An Open-Label, Safety Study for Previously Treated Vatiquinone (PTC743) Subjects With Inherited Mitochondrial Disease
Phase: PHASE3
Conditions: Inherited Mitochondrial Disease
Sponsor: PTC Therapeutics

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CLINICAL PROTOCOL 
VATIQUINONE (PTC743, FORMERLY KNOWN AS EPI-743) 
AN OPEN-LABEL, SAFETY STUDY FOR PREVIOUSLY TREATED 
VATIQUINONE (PTC743) SUBJECTS WITH INHERITED 
MITOCHONDRIAL DISEASE 
PTC743-CNS-005-LSEP 
25 JANUARY 2023 
VERSION 3.0 
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 #: NCT05218655

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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC743-CNS 
International Nonproprietary Name 
Vatiquinone 
Therapeutic Area 
Neurology 
PTC Therapeutics Substance Identifier 
PTC743 (formerly EPI-743) 
IND Number 
107401; 140755 
EudraCT 
2020-002100-39 
Protocol Number 
PTC743-CNS-005-LSEP 
Protocol Version 
3.0 
Protocol Version Date 
25 January 2023 
Protocol Phase 
3 
Protocol Title 
An Open-label, Safety Study for Previously Treated 
Vatiquinone (PTC743) Subjects With Inherited 
Mitochondrial Disease 
PTC Clinical Lead 
 
PTC Medical Monitor 
 
PTC Biostatistician 
 
PTC Study Manager 
 
 
PPD
PPD
PPD
PPD

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SIGNATURE PAGE 
Sponsor’s Approval 
The protocol has been approved by PTC Therapeutics. 
 
Sponsor’s Authorized Officers: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTC Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
The eSignature Page is located on the last page. 
PPD
PPD
PPD

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INVESTIGATOR’S AGREEMENT 
 
I have read the protocol document and, on behalf of my institution, agree to comply with the protocol and 
all applicable regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
<<Institution Name>> 
<<Address>> 
<<Telephone Number>> 
<<Fax Number>> 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 

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TABLE OF CONTENTS 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ...........................................................2 
SIGNATURE PAGE .......................................................................................................................3 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................8 
LIST OF FIGURES .........................................................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................9 
1. 
SYNOPSIS .................................................................................................................10 
1.1. 
Clinical Study Participation History ...........................................................................13 
1.2. 
Schema ........................................................................................................................13 
1.3. 
Schedule of Assessments ............................................................................................14 
2. 
INTRODUCTION ......................................................................................................16 
2.1. 
Study Rationale ...........................................................................................................16 
2.2. 
Background .................................................................................................................16 
2.2.1. 
Nonclinical Safety Assessment Studies ......................................................................16 
2.2.2. 
Clinical Safety Studies ................................................................................................17 
2.3. 
Benefit/Risk Assessment ............................................................................................17 
2.3.1. 
Risk Assessment .........................................................................................................17 
2.3.2. 
Benefit Assessment .....................................................................................................17 
2.3.3. 
Overall Benefit/Risk Conclusion ................................................................................18 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................19 
4. 
STUDY DESIGN .......................................................................................................20 
4.1. 
Overall Design ............................................................................................................20 
4.2. 
Scientific Rationale for Study Design ........................................................................20 
4.3. 
Justification for Dose ..................................................................................................21 
4.4. 
End of Study Definition ..............................................................................................21 
5. 
STUDY POPULATION .............................................................................................22 
5.1. 
Inclusion Criteria ........................................................................................................22 
5.2. 
Exclusion Criteria .......................................................................................................23 
5.3. 
Lifestyle Considerations .............................................................................................23 
5.4. 
Screen Failures ............................................................................................................23 
6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY .............................24 

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6.1. 
Study Intervention Administered ................................................................................24 
6.2. 
Preparation, Handling, Storage, and Accountability ..................................................25 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................25 
6.4. 
Study Intervention Compliance ..................................................................................25 
6.5. 
Dose Modification ......................................................................................................25 
6.6. 
Continued Access to Study Intervention After the End of the Study .........................25 
6.7. 
Treatment of Overdose ...............................................................................................25 
6.8. 
Concomitant Therapy .................................................................................................26 
6.8.1. 
Rescue Medicine .........................................................................................................26 
6.8.2. 
Prohibited Medications ...............................................................................................26 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................27 
7.1. 
Discontinuation of Study Intervention........................................................................27 
7.2. 
Participant Discontinuation/Withdrawal From the Study ...........................................27 
7.3. 
Lost to Follow-up .......................................................................................................28 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................29 
8.1. 
Efficacy Assessments .................................................................................................29 
8.1.1. 
Seizure Assessment – Subjects Previously Enrolled in Study MIT-E Only ..............29 
8.1.2. 
Newcastle Pediatric Mitochondrial Disease Scale – Subjects Previously 
Enrolled in Study MIT-E Only ...................................................................................29 
8.1.3. 
Quality of Life – Subjects Previously Enrolled in Study MIT-E Only ......................29 
8.2. 
Safety Assessments .....................................................................................................29 
8.2.1. 
Demographic/Medical History ...................................................................................29 
8.2.2. 
Physical Examination, Height, Weight, and Vital Signs ............................................29 
8.2.3. 
12-Lead Electrocardiograms .......................................................................................30 
8.2.4. 
Clinical Safety Laboratory Assessments ....................................................................30 
8.2.4.1. 
Hematology .................................................................................................................30 
8.2.4.2. 
Coagulation .................................................................................................................30 
8.2.4.3. 
Serum Chemistry ........................................................................................................30 
8.2.4.4. 
Urinalysis (Dipstick or Serum) ...................................................................................31 
8.2.5. 
Pregnancy Testing ......................................................................................................31 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................31 
8.3.1. 
Definition of Adverse Events .....................................................................................31 

