safety variables. 
Exposure to study drug and study drug compliance will be summarized for both the double-blind 
and open-label extension periods. 
8.4.4.1. 
Adverse Events  
Adverse events will be coded using MedDRA. Treatment-emergent AE (TEAE) is defined as AE 
first occurred on or after the first dose date and up to 30 days after the last dose or with onset 
prior to the first dose but worsened in severity.  
An overall AE summary will be provided to show number and percentage of subjects with 
TEAE, SAE, treatment-emergent SAE (TESAE), study-drug related TEAE, discontinuation due 
to AE, and death. Treatment-emergent AE will be summarized by System Organ Class (SOC) 
and Preferred Term (PT) for treatment subjects received.  
Double-blind Period 
Summary TEAE tables for each treatment will be presented for the following for each treatment 
group: 
• All TEAEs  
• All TEAEs by relationship to study drug 
• All TEAEs by severity  
• All TESAEs 
• All TEAEs leading to discontinuation of study drug 
Multiple events by PT and SOC will be counted once only per subject for each treatment. 
For summaries by severity, the most severe event with the same PT will be selected for that PT. 
For summaries by relationship, the most related event with the same PT will be selected for that 
PT. 

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Long-term Follow-up 
Subjects randomized to placebo will have AE summary presented side-by-side for the period 
they received placebo and the period they received vatiquinone. 
Subjects randomized to vatiquinone will have all their AEs occurred during double-blind and 
follow-up portion combined and presented as one table. In addition, summary of new AEs 
occurred during double-blind and during long-term follow-up will be presented side-by-side. 
All AEs occurring during vatiquinone treatment (combining original vatiquinone-treated subject 
data and follow-up data of originally placebo-treated subjects’ data) will also be presented for all 
TEAEs and all TESAEs in the same fashion as in the double-blind period.  
Listings of all AEs and SAEs reported will be presented as well. 
8.4.4.2. 
Clinical Laboratory Evaluations 
Double-blind Period 
Laboratory data will be summarized at baseline and at each time point by treatment. 
Change from baseline will also be summarized. A shift table, presenting 2-way frequency 
tabulation for baseline and the worst posttreatment value, will be provided.  
Long-term Follow-up 
Laboratory data and change from treatment baseline will be presented for subjects originally 
treated with vatiquinone as well as for subjects originally treated with placebo.  
Only values obtained at scheduled assessment times will be included in the summary. 
8.4.4.3. 
Vital Signs, Weight, and Oxygen Saturation 
Double-blind Period 
Descriptive statistics will be provided by treatment group for the vital sign, body weight, and 
oxygen saturation measurements and changes from baseline by scheduled time of evaluation and 
the maximum and minimum posttreatment values for double-blind.  
Long-term Follow-up 
Descriptive statistics will be provided for change from treatment baseline to each visit. 
Treatment baseline is defined as the last observed values during double-blind period for original 
placebo-treated subjects. All vital sign data will also be listed. 
8.4.4.4. 
Electrocardiogram and Echocardiogram 
Double-blind Period 
Descriptive statistics and listings will be provided by treatment group for ECG parameters and 
changes from baseline by scheduled time of evaluation.  
The number and percentage of subjects with investigator findings of normal, abnormal (NCS) 
and abnormal (CS) as well as shift from baseline to each visit will be provided for ECG and for 
echocardiogram. 

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Long-term Follow-up 
Descriptive statistics for change from vatiquinone treatment baseline will be presented for 
subjects originally treated with vatiquinone as well as for subjects originally treated with placebo 
to each visit in the same fashion as described for double-blind period. 
8.4.4.5. 
Physical Examination 
Physical examination findings will be listed for both double-blind period and open-label period. 
8.4.4.6. 
Columbia-Suicide Severity Rating Scale 
Double-blind Period 
Number and percentage of subjects’ response for each question will be provided at each visit for 
each treatment group for both double-blind period and open-label long-term follow-up period. 
Shift table presenting responses to each question at baseline versus each visit for each treatment 
group will be provided. 
Listing of the response will also be provided for each subject. 
Long-term Follow-up Period 
Number and percentage of subjects’ response for each question will be provided at each visit for 
open-label portion of the data. Shift table presenting responses to each question at treatment 
baseline versus each visit for each originally randomized group will be presented. 
8.4.4.7. 
Concomitant Medication 
Concomitant medications will be coded using the World Health Organization (WHO) drug 
dictionary (most recent version). Number and percentage of subjects taking concomitant 
medications will be summarized for both double-blind and long-term follow-up periods. 
Concomitant medications will also be listed. 
8.4.5. 
Baseline Descriptive Statistics 
8.4.5.1. 
Disposition of Subjects 
The summary of disposition of subjects will provide the number of subjects screened, number 
and percentage (by randomized treatment and overall) for randomized subjects, in the full 
analysis set (FAS), safety analysis set, PK set, completing treatment in the double-blind portion 
of the study, discontinued from the double-blind portion of the study, enrolled in long-term 
follow-up, discontinued from the long-term follow-up portion of the study.  
Number and percentage will also be provided for reason of discontinuing treatment in the 
double-blind and long-term follow-up by treatment group and overall. 
8.4.5.2. 
Demographic and Baseline Characteristics 
Summary of demographic information, genetic confirmation of FA diagnosis and baseline 
mFARS, FARS-ADL, 1MWT, MFIS, and EQ-5D-5L will be summarized by treatment group for 
subjects randomized to the double-blind portion of the study.  

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Demographic information will also be summarized for subjects who rollover to the long-term 
follow-up by the original randomized treatment and overall. 
Number of subjects, mean, median, standard deviation, minimum, and maximum will be 
provided for continuous variables and number and percentage will be provided for categorical 
variables. 
Listing will be provided for demographic, genetic confirmation of Friedreich ataxia, and medical 
history. 
8.4.6. 
Pharmacokinetic Analyses 
Due to sampling schedule, no PK parameters will be calculated for this study. Modeling and 
simulation using the blood concentration will be described and reported in a separate report. 
8.4.7. 
Planned Interim Analyses 
There is no planned interim analysis. 
8.4.8. 
Subgroup Analyses 
Subgroup summaries will be provided for age of disease onset in change from treatment baseline 
to each visit for mFARS, FARS-ADL, one-minute walk test, MFIS score, Upright Stability 
subscale of the mFARS, and for observed number of falls in between visits. 
For double-blind treatment period, this will be performed for each treatment group.  
Once all subjects completed long-term follow-up, this subgroup summary will be presented as 
described for long-term follow-up in Section 8.4.2. 
8.4.9. 
Sensitivity Analysis 
Sensitivity analysis will be performed for the primary efficacy variable by using placebo 
multiple imputation to test the robustness of the results. The placebo multiple imputation method 
will be performed following the creation of a monotone data structure using methods as 
described for the primary analysis. The missing mFARS score is then imputed adjusting for 
covariates (age, region) based on information from the placebo arm only. Values of shift 
parameters used in the pattern mixture model for the primary analysis will be perturbed to further 
test the robustness of the primary results. Analysis of the imputed data will follow the same 
approach as the primary analysis. 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations 
9.1.1. 
Informed Consent Process 
By signing the protocol, the investigator assures that informed consent/assent will be obtained 
from each subject prior to study entry and that the informed consent/assent will be obtained in 
accordance with current regulations. 

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The investigator or subinvestigator will give each subject full and adequate verbal and written 
information regarding the objectives and procedures of the study and the possible risks involved. 
An informed consent/assent document will be provided to each subject in a language in which 
the subject is fluent. This information must be provided to the subject prior to undertaking any 
study-related procedure. Adequate time should be provided for the subject to read the informed 
consent, to understand the risks and benefits of participating in the study, and to ask any 
questions that the subject may have about the study. The subject should be able to ask additional 
questions as and when needed during the conduct of the study. The subject’s signature on the 
ICF should be obtained at the investigator site in the presence of the investigator or a qualified 
representative (eg, subinvestigator). Where applicable, the subject will sign an age-appropriate 
assent form. If a subject reaches adulthood while on study, he or she will be reconsented as an 
adult. 
Each subject will be given a copy of the signed consent/assent form. The original signed ICFs 
will be retained by the investigator with the study records. 
The written subject information must not be changed without prior approval by PTC and the 
IRB/IEC. 
9.1.2. 
Study Discontinuation and Closure 
PTC reserves the right to discontinue the study prior to inclusion of the intended number of 
subjects. The investigator, after consultation with the PTC medical monitor, reserves the right to 
discontinue the study at the investigator site for safety reasons at any time. 
After a decision to terminate the study, investigators must contact all subjects who are continuing 
their participation in the study and must do so within a time period set by PTC. As directed by 
PTC, all study materials must be collected and all electronic data entry forms completed to the 
greatest extent possible. 
9.1.3. 
Confidentiality and Privacy 
Research records will be collected and stored in a manner that protects the confidentiality of 
subject information. The names and identities of all research subjects will be kept in strict 
confidence and will not appear on eCRFs or other records provided to or retained by PTC (or its 
authorized designee). The names and identities of the subjects need not be divulged; however, 
the records must nevertheless be inspected. This will be accomplished by blanking out the 
subject’s name and replacing the name with the subject’s study identification number on any 
record provided to or retained by PTC. The ICF must include appropriate statements explaining 
these requirements. 
By signing this protocol, the investigator affirms to PTC that the investigator will maintain, in 
confidence, information furnished by PTC and will divulge such information to the IRB/IEC 
under an appropriate understanding of confidentiality with such board. 
9.1.4. 
Future Use of Stored Specimens and Data 
As part of the current study, serum and plasma blood samples are being collected.  