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8.3.2. 
Definition of Serious Adverse Events ........................................................................32 
8.3.3. 
Unexpected Adverse Events .......................................................................................33 
8.3.4. 
Eliciting Adverse Event Information ..........................................................................33 
8.3.5. 
Recording Nonserious Adverse Events and Serious Adverse Events ........................33 
8.3.6. 
Describing Adverse Event Relationship to Study Drug .............................................34 
8.3.7. 
Grading of Severity of Adverse Event ........................................................................34 
8.3.8. 
Adverse Event Reporting ............................................................................................35 
8.3.9. 
Reporting Serious Adverse Events .............................................................................35 
8.3.10. 
Reporting Pregnancy ..................................................................................................36 
8.3.11. 
PTC Safety Reporting Requirement ...........................................................................37 
8.4. 
Pharmacokinetics ........................................................................................................37 
8.5. 
Genetics ......................................................................................................................37 
8.6. 
Biomarkers ..................................................................................................................37 
9. 
STATISTICAL CONSIDERATIONS .......................................................................38 
9.1. 
Statistical Hypotheses .................................................................................................38 
9.2. 
Analysis Sets ...............................................................................................................38 
9.3. 
Statistical Analyses .....................................................................................................38 
9.3.1. 
General Considerations ...............................................................................................38 
9.3.2. 
Subject Disposition and Baseline Characteristics.......................................................38 
9.3.3. 
Analysis of Efficacy ...................................................................................................38 
9.3.4. 
Analysis of Safety .......................................................................................................39 
9.4. 
Interim Analysis ..........................................................................................................39 
9.5. 
Sample Size Determination ........................................................................................39 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................40 
10.1. 
Regulatory, Ethical, and Study Oversight Consideration ...........................................40 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................40 
10.1.2. 
Informed Consent Process ..........................................................................................41 
10.1.3. 
Confidentiality and Privacy ........................................................................................41 
10.1.4. 
Clinical Monitoring ....................................................................................................42 
10.1.5. 
Data Quality Assurance ..............................................................................................42 
10.1.6. 
Data Handling and Record Keeping ...........................................................................42 
10.1.7. 
Study and Site Start and Closure ................................................................................43 

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10.1.8. 
Publication and Data Sharing Policy ..........................................................................43 
11. 
PROTOCOL AMENDMENT HISTORY ..................................................................45 
11.1. 
Amendment 2 (Version 3.0): 25 January 2023 ...........................................................45 
11.2. 
Amendment 1 (Version 2.0): 11 April 2022 ...............................................................46 
12. 
REFERENCES ...........................................................................................................49 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................14 
Table 2: 
Weight-Based Dosing in mL of the 100-mg/mL Solution .........................................21 
Table 3: 
Investigational Product ...............................................................................................24 
Table 4: 
Relationship of Study Drug to Adverse Event Relationship ......................................34 
Table 5: 
Grading of Adverse Event Severity Grade .................................................................34 
Table 6: 
Investigator Site Requirements for Reporting Adverse Events ..................................35 
 
LIST OF FIGURES 
Figure 1: 
Clinical Study Participation History of Subjects in Study PTC743-CNS-005-
LSEP ...........................................................................................................................13 
Figure 2: 
Study Schema .............................................................................................................13 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialized Term 
Explanation 
15-LO 
15-lipoxygenase 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Event 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
End-of-Treatment 
ET 
Early Termination 
G-tube 
gastrostomy tube 
GCP 
Good Clinical Practice 
Gpx4 
glutathione peroxidase 4 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELAS 
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes 
MERRF 
myoclonic epilepsy with ragged-red fibers 
NOAEL 
no-observed-adverse-effect level 
NPMDS 
Newcastle Pediatric Mitochondrial Disease Scale 
PCH6 
pontocerebellar hypoplasia type 6 
PedsQL 
Pediatric Quality of Life Inventory™ 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
Study MIT-E 
Study PTC743-MIT-001-EP 
SURF1 
surfeit locus protein 1 
SUSAR 
suspected unexpected serious adverse reaction 
TID 
three times a day 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 

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1. 
SYNOPSIS 
Name of Sponsor/Company: PTC Therapeutics, Inc.  
Name of Investigational Product: Vatiquinone (PTC743, formerly known as EPI-743) 
Name of Active Ingredient: Alpha-tocotrienol quinone 
Protocol Number: PTC743-CNS-005-LSEP 
Phase: 3 
Country: Global 
Title of Study: 
An Open-label, Safety Study for Previously Treated Vatiquinone (PTC743) Subjects With 
Inherited Mitochondrial Disease 
Studied period (years): 
June 2021 until approximately March 2025.  All subjects will receive a minimum of 
12 months of treatment.   
Objectives: 
Primary: To assess the safety of vatiquinone in subjects with inherited mitochondrial disease 
who participated in a previous vatiquinone clinical study or treatment plan. 
Exploratory:  
• 
To explore the effects of vatiquinone in motor seizure count in subjects previously enrolled 
in Study PTC743-MIT-001-EP (Study MIT-E). 
• 
To explore the effects of vatiquinone based on the Newcastle Pediatric Mitochondrial 
Disease Scale (NPMDS) in subjects previously enrolled in Study MIT-E. 
• 
To demonstrate the effects of vatiquinone on health-related quality of life in subjects 
previously enrolled in Study MIT-E. 
Study Design: This is an open-label, Phase 3, safety study of vatiquinone in subjects with 
inherited mitochondrial disease who participated in a previous clinical study or treatment plan 
(parent study). A target of approximately 200 previously treated vatiquinone subjects will be 
enrolled at up to approximately 40 investigational sites worldwide. Subjects will receive 
vatiquinone oral solution (100 mg/mL), up to 400 mg, administered orally or via feeding tube 
three times a day (TID). Subjects will continue the dosing regimen from their parent study. 
The study will include a Screening/Baseline Visit, a Treatment Period, and an 
End-of-Treatment Visit. For subjects that will discontinue early, an Early Termination Visit 
will be performed 6 weeks after discontinuation. 
Safety assessments for subjects will be performed at Screening/Baseline and every 6 months. 
Safety assessments will also be collected for all subjects at the End-of-Treatment Visit. 
Sample Size Justification: 
The sample size for this study is based on the number of subjects in previous vatiquinone 
studies and is not based upon any formal statistical hypothesis. 
Number of patients (planned): 
Up to 200 subjects 
Diagnosis and main criteria for inclusion: 
Inclusion criteria: 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Subjects with inherited mitochondrial disease including Leigh syndrome, Alpers 
syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes 
(MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), pontocerebellar 
hypoplasia type 6 (PCH6), or other mitochondrial disease who participated in a 
previous vatiquinone clinical study or treatment plan. 