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Sample processing will be performed by a laboratory under the direction of the sponsor. 
Processing, analysis, and storage will be performed at a secure laboratory facility to protect the 
validity of the data and maintain subject privacy. 
Samples will only be used for the purposes described in this protocol. Laboratories contracted to 
perform the analysis on behalf of the sponsor will not retain rights to the samples beyond those 
necessary to perform the specified analysis and will not transfer or sell those samples. The 
sponsor will not sell the samples to a third party. 
Samples will be stored until the completion of the study (defined as submission of the clinical 
study report to the appropriate regulatory agencies). At the end of the storage period, samples 
will be destroyed. Samples may be stored longer if a health authority (or medicinal product 
approval agency) has active questions about the study. In this special circumstance, the samples 
will be stored until the questions have been adequately addressed. 
No subject-identifying information (eg, initials, date of birth, government identifying number) 
will be associated with any of the biologic samples. All samples will be single coded. The 
sponsor will take steps to ensure that data are protected accordingly, and confidentiality is 
maintained as far as possible. Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection. 
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research. These include: 
• Contract research organizations (CROs) retained by the sponsor 
• IECs or IRBs that have responsibility for this research study 
• National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which can include part or all 
of the coded data, in listing or summary format. Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of the 
population in the study, and no identified individual results will be disclosed. 
Given the research nature of the data analysis, it will not be possible to return individual data to 
subjects. The results that may be generated are not currently anticipated to have clinical 
relevance to the patients or their family members. Therefore, these results will not be disclosed 
to the patients or their physicians. 
9.1.5. 
Safety Oversight 
External oversight for this trial will be provided by a DSMB. The DSMB consists of 3 members, 
including an unblinded statistician with experience in the indication and will meet approximately 
quarterly or more frequently if there are safety concerns. The primary responsibility of the 
DSMB is to protect the safety and welfare of subjects participating in this clinical trial and to 
ensure the integrity of the clinical trial. 
Specifically, for this study, the DSMB will be responsible for: 
• Examining accumulated safety data and compliance data in order to make 
recommendations concerning continuation, termination, or modification of the trial 
based on the safety of the interventions under study 

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• Reviewing major study design modifications proposed by PTC or the investigators 
prior to implementation of those modifications 
• Reviewing the general progress of the study as in regard to accrual, protocol 
deviations, and study conduct 
The DSMB may review the safety data at any time as warranted by emerging results. Based on 
review of the safety data, the DSMB can recommend continuation of the study unchanged, study 
interruption, study termination, modification of the trial, or alteration in the DSMB monitoring 
plan. Further information regarding the DSMB review process is provided in the DSMB charter 
(see the Study Manual). 
9.1.6. 
Clinical Monitoring 
In accordance with 21 CFR Part 312.56 and/or relevant ICH guidelines, PTC or a designee will 
periodically inspect all eCRFs, study documents, research facilities, and clinical laboratory 
facilities associated with this study at mutually convenient times, before, during, and after 
completion of the study. As required by applicable regulations (Responsibilities of Sponsors and 
Investigators), the monitoring visits provide PTC with the opportunity to evaluate the progress of 
the study; verify the accuracy and completeness of data in the eCRFs; ensure that all protocol 
requirements, relevant regulations, and investigator’s obligations are being fulfilled; and resolve 
any inconsistencies in the study records. This includes inspection of all documents and records 
required to be maintained by the investigator, including but not limited to medical records 
(office, clinic, or hospital) for the subjects in this study. The names and identities of all research 
subjects will be kept in strict confidence and will not appear on eCRFs or other records provided 
to or retained by PTC. The investigator/institution guarantees direct access to source documents 
by PTC and appropriate regulatory authorities. 
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
9.1.7. 
Quality Assurance and Quality Control 
To ensure compliance with Good Clinical Practice (GCP) and all applicable regulatory 
requirements, PTC, PTC’s representatives, a regulatory authority, or/and IRB may conduct a 
quality assurance audit. Reasons for quality assurance audit may include but are not limited to 
random selection, geographic proximity, suspected GCP violation, high enrolling site, recurring 
protocol deviations, etc. The purpose of a sponsor audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. The 
investigator should contact the sponsor immediately if contacted by a regulatory agency about an 
inspection. 

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9.1.8. 
Data Handling and Record Keeping 
To enable evaluations and/or audits from regulatory authorities or PTC, the investigator agrees to 
keep accurate and complete records, including the identity of all participating subjects (sufficient 
information to link eCRFs and clinic records/source documents), all original signed ICFs, 
electronic copies (ie, CD-ROM, USB, etc.) or paper copies of the data that have been captured in 
the electronic data capture for each subject (eCRFs), and detailed records of study drug 
disposition. All records and documents pertaining to the study will be maintained by the 
investigator until notification is received from PTC that the records no longer need to be 
retained. 
The investigator must obtain written permission from PTC before disposing of any records. The 
investigator will promptly notify PTC in the event of accidental loss or destruction of any study 
records. If the investigator relocates, retires, or for any reason withdraws from the study, the 
study records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to PTC as applicable. 
9.1.9. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc. - either tests not done, incorrect 
tests done, or not done within the time frame specified in the protocol 
• Procedural deviations such as incorrect storage of study drug, failure to update the 
ICF when new risks become known, or failure to obtain IRB/IEC approvals for the 
protocol and ICF revisions 
Major deviations are any deviations that impact subject eligibility (ie, protocol 
inclusion/exclusion violations), subject safety or a subject’s ability to continue in the clinical 
trial. 
At the outset of the study, a process for defining and handling protocol deviations will be 
established with the CRO. This will include determining which deviations will be designated as 
major; thus, requiring immediate notification to the PTC medical monitor and the sponsor. 
Prospective deviations (eg, protocol waivers) are prohibited per PTC policy. 
The investigator is responsible for seeing that any known protocol deviations are recorded as 
agreed. 

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9.1.10. 
Publication and Data Sharing Policy 
The information developed during the conduct of this clinical study is considered confidential by 
PTC. This information may be disclosed as deemed necessary by PTC. 
PTC intends that the data from this study will be presented and published. The PTC staff under 
the direction of the PTC Chief Medical Officer or designee in collaboration with the investigator 
will be responsible for writing presentations and manuscripts for publication. investigators will 
not be allowed to publish or present the data from this study without prior agreement with PTC. 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any 
public disclosure (including publicly accessible websites) related to the protocol or study results, 
other than study recruitment materials and/or advertisements, is the sole responsibility of the 
sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
Data from all sites participating in the study will be pooled and analyzed by the sponsor or the 
sponsor’s designee. The first publication of the study results shall be made in conjunction with 
the results from other study sites as a multicenter publication. If a multicenter publication is not 
forthcoming within 24 months of completion of the study at all sites, the investigator may 
publish or present the results generated at his or her site. 
The investigator will provide the sponsor with a copy of any proposed publication or 
presentation for review and comment at least 60 days prior to such presentation or submission 
for publication. The sponsor shall inform the investigator in writing of any changes or deletions 
in such presentation or publication required to protect the sponsor’s confidential and proprietary 
technical information and to address inaccurate data or inappropriate interpretations in the 
context of any pooled multicenter results. At the expiration of such 60-day period, the 
investigator may proceed with the presentation or submission for publication unless the sponsor 
has notified the institution or the investigator in writing that such proposed publication or 
presentation discloses the sponsor’s confidential and proprietary technical information. Further, 
upon the request of the sponsor, the investigator will delay the publication or presentation for an 
additional 90 days to permit the sponsor to take necessary actions to protect its intellectual 
property interests. 