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2. Women of childbearing potential (as defined in (CTFG 2020)) must have a negative 
pregnancy test at Screening/Baseline and agree to abstinence or the use of at least one 
of the following highly effective forms of contraception (with a failure rate of <1% per 
year when used consistently and correctly). Highly effective contraception or 
abstinence must be continued for the duration of the study and for up to 50 days after 
the last dose of study drug: 
• combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral 
− injectable 
− implantable 
• intrauterine device 
• intrauterine hormone-releasing system 
• vasectomized partner with confirmed azoospermia 
All females will be considered of childbearing potential unless they are 
postmenopausal (at least 12 months consecutive amenorrhea in the appropriate age 
group without other known or suspected cause) or have been sterilized surgically 
(eg, bilateral tubal ligation, hysterectomy, bilateral oophorectomy). 
3. Fertile men, as defined in (CTFG 2020), who are sexually active with women of 
childbearing potential and who have not had a vasectomy, must agree to use a barrier 
method of birth control during the study and for up to 50 days after the last dose of 
study drug. 
Exclusion criteria: 
Participants are excluded from the study if any of the following criteria apply: 
1. Current participation in any other interventional study 
2. Pregnancy or breastfeeding 
Investigational product, dosage, and mode of administration: 
Vatiquinone oral solution (100 mg/mL), up to 400 mg, administered orally or via feeding tube, 
TID. Subjects will continue the dosing regimen from their parent study. 
Duration of treatment: 
The duration of vatiquinone treatment will be subject to the following conditions: 
• The subject has the right to withdraw consent and discontinue vatiquinone at any time. 
• The relevant regulatory authority and/or PTC Therapeutics (PTC) may discontinue the 
study at any time. 
• If the subject’s condition substantially worsens after initiating vatiquinone treatment in 
this study, the subject will be carefully evaluated by the investigator in consultation with 
the PTC medical monitor. The subject will be withdrawn from treatment if continuing 
would place the subject at risk. 
• The investigator may withdraw the subject from vatiquinone treatment if, in the 
investigator’s clinical judgment, it is not in the subject’s best interest to continue. 

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• If the subject is unable to tolerate vatiquinone, the subject will be withdrawn from 
treatment. 
Reference therapy, dosage, and mode of administration: 
None 
Criteria for evaluation: 
Efficacy: 
Efficacy assessments will include number of motor seizures recorded in the seizure diary for 
rollover subjects previously enrolled in Study MIT-E only. The NPMDS and health-related 
quality of life as measured by the CarerQoL-7D and the Pediatric Quality of Life Inventory™ 
(PedsQL) questionnaires will be assessed for rollover subjects previously enrolled in Study 
MIT-E only. 
Safety: 
Subjects will be monitored for adverse events (AEs)/serious adverse events (SAEs), laboratory 
abnormalities, vital signs, and electrocardiograms (ECGs). 
Statistical methods: 
All subjects who receive ≥1 dose of vatiquinone will be included in the analyses of safety. 
All statistical methods will be descriptive in nature. For continuous variables, median, mean, 
standard deviation, minimum, maximum, and number of subjects with non-missing data will 
be presented. For categorical variables, the number (percent) of subjects in each category will 
be provided. 
Frequencies of AEs will be tabulated by Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class, Preferred Term, severity, relationship to study drug, and 
seriousness. 
The change in the NPMDS score (sum of Sections 1 to 3) and the health-related quality of life, 
as measured by the CarerQoL-7D and PedsQL, will be summarized descriptively based on the 
safety population in subjects previously enrolled in Study MIT-E. 
Vital signs, laboratory data, and ECG will be summarized by visit. Changes from baseline will 
be summarized by visit, where appropriate. 

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1.1. 
Clinical Study Participation History 
Clinical study participation history of subjects who were previously treated with vatiquinone is 
shown in Figure 1. 
Figure 1: 
Clinical Study Participation History of Subjects in Study PTC743-CNS-005-LSEP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2. 
Schema 
The study schema is shown in Figure 2. 
Figure 2: 
Study Schema 
 
 
Study PTC743-MIT-001-EP 
Placebo-controlled efficacy and safety 
study with long-term extension in 
subjects with mitochondrial disease with 
refractory epilepsy 
Study EPI743-13-023 
Long-term safety & efficacy study in 
subjects with Leigh Syndrome 
Study OPBGC&RS 2011-004_CA2012 (Italy) 
Efficacy & long-term safety study in subjects 
with Leigh Syndrome 
Study EPI2009-1 
Emergency use protocol in subjects with 
inherited mitochondrial disease 
Study PTC743-CNS-005-LSEP 
Safety study for previously treated vatiquinone 
(PTC743) subjects with inherited mitochondrial 
disease 

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1.3. 
Schedule of Assessments 
Table 1: 
Schedule of Assessments 
Study Period 
Screening/Baselinea 
Treatment 
EOT Visit 
ET (6 Weeks 
After D/C)b 
Study Month 
Day 1 
Telephone Visits 
3 Months (84±7 Days) 
After On-Site Visits 
Every 6 Months  
(168±7 Days) 
Informed consent 
Xc 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Vital signs 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
Weight 
X 
Xd 
X 
X 
X 
Physical examination 
X 
 
X 
X 
X 
12-Lead ECG 
X 
 
X 
X 
X 
Urine pregnancy test (WOCBP)l 
X 
 
X 
Xe 
X 
Hematology (CBC w/ differential) 
Xm 
 
Xm 
Xm 
Xm 
Serum chemistry 
Xm 
 
Xm 
Xm 
Xm 
Coagulation panel 
Xm 
 
Xm 
Xm 
Xm 
Urinalysisf 
X 
 
X 
X 
X 
NPMDSg 
X 
 
X 
X 
X 
CarerQoL-7Dg 
Xh 
 
X 
X 
X 
PedsQLg 
Xh 
 
X 
X 
X 
Drug dispensedi 
X 
X 
X 
 
 
Pre-/post-shipment contactj 
 
X 
 
 
 
Drug compliancek 
 
 
X 
X 
X 
AE/SAE assessment 
X 
Xd 
X 
X 
X 
Prior/concomitant medication 
X 
Xd 
X 
X 
X 
Abbreviations: AE, adverse event; CBC, complete blood count; D/C, discontinuation; ECG, electrocardiogram; EOT, End-of-Treatment; ET, Early Termination; 
NPMDS, Newcastle Pediatric Mitochondrial Disease Scale; PedsQL, Pediatric Quality of Life Inventory™; SAE, serious adverse event; Study MIT-E, Study 
PTC743-MIT-001-EP; WOCBP, women of childbearing potential 
a On-site visit applicable to all subjects rolling over to this study. For subjects rolling over from Study MIT-E, the Screening/Baseline Visit in this study will also be 
the Week 72 visit in Study MIT-E. 
b Subjects who discontinue vatiquinone prematurely should complete an ET Visit.  
c Informed consent will be signed before any study procedures. In case the subject/caregivers cannot attend the Screening/Baseline Visit in the clinic, remote 
consenting can be obtained. 
d Clinical site staff will contact subject or parent(s)/legal guardian(s) every 3 months (by telephone if there is no clinic visit) to assess AEs, weight, and concomitant 
medications. 

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e At-home urine pregnancy test kits will be provided; subjects will be required to perform the test at home 30 days after the last dose of study drug and self-report 
the results via telephone. 
f Urinalysis by dipstick collection or serum test. 
g To be performed only for subjects previously enrolled in Study MIT-E.   
h These assessments will be performed at Week 72 of Study MIT-E and will be used as the Baseline assessment for this study. 
i Drug will be dispensed to the subject every 3 months. 
j Clinical site staff will contact the subject or parent(s)/legal guardian(s) to confirm details and timing of the upcoming study drug shipment. Post-shipment contact 
will confirm receipt of and condition of study drug. 
k Subjects or parent(s)/caregiver(s) or legal guardian(s) should return all used and unused bottles of vatiquinone as instructed in order to assess study drug 
compliance. 
l A pregnancy test will be administered every 6 months throughout the study. If urine pregnancy test is not possible, subjects can have a serum pregnancy test 
done. 
m Approximately 7.7 mL of blood will be drawn per visit 
Note: If a site visit is not possible, a telephone visit and local laboratory may be performed and reviewed by the investigator to assess safety and concomitant 
medications. 
 

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2. 
INTRODUCTION 
Vatiquinone (PTC743, EPI-743, alpha-tocotrienol quinone) is a novel small molecule therapeutic 
in development for the treatment of mitochondrial diseases and associated disorders of oxidative 
stress and inflammation. Vatiquinone inhibits 15-lipoxygenase [15-LO], an oxidoreductase 
enzyme involved in response to oxidative stress and can promote inflammation and cell death. 
Vatiquinone is the quinone oxidation product of alpha-tocotrienol and is a member of the 
para-benzoquinone class of drugs. Vatiquinone is administered orally, crosses the blood-brain 
barrier, and works by targeting oxidoreductases that are critical to energy metabolism, oxidative 
stress, and inflammation. 
For the most comprehensive nonclinical and clinical information regarding vatiquinone refer to 
the latest version of the Investigator’s Brochure (IB) for vatiquinone. 
2.1. 
Study Rationale 
This open-label study will serve as a continued access study for subjects that have previously 
participated in a vatiquinone study. The purpose of this study is to ensure continued safety of 
vatiquinone dosing in previously treated subjects. To date, vatiquinone has been evaluated in a 
number of clinical studies for the treatment of mitochondrial diseases and has demonstrated a 
reduction of seizure- and disease-related morbidity in clinical studies of patients with 
mitochondrial disease and associated refractory epilepsy and has been shown to prevent cell 
death in cellular models for diseases of mitochondrial dysfunction. 
This study explores the safety and efficacy of long-term treatment with vatiquinone. 
2.2. 
Background 
2.2.1. 
Nonclinical Safety Assessment 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 (Study 1660-045) and 9-month (Study 1660-046) 
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 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 values of 48786 (rat) and 
107426 ng.h/mL (dog). The dose-limiting adverse effect in both rat and dog studies was 
anticoagulation as demonstrated by prolonged prothrombin time (PT) and activated partial 
thromboplastin time (PTT) that most likely results from weak vitamin K antagonism exhibited 
by this class of compounds. 
Vatiquinone was negative in the Good Laboratory Practice 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 rats 
(Studies AD75SX.503.BTL, AD75SX.348ICH.BTL, and AD75SX.125012ICH.BTL). 
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 