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9.2. 
Protocol Amendment History 
Version 1.0: 15 April 2020 
Amendment 1: 31 July 2020 (Version 2.0) 
Amendment 2: 28 August 2020 (Version 3.0) 
Amendment 3: 03 March 2021 (Version 3.1) 
Amendment 4: 15 April 2021 (Version 4.0) 
Amendment 5: 21 May 2021 (Version 5.0) 
9.2.1. 
Amendment 2: 28 August 2020 (Version 3.0) 
The overall reasons for Version 3.0 of the protocol was to revise the length of the 
placebo-controlled portion of the trial from 48 weeks to 72 weeks and the open-label portion 
from 48 weeks to 24 weeks and to add Upright Stability subscale as an exploratory endpoint. 
Item 
No. 
Protocol 
Section  
Version 3/Update 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical errors, punctuation, 
tenses, abbreviations) were incorporated to provide clarity. 
The synopsis was updated to be consistent with changes in 
the protocol. 
Update 
2 
Section 2.1.1  
Clarification added that the efficacy in the primary objective 
will be assessed using the mFARS 
Clarification 
3 
Section 2.1.3 
Upright Stability subscale was added to the exploratory 
objectives. 
Update 
4 
Section 2.2.3  
Upright stability subscale was added to the exploratory 
endpoints. 
Update 
5 
Section 3.1  
Clarification that dose will also be adjusted if the subject’s age 
changes from 11 to 12 years 
Sentence added to indicate that subjects who complete the 
study may have the option to enter into an open-label 
expanded access study to continue receiving vatiquinone. 
Update and 
Clarification 
6 
Section 3.1 
and 
Section 3.1.1  
Screening period revised from 35 days (±5 days) to up to 
42 days 
Update 
7 
Section 3.1.2  
Revisions to reflect the change in length of the placebo-
controlled phase from 48 to 72 weeks along with the 
applicable revisions to the timing of the in-person and 
telephone visits 
Update 
8 
Section 3.1.4 
Revisions to reflect the change in length of the open-label 
extension phase from 48 to 24 weeks along with the 
applicable revisions to the timing of the in-person and 
telephone visits 
Clarification that dose will also be adjusted if the subject’s age 
changes from 11 to 12 years 
Update and 
Clarification 
9 
Section 3.1.8  
Revision to state that the end of treatment visits will include 
the same assessments noted for the Week 96 visit 
Clarification 
10 
Section 3.2 
Explanation of the Upright Stability subscale score added  
Revision of endpoint evaluation from 48 to 72 weeks and 
revision to 72 and 24 weeks of the placebo-controlled and 
open-label extension phases, respectively  
Update 

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Item 
No. 
Protocol 
Section  
Version 3/Update 
Reason/ 
Rationale 
11 
Section 4.2  
Addition of a sub-bullet noting that if a subject is taking a 
prohibited concomitant medication at Screening, the 
difference in mFARS is to be assessed between a 
Post-Discontinuation Visit and Baseline Visit 
Update 
12 
Section 4.3  
Reversed numbering of exclusion criteria 10 and 11 
Revision to criterion 11 (previously criterion 10) to exclude 
use of any investigational drug in any other clinical trial within 
60 days prior to the Baseline Visit and addition of statement 
that subjects may be rescreened after the exclusionary period 
of 60 days have passed. 
Revision to criterion 12 to exclude CoQ10, vitamin E, 
idebenone, or any other non-approved medication within 
30 days prior to the Screening Visit. Clarification added that 
these medications may be discontinued at the Screening Visit, 
and if this is the case, Screening mFARS must be repeated 
following a 30-day washout. 
Update 
13 
Section 5.5  
Revisions to concomitant medications for consistency with 
updates in exclusion criteria 11 and 12 
Update 
14 
Section 6.1  
Clarification added that any sites should make every effort to 
complete the Termination Visit and final Follow-up Visit for 
subjects who discontinue from the study prematurely 
Clarification 
15 
Section 7.1 
“Post-Discontinuation” Screening Visit added for mFARS 
assessment, consistent with revisions to exclusion criterion 12 
Revision of screening period from 35±5 days to up to 42 days 
Revisions to visit schedule to reflect change in lengths of 
placebo-controlled and open-label phases of the study 
Addition of baseline fall assessment to be collected with 
medical history 
Revision to include an extra Screening mFARS assessment 
(if needed) and revision to the applicable footnote (14) 
Updates  
16 
Section 7.2 
Revision from 48 to 72 weeks for efficacy assessments 
Addition of baseline fall history to be collected with medical 
history 
Addition of explanation of Upright Stability 
Updates  
17 
Section 8 
Section 8.1 
Section 8.3.2 
and 
Section 8.3.3 
Revision from “Week 48” to “Week 72” to reflect revised 
timing of efficacy analyses 
Update 
18 
Section 8.2  
Sample size determination language revised to reflect 
18-month data due to change in randomized portion of the 
study from 48 to 72 weeks 
Update 
19 
Section 8.4.2 
Revision from 48 to 72 weeks for analysis of primary efficacy 
endpoints and related revisions in “change from baseline” 
measurements 
Update 
20 
Section 8.4.3 
Revision from 48 to 72 weeks for all efficacy endpoints 
Addition of the Upright Stability subscale as an exploratory 
endpoint 
Revision of assessment approach for the secondary endpoint 
of falls 
Updates 
21 
Section 8.4.9  
Clarification of analysis of primary mFARS results  
Clarification 
Abbreviations: DSUR, Development Safety Update Report; FA, Friedreich ataxia; FARS-ADL, Friedreich Ataxia 
Rating Scale Activities of Daily Living; ITT, intent-to-treat; mFARS, modified Friedreich Ataxia Rating Scale; 
mITT, modified intent-to-treat; No., number; SAEs, serious adverse events; SOPs, standard operating procedures 