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inhibitor of human ether-à-go-go-related gene channel current (Study 130416.FEK). Vatiquinone 
did not influence respiratory function in rat (Study 1660-032). 
An in vitro phototoxicity study conducted in BALB/c 3T3 mouse fibroblasts to assess phototoxic 
potential, demonstrated that vatiquinone had no phototoxic potential when administered to the 
fibroblasts at concentrations up to 17.8 µg/mL (approximately 2 times the Cmax NOAEL of 
8.828 µg/mL in rats). 
2.2.2. 
Clinical Safety Studies 
To date, over 500 patients have been treated with vatiquinone, ranging in age at enrollment from 
<1 year to 70 years old. Total drug exposure to date is more than 523000 patient days, with the 
longest exposure being over 10 years in a pediatric subject with Leigh syndrome (surfeit locus 
protein 1 [SURF1] variant). There have been 7 serious adverse events (SAEs) deemed possibly 
related to vatiquinone: 
• One subject experienced 3 SAEs (pneumonia, tachycardia, and increased 
unresponsiveness) assessed as possibly related to vatiquinone by the investigator 
• One subject experienced hypoglycemia assessed as possibly related to vatiquinone by 
the investigator 
• One subject experienced depression assessed as possibly related to vatiquinone by the 
investigator 
• One subject developed pancreatitis assessed as possibly related to vatiquinone by the 
investigator 
• One subject developed neutropenia assessed as possibly related by the Investigator 
and the Sponsor 
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. 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
At the dose levels selected for this study it is not foreseen that subjects will endure any risks 
greater than minimal. However, as the dose-limiting adverse effect in nonclinical toxicology 
studies was anticoagulation, 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 
(PT, PTT) are found to be increased to more than 1.5× upper limit of normal (ULN). 
2.3.2. 
Benefit Assessment 
There are no effective and/or approved treatments available for seizures in the majority of 
patients with mitochondrial disease. In order to participate in this study, subjects must have 
frequent seizure episodes despite treatment with existing antiepileptic therapies. In addition to 
improved seizure control, potential benefits may manifest in a variety of ways, such as in 
disease-related parameters, functioning, and quality of life. 

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2.3.3. 
Overall Benefit/Risk Conclusion 
The Screening criteria for this study include that subjects must have seizures that are refractory 
to antiepileptic therapies. Therefore, the potential benefit to subjects is better control of their 
seizure activity. In order to further minimize risks, subjects will be closely monitored with a 
variety of safety measures. 

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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To assess the safety of vatiquinone in 
subjects with inherited mitochondrial disease 
who participated in a previous vatiquinone 
clinical study or treatment plan 
• 
Adverse events (AEs)/SAEs, ECGs, vital 
signs, and laboratory data (hematology, 
biochemistry, and urine data) 
Exploratory 
• 
To explore the effects of vatiquinone in motor 
seizure count in subjects previously enrolled in 
Study PTC743-MIT-001-EP (Study MIT-E) 
• 
Total frequency of motor seizures per 28 days 
• 
To explore the effects of vatiquinone based on 
the Newcastle Pediatric Mitochondrial Disease 
Scale (NPMDS) in subjects previously 
enrolled in Study MIT-E 
• 
Change in the total score for NPMDS 
Sections 1 to 3 
• 
To demonstrate the effects of vatiquinone on 
health-related quality of life in subjects 
previously enrolled in Study MIT-E 
• 
Measured by the CarerQoL-7D and Pediatric 
Quality of Life Inventory™ [PedsQL] 
questionnaires 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label, Phase 3, safety study of vatiquinone in subjects with inherited 
mitochondrial disease who vatiquinone clinical study or treatment plan (parent study). 
A target of approximately 200 previously treated vatiquinone subjects will be enrolled at up to 
approximately 40 investigational sites worldwide. Subjects will receive vatiquinone oral solution 
(100 mg/mL), up to 400 mg, administered orally or via feeding tube, three times a day (TID). 
Subjects will continue the dosing regimen from their parent study (Figure 1). 
The study will include a Screening/Baseline Visit, a Treatment Period, and an End-of-Treatment 
Visit. For subjects that discontinue early, an Early Termination Visit will be performed 6 weeks 
after discontinuation. 
The duration of vatiquinone treatment will be subject to the following conditions: 
• The subject has the right to withdraw consent and discontinue vatiquinone at any 
time. 
• The relevant regulatory authority and/or PTC Therapeutics (PTC) may discontinue 
the study at any time. 
• If the subject’s condition substantially worsens after initiating vatiquinone treatment 
in this study, the subject will be carefully evaluated by the investigator in consultation 
with the PTC medical monitor. The subject will be withdrawn from treatment if 
continuing would place the subject at risk. 
• The investigator may withdraw the subject from vatiquinone treatment if, in the 
investigator’s clinical judgment, it is not in the subject’s best interest to continue. 
• If the subject is unable to tolerate vatiquinone, the subject will be withdrawn from 
treatment. 
Safety assessments for subjects will be performed at Screening/Baseline and every 6 months. 
Safety assessments will also be collected for all subjects at the End-of-Treatment Visit. 
A diagram of the study design is provided in Section 1.2. 
4.2. 
Scientific Rationale for Study Design 
Seizures are a common symptom of mitochondrial disease and occur in up to 60% of patients 
with inherited mitochondrial disease. Over 90% of patients with mitochondrial 
disease-associated epilepsy have seizures that are refractory to traditional antiepileptic therapies 
(Saneto 2017). The refractory nature of seizures that occur in patients with inherited 
mitochondrial disease may be related to the fact that traditional antiepileptic therapies do not 
target the energetic pathways that underpin seizure pathology in these patients (Verrotti 2020). 
Furthermore, traditional antiepileptic therapies have been reported to increase oxidative stress 
which could have the potential to exacerbate mitochondrial disease pathology (Hamed 2004, 
Aycicek 2007). There is increasing evidence that seizure pathology is associated with ferroptosis 
(a form of programmed cell death that is regulated by the enzymes 15-LO and glutathione 
peroxidase 4 [Gpx4]). Vatiquinone, a novel small molecule therapeutic in development for 

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inherited mitochondrial disease, inactivates 15-LO and downregulates the production of oxidized 
lipid signaling molecules key to the mechanism of ferroptosis. In preclinical studies, vatiquinone 
has been demonstrated to rescue cells from patients with mitochondrial disease and associated 
epilepsy by inhibiting 15-LO. In previous clinical studies, vatiquinone therapy has been 
associated with a decrease in seizure frequency and seizure-related morbidity in patients with 
refractory epilepsy and mitochondrial disease. 
4.3. 
Justification for Dose 
Subjects will continue the dosing regimen from their parent study and the dose will be adjusted 
based on the subject’s body weight, if applicable (Table 2). 
Table 2: 
Weight-Based Dosing in mL of the 100-mg/mL Solution 
Subject Weight (kg) 
Dose (mg/kg) TID 
Dose Volume (mL) 
4 
15 
0.6 
5 
15 
0.8 
6 
15 
0.9 
7 
15 
1.1 
8 
15 
1.2 
9 
15 
1.4 
10 
15 
1.5 
11 
15 
1.7 
12 
15 
1.8 
13 
15 
2.0 
Above 13 kg 
200 mg per dose 
2.0 
Subjects enrolled from Study MIT-E 
Vatiquinone oral solution is manufactured at 100 mg/mL for oral administration. The dose of 
15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, TID (Table 2) was selected 
on the basis of clinical experience with vatiquinone and plasma concentration data in pediatric 
patients treated with doses of 100 to 200 mg TID. This dose range was well tolerated in all 
patients, showed biochemical evidence of target engagement, and was associated with clinical 
improvements in pediatric patients with mitochondrial disease. Using body weight-based dosing 
is standard of care for pediatric patients and eliminates the potential for overdose in low body 
weight patents, and also allows adequate plasma concentrations to be achieved in the face of 
significant variability in bioavailability. 
Weight-based dose adjustment exposed above is only applicable to subjects transitioning from 
Study MIT-E. Subjects transitioning from Studies EPI743-13-023, OPBGC&RS 
2011-004_CA2012(Italy), and EPI2009-1 will continue the vatiquinone dosing regimen from 
their parent study. 
4.4. 
End of Study Definition 
The end of the study per subject disposition will be the date of the last study visit for the last 
subject in the study. 

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5. 
STUDY POPULATION 
The study population consists of male and female subjects who have genetically determined 
mitochondrial disease and associated refractory epilepsy (defined as those who were 
unsatisfactorily treated with at least 2 antiepileptic drugs). 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Subjects with inherited mitochondrial disease including Leigh syndrome, Alpers 
syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes 
(MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), pontocerebellar 
hypoplasia type 6 (PCH6), or other mitochondrial disease who participated in a previous 
vatiquinone clinical study or treatment plan. 
2. Women of childbearing potential, as defined in (CTFG 2020), must have a negative 
pregnancy test at Screening/Baseline and agree to abstinence or the use of at least one of 
the following highly effective forms of contraception (with a failure rate of <1% per year 
when used consistently and correctly). Highly effective contraception or abstinence must 
be continued for the duration of the study, and for up to 50 days after the last dose of 
study drug: 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− oral 
− intravaginal 
− transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation: 
− oral 
− injectable 
− implantable 
• intrauterine device 
• intrauterine hormone-releasing system 
• vasectomized partner with confirmed azoospermia 
All females will be considered of childbearing potential unless they are postmenopausal 
(at least 12 months consecutive amenorrhea in the appropriate age group without other 
known or suspected cause) or have been sterilized surgically (eg, bilateral tubal ligation, 
hysterectomy, bilateral oophorectomy). 
3. Fertile men, as defined in (CTFG 2020), who are sexually active with women of 
childbearing potential and who have not had a vasectomy, must agree to use a barrier 
method of birth control during the study and for up to 50 days after the last dose of study 
drug. 

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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Current participation in any other interventional study. 
2. Pregnancy or breast feeding. 
5.3. 
Lifestyle Considerations 
Potential subjects must be willing and able to adhere to the following lifestyle restrictions during 
the study to be eligible for participation: 
1. Refer to Section 6.8 for details regarding prohibited and restricted therapy during the 
study. 
2. Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements). 
5.4. 
Screen Failures 
Any subject that does not meet inclusion or exclusion criteria at Screening/Baseline prior to 
enrollment, will be considered a screen failure. Screen failures can be rescreened after 
consultation with the medical monitor. 

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6. 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational product(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1. 
Study Intervention Administered 
Details for the investigational product are shown in Table 3. 
Table 3: 
Investigational Product 
 
Investigational Product 
Product Name 
Vatiquinone 
Product Description 
Oral solution (100 mg/mL) is a solution of vatiquinone drug 
substance in super refined, preservative free sesame oil 
Type 
Drug 
Dose Formulation 
Oral solution 
Unit Dose Strength(s) 
100 mg/mL 
Dose Level(s) 
Parent study: Study MIT-E 
Vatiquinone at a dose of 
15 mg/kg if body weight 
<13 kg, and 200 mg if body 
weight ≥13 kg TID 
Parent Study: Studies other 
than Study MIT-E 
Subjects will continue the 
vatiquinone dosing regimen 
from their parent study 
Route of Administration 
Oral or via gastric or nasogastric feeding tube 
Use 
Experimental 
Investigational Medicinal Product 
Yes 
Sourcing 
Centrally by sponsor or locally by the study site, subsidiary, or 
designee 
Packaging and Labeling 
Oral Solution Bottles (Booklet Labels)  
Current/Former Names 
PTC743/EPI-743 
Abbreviations: Study MIT-E, Study PTC743-MIT-001-EP 
Food is required for appropriate absorption of vatiquinone from the gastrointestinal tract. For 
subjects who have a gastrostomy tube (G-tube) installed, the study drug will be instilled into the 
G-tube using an oral dispenser. For subjects who are receiving continuous feed with liquid 
nutritional preparation such as PediaSure, the feed is interrupted to allow instillation of the drug 
solution into the G-tube using an oral dispenser, followed by resumption of the continuous feed 
to flush the drug into the stomach. For subjects who received G-tube feeding as bolus, the study 
drug is instilled into the G-tube using an oral dispenser, followed by the feed bolus to flush the 
drug into the stomach. The same procedures are to be followed in case the subject has a 
nasogastric tube installed. Additional detail on vatiquinone can be found in the Pharmacy 
Manual. 
For subjects who do not have a G-tube installed and who can swallow, the study drug is given 
orally using an oral dispenser along with a meal that includes foods such as cream cheese, peanut 
butter, or other fatty components. The dose of study drug needs to be followed by eating yogurt, 
ice cream (no non-fat), or any other food with at least 25% calories from fat. 