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9.2.2. 
Amendment 3: 03 March 2021 (Version 3.1) 
The overall reasons for Version 3.1 of the protocol was to clarify unblinding procedures, clarify 
disease worsening as a reason for discontinuation from study treatment, add a table (Appendix 1) 
of prohibited medications, add an echocardiogram at Week 36, and add text clarifying the 
volume of blood that will be drawn during the study.  
Item 
No. 
Protocol 
Section  
Version 3.1/Update 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical errors, punctuation, 
tenses, abbreviations) were incorporated to provide clarity. 
The synopsis was updated to be consistent with changes in 
the protocol. 
Update 
2 
Section 5.3.1  
Addition of this section to indicate details on unblinding 
Clarification 
3 
Section 6.1  
Revision of text in the second point has been revised to 
replace “vatiquinone” with “study drug” 
Clarification 
4 
Section 7.1  
Revision of the Schedule of Events and Study Parameters to 
add an echocardiogram at Week 36 and to indicate that 
unscheduled echocardiograms may be performed at the 
investigator’s discretion 
Update 
5 
Section 7.4.2  
Revision of approximate total of blood volume to be drawn 
over the course of the study and addition of draw volumes of 
chemistry, hematology, pregnancy, and PK samples 
Update and 
clarification 
6 
Section 9.1.5  
Update of Safety Oversight to remove PK data assessment by 
the DSMB 
Update 
7 
Appendix 1  
Addition of Appendix 1  
Update 
Abbreviations: AE, adverse event; DSMB, Data Safety Monitoring Board; PK, pharmacokinetic 
9.2.3. 
Amendment 4: 15 April 2021 (Version 4.0) 
The overall reasons for Version 4.0 of the protocol was to add risk/benefit language with regard 
to the pediatric population, revise the timing of the follow up visit from 10 to 30 days to 
approximately 30 days, and add details regarding maintaining the blind.  
Protocol 
Section  
Amendment/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. Editorial 
revisions (eg, typographical errors, punctuation, tenses, abbreviations) 
were incorporated to provide clarity. The synopsis was updated to be 
consistent with changes in the protocol. 
Update of Biostatistician to 
 
Update 
Section 1.4  
Addition of in vitro phototoxicity study summary result 
Update 
Section 1.5  
Date of review period removed 
Update of vatiquinone exposure from “over 9 years” to “over 10 years”  
Update 
Section 1.6  
Risk/benefit language with regard to pediatric population added 
Update 
Section 3.1  
Section 3.1.5  
Section 7.1  
Timing of follow-up visit revised from 10 to 30 days to approximately 30 
days (±5 days) after last dose or termination visit to align with follow-up 
pregnancy test 
Update 
Section 3.1.8  
Addition of statement indicating all safety and efficacy assessments 
should be continued according to the Schedule of Events and Study 
Parameters in the event of early termination 
Clarification 
Section 4.2  
Note added to Inclusion Criterion #4 that the size of GAA repeat is not 
required for eligibility 
Clarification 

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Protocol 
Section  
Amendment/Update 
Reason/ 
Rationale 
Section 4.2 
Section 5.5  
Revision of 4 weeks to 30 days for exclusion of potent CYP 3A4 
inducers/inhibitors (eg, ketoconazole, rifampin, St. John’s wort, 
grapefruit juice) 
Addition of “any grapefruit product” along with grapefruit juice 
Addition of text regarding discontinuation of anticoagulants 
Updates 
Section 4.2  
Section 7.5.10  
Addition of statement indicating that male subjects must agree not to 
donate sperm during the study and for at least 30 days after treatment 
discontinuation 
Clarification 
Section 4.3 
Separation of previous exclusion criterion #2 (Previous treatment with 
vatiquinone or allergy to vatiquinone, sesame oil, gelatin [bovine and/or 
porcine], titanium dioxide, or red iron oxide) into 2 separate criteria (ie, 
#2 [Previous treatment with vatiquinone] and #3 [Allergy to vatiquinone, 
sesame oil, gelatin (bovine and/or porcine), titanium dioxide, or red iron 
oxide]) 
Clarify that subjects cannot have had suicidal ideation or behavior 
based on C-SSRS within 3 months prior to screening or at baseline 
since the last visit 
Clarification 
Section 4.3  
Section 5.5  
Section 7.1  
Idebenone removed as a prohibited concomitant medication and 
revision of statement to reflect “any approved or non-approved” 
medication for FA 
Update 
Section 5.1.2  
Section 5.2.1  
Section 7.1  
Removed dosing diary language for consistency with administrative 
letter dated 29 October 2020 
Update 
Section 5.2.1  
Revision of compliance range from 80% to 100% to 80% to 110% 
Update 
Section 5.2.1  
Section 7.1  
Clarification added that all used/unused study drug from the placebo-
controlled phase of the study should be returned at the Week 72 visit 
and new study drug will be dispensed for the open-label phase at this 
visit. 
Footnote 19 added in Section 7.1 for consistency with this revision in 
Section 5.2.1 
Clarification 
Section 5.2.2  
Revised description of placebo to include more detail 
Clarification 
Section 5.3 
Section revised to further detail how the blind will be maintained  
Clarification 
Section 5.6.1  
New section (Procedure for Dose Modification) added 
Update 
Section 6.1  
Clarification that all study visits should be completed for subjects who 
discontinued study drug prematurely (unless consent is withdrawn)  
Clarification  
Section 7.1  
Footnote 4 updated to clarify the size of GAA repeat is not required for 
eligibility  
Footnote 9 updated to reflect an 8 hour fast for laboratory draws and to 
note that local laboratories may be used at screening and sparingly for 
coagulation values 
Clarification 
and update 
Section 7.4  
Addition of text to specify who can administer the C-SSRS and that 
sites will follow their internal processes for referrals, if indicated 
Clarification 
Section 7.4.1  
Addition of temperature to vital signs  
Clarification 
Section 7.4.2  
Addition of details on blood volume to be drawn during the study 
Update 
Section 7.5.2  
Clarification added to indicate that events leading to treatment in the 
emergency room or hospitalization <24 hours may be serious due to 
another seriousness criterion 
Clarification 
Section 7.5.9  
Revision to indicate that SAEs occurring from the time of informed 
consent through 30 days following the last dose of study drug should be 
reported  
Clarification  
Section 8.2  
Revision of statistical difference in mFARS of -4.87 to -4.57 to correct 
typographical error 
Clarification 

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Abbreviations: AE, adverse event; C-SSRS, Colombia Columbia-Suicide Severity Rating Scale; CYP, cytochrome 
P450; FA, Friedreich ataxia 
9.2.4. 
Amendment 5: 21 May 2021 (Version 5.0) 
The overall reason for Version 5.0 of the protocol was clarify concomitant medication use and 
add exclusion of illicit drug use. 
Protocol 
Section  
Amendment/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. Editorial 
revisions (eg, typographical errors, punctuation, tenses, abbreviations) 
were incorporated to provide clarity. The synopsis was updated for 
consistency with changes in the protocol. 
Update 
Section 3.1.1  
Clarification of medications that need to be washed out for at least 
30 days prior to the Screening Visit.  
Expansion of explanation of timing of mFARS assessments with regard 
to washout period 
Clarification 
Section 3.1.8  
Clarification that “early termination” refers to early termination from 
study drug 
Clarification that all visits should be continued in the event of early 
termination from study drug unless consent is withdrawn 
Clarification 
Section 4.2  
Removal of bullet point regarding post-discontinuation mFARS in 
inclusion criterion #6 
Clarification that contraception must be used until 30 days after the last 
dose of study drug or early termination visit (revised from “treatment 
discontinuation”) 
Clarification 
Section 4.3  
Clarification that suicidal behavior in the past year at the time of 
screening or between screening and baseline is exclusionary (criterion 
#6) 
Clarification in exclusion criterion #13 of “interventional” use of CoQ10, 
vitamin E, or any approved or non-approved medication for FA is 
excluded 
Addition of illicit drug use 30 days prior to screening and during the 
study as an exclusion criterion (#14) 
Update 
Section 5.2.1   
Clarification that subjects should return all used/unused study drug at 
each in person visit and that Week 72 marks the end of the 
placebo-controlled period 
Clarification 
Section 5.2.2  
Addition of statement that blister packs may be approved for use in the 
open-label extension phase later in the study 
Update 
Section 5.5  
Clarification in exclusion criterion #13 of “interventional” use of CoQ10, 
vitamin E, or any approved or non-approved medication for FA is 
excluded 
Addition of illicit drug use 30 days prior to screening and during the 
study as an exclusion criterion (#14) 
Clarification 
Section 7.1  
Addition of 10 panel urine drug screen at screening 
Clarification in footnote 1 that screening may be up to 42 days for 
subjects requiring a washout 
Clarification in footnote 9 that local laboratories may also be used 
sparingly for follow-up INR AE 
Clarification in footnote 19 that subjects should return all used/unused 
study drug at each in person visit and that Week 72 marks the end of 
the placebo-controlled period 
Update and 
clarification 