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6.2. 
Preparation, Handling, Storage, and Accountability 
Preparation/Handling/Storage 
No preparation is required; vatiquinone is provided as a ready to use oral solution. 
At room temperature, vatiquinone is a yellow to orange clear liquid. Fifty-four mL of the 
solution is filled into a 60 mL amber glass bottle and closed with child resistant cap suitable for 
multiple dose administration. 
Each bottle will be labeled with the following but not limited to: Product name, concentration, 
batch number, expiration date, storage conditions, and a caution limiting it for Clinical Trial Use 
Only. 
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 assess drug accountability and will request to review the 
Pharmacy Records and investigator study file to assure the study drug is prescribed by the 
investigator or designee for the purpose of this study. 
At study completion, all drug supplies including partially used and empty containers must be 
either returned to the Sponsor or designee or destroyed per your institution’s guidelines for 
destruction of investigational product after drug accountability has been performed by the study 
monitor. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. Subjects will continue the dosing regimen from their parent study. 
6.4. 
Study Intervention Compliance 
Study drug will be reviewed to assess compliance on an ongoing basis. Subjects who take >80% 
of the prescribed doses and no more than 120% of the prescribed doses will be considered 
compliant. Subjects who fall outside of this threshold will be counseled and instructed on dosing 
procedures. Medication compliance will be recorded in the diary. 
6.5. 
Dose Modification 
This protocol allows some alteration from the currently outlined dosing schedule as described in 
Section 4.3. 
6.6. 
Continued Access to Study Intervention After the End of the Study 
There is no planned continued access after the end of the study. 
6.7. 
Treatment of Overdose 
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 AE as described in the applicable clinical study 
protocol. 

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6.8. 
Concomitant Therapy 
Any medication taken by a subject 30 days prior to the Screening/Baseline Visit and during the 
course of the study and the reason for use of the medication will be recorded on the electronic 
case report form (eCRF)/paper case report form (CRF). During the Screening/Baseline Visit, 
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 medication throughout the study 
(including over-the-counter medications) without consulting the investigator. 
All immunizations will be considered as concomitant medications and will be recorded in the 
eCRF/CRF. Subjects will be instructed to consult the investigator before immunization. The final 
decision on any immunization should be made by the treating physician in consultation with the 
patient and/or caregiver. 
6.8.1. 
Rescue Medicine 
Use of rescue medications for epilepsy will be collected. The following standardized criteria 
should be used for use of rescue medications: 
• Seizure lasting longer than 4 minutes 
• Occurrence of status epilepticus 
• Cluster of 15 or more seizures 
6.8.2. 
Prohibited Medications 
Subjects will be required to maintain a stable regimen of mitochondrial disease supplements 
from Screening throughout the study. 
Anticoagulants such as vitamin K antagonists, Factor Xa inhibitors are not permitted during the 
course of the study because of the potential interaction with vatiquinone on vitamin K associated 
coagulation factor synthesis. 
Cytochrome P450 (CYP) inhibitors such as itraconazole have been demonstrated to significantly 
increase the plasma concentrations of vatiquinone (up to 2-fold). CYP inducers such as rifampin 
significantly reduce the plasma concentrations of vatiquinone (up to 50% less). Therefore, strong 
CYP inducers and inhibitors, including grapefruit/grapefruit juice and St John’s wort extract, 
should be avoided during the course of the study. 
In case treatment with a CYP inhibitor is required during the course of the study, coagulation 
parameters should be monitored and vatiquinone dose should be reduced by 33% in case 
international normalized ratio (INR) increases over 1.5×ULN or Common Terminology Criteria 
for Adverse Event (CTCAE) Grade 2. 
In the event that a CYP inducer is used, no adjustment of the study drug dose will be required 
because there are no safety concerns with CYP inducers. 

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7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Subjects receive study drug until treatment discontinuation for one of the reasons listed below. 
However, subjects may discontinue study drug or withdraw their consent to participate in the 
study at any time without prejudice. 
The following conditions require subject discontinuation from all study drug: 
• 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 vatiquinone 
and, in the investigator’s or the Sponsor’s medical judgment, continuation of 
treatment would be detrimental to the subject 
• Spontaneous bleeding in a 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 (Section 5.1) 
• If a subject becomes pregnant 
• Significant noncompliance with the protocol in the opinion of the Investigator or the 
Sponsor 
• Use of prohibited concomitant medication 
7.2. 
Participant Discontinuation/Withdrawal From the Study 
In all cases of subject withdrawal or discontinuation, the reason for withdrawal must be recorded 
in the eCRF/CRF 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 Section 8.3. 
Evaluations should be performed on all subjects who participate but do not complete the study 
according to protocol. The investigator will make every effort to contact subjects lost to 
follow-up. 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. 