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Protocol 
Section  
Amendment/Update 
Reason/ 
Rationale 
Section 7.2  
Addition of statement indicating that all falls resulting in injury should be 
reported as AEs 
Clarification 
Section 7.4.2.3  Addition of section for 10-panel urine drug screen 
Update 
Section 7.5.10  
Clarification added that contraception should be used and pregnancy 
should be avoided through ~30 days after the last dose or early 
termination 
Clarification 
Appendix 1  
Appendix revised to indicate exclusion of investigational medications 
as in a clinical study and movement of CoQ10 and vitamin E into the 
Interventional medications and supplements for FA category 
Clarification 
 

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10. 
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Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
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Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic 
PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81-90. 
Li QQ, Li Q, Jia JN, Liu ZQ, Zhou HH and Mao XY. 12/15 lipoxygenase: A crucial enzyme in 
diverse types of cell death. Neurochem Int. 2018;118:34-41. 
Little R and Rubin D (2002). Statistical Analysis with Missing Data; A John Wiley & Sons, Inc. 
Lynch D, Perlman S and Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone 
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Page 80 of 81 
APPENDIX 1. 
PTC743-NEU-003-FA PROHIBITED MEDICATION LIST 
Table 6: 
PTC743-NEU-003-FA Prohibited Medication List 
Prohibited Medications 
Examples 
Anticoagulants  
• heparin 
• warfarin 
• aspirin 
• clopidogrel/Plavix 
• apixaban/Eliquis 
• dabigatran/Pradax 
• edoxaban/Savaysa 
• enoxaparin/Lovenox 
• rivaroxaban/Xarelto 
CYP3A4 Strong Inducers 
• apalutamide 
• carbamazepine 
• enzalutamide 
• mitotane 
• phenytoin 
• rifampin 
• St. John’s wort 
CYP3A4 Strong Inhibitors 
• boceprevir 
• cobicistat 
• danoprevir and ritonavir 
• elvitegravir and ritonavir 
• grapefruit juice (any grapefruit product) 
• indinavir and ritonavir 
• itraconazole 
• ketoconazole 
• lopinavir and ritonavir 
• paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
• posaconazole 
• ritonavir 
• saquinavir and ritonavir 
• telaprevir 
• tipranavir and ritonavir 
• telithromycin 
• troleandomycin 
• voriconazole 
• clarithromycin 
• idelalisib 
• nefazodone 
• nelfinavir 
Investigational Medications 
• as in a clinical study 
Interventional 
Medications/Supplements for FAa 
• Idebenone 
• CoQ10 
• vitamin E 
• etravirine 
• resveratrol 
• vitamin B3/nicotinamide  
• vitamin D3/calcitriol 
Abbreviations: CoQ10, coenzyme Q10; CYP3A4, cytochrome p450 3A4; FA, Friedreich ataxia 
Note: This list is neither comprehensive, nor final. Please contact the medical monitor with any questions regarding 
prohibited medications. 

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Page 81 of 81 
a Low doses of Vitamin E and/or CoQ10, for general health/as part of a multivitamin and Vitamin D3 for deficiency or 
for bone health are allowable if the dose remains stable throughout the study. 

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