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7.3. 
Lost to Follow-up 
Subjects are considered lost to follow-up if the subject does not return to the clinic and attempts 
to contact the subject are unsuccessful. Efforts must be made on the part of the site to avoid any 
subject being lost to follow-up during the study. Before subjects are considered lost to follow-up, 
a minimum of 2 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. After being 
considered lost to follow-up, a subject’s status may be changed if the subject makes contact at a 
later time provided the study is ongoing. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
The Schedule of Assessments (Table 1) summarizes the frequency and timing of safety 
measurement applicable to the study. Every effort should be made to keep participants on the 
planned study schedule. 
8.1. 
Efficacy Assessments 
8.1.1. 
Seizure Assessment – Subjects Previously Enrolled in Study MIT-E Only 
Efficacy assessments will include numbers of motor seizures recorded in the seizure diary. 
8.1.2. 
Newcastle Pediatric Mitochondrial Disease Scale – Subjects Previously Enrolled 
in Study MIT-E Only  
The NPMDS assessment that corresponds to the subject’s age at the time of informed consent 
will be used. According to the NPMDS manual, NPMDS Sections 1 to 3 will be assessed by the 
investigator or subinvestigator (by the same physician during the entire study period, whenever 
possible), and NPMDS Section 4 will be assessed by the subject’s guardian (by the same 
guardian during the entire study period, whenever possible) and the subject (if he or she is 
7 years of age or older and is able to complete the assessment). The investigator or 
subinvestigator are to record the dates and results of assessments in the CRF.  
Cognitive function in NPMDS Section 3 is not planned to be measured. 
8.1.3. 
Quality of Life – Subjects Previously Enrolled in Study MIT-E Only 
The health-related quality of life, as measured by the CarerQoL-7D and the PedsQL 
questionnaires, will be captured in the electronic diary or recorded on the appropriate page of the 
CRF. 
8.2. 
Safety Assessments 
AEs will be reported and followed by the investigator as specified in Section 8.3. 
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Assessments (Table 1). 
8.2.1. 
Demographic/Medical History 
Medical history and demographics including age, gender, and race, will be collected at the 
Screening/Baseline Visit. The investigator should review the study candidate’s clinical history, 
including details relating to inherited mitochondrial disease and any other medical conditions. 
Information regarding current medications must be captured on the concomitant medication 
eCRF/CRF. 
8.2.2. 
Physical Examination, Height, Weight, and Vital Signs 
Complete physical exams will be conducted (excluding genital/rectal exam) at protocol specified 
study visits. The physical examination will consist of an examination of the following: general 
appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, chest, 
heart, abdomen, and extremities (Table 1). 

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Standing height (in cm) will be measured at Screening/Baseline Visit. Weight (kg) will be 
measured at Screening/Baseline Visit, every 3 months, End-of-Treatment Visit, and at the Early 
Termination Visit (6 weeks after discontinuation of study drug), if applicable. As noted in 
Table 1, when not at the clinical site, weight will be collected by telephone. Weight will be 
measured in ordinary indoor clothing (ie, street clothes, scrubs) with shoes off. 
Vital signs measurements (including systolic and diastolic blood pressure, pulse rate, 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). Vital signs will be monitored at the 
Screening/Baseline Visit, every on-site treatment visit, End-of-Treatment Visit, and at the Early 
Termination Visit (6 weeks after discontinuation of study drug), if applicable (Table 1). 
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. 
8.2.3. 
12-Lead Electrocardiograms 
12-Lead ECG will be measured at Screening/Baseline Visit, every on-site treatment visit, and 
End-of-Treatment Visit as noted in Table 1. 
8.2.4. 
Clinical Safety Laboratory Assessments 
Hematology, serum chemistry, and urinalysis will be collected as noted in Table 1 to assess 
safety. Subjects will have approximately 15 mL of blood drawn per visit over the course of the 
study. The total amount of blood drawn will vary per subject depending on the duration of study 
participation. 
8.2.4.1. 
Hematology 
• Erythrocytes: red blood cell count, hematocrit, hemoglobin, mean corpuscular volume 
• Leukocytes: white blood cell count and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) 
• Platelets: platelet count 
8.2.4.2. 
Coagulation 
• PT with INR and PTT 
8.2.4.3. 
Serum Chemistry 
• Liver: Alkaline phosphatase, alanine aminotransferase (ALT), serum glutamic-
pyruvic transaminase), aspartate aminotransferase (AST), serum glutamic-oxaloacetic 
transaminase), bilirubin (total, direct), gamma-glutamyl transferase, and lactic 
dehydrogenase 
• Renal: blood urea nitrogen and creatinine 
• Electrolytes: sodium, potassium, chloride, carbon dioxide, calcium, magnesium, 
phosphate 

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• General: total protein, albumin, glucose 
• Lipids: cholesterol (total) and triglycerides 
8.2.4.4. 
Urinalysis (Dipstick or Serum) 
• pH 
• Protein 
• Glucose 
• Ketones 
• Blood 
• Bilirubin 
8.2.5. 
Pregnancy Testing 
Urine or serum pregnancy test will be measured on all female subjects of childbearing potential 
as noted in Table 1. At-home urine pregnancy test kits will be provided; subjects will be required 
to perform the test at home 30 days after the last dose of study drug and self-report the results via 
telephone. 
8.3. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
8.3.1. 
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) 

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• 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. 
• A preexisting condition (eg, allergic rhinitis) must be noted on the appropriate eCRF, 
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 8.3.2 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 nonserious by the investigator using medical and 
scientific judgment. 
8.3.2. 
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 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization* 
• Results in persistent or significant disability or incapacity 
• 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). 

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*Excluding hospitalizations for administration of vatiquinone, procedures required by the study 
protocol, or treatment-related diagnostic procedures, other planned hospitalizations, or 
hospitalizations related only to progression of disease. Emergency room visits that do not require 
admission to the hospital do not fall into this category, but the event may be serious due to 
another seriousness criterion. 
Serious adverse events will be assessed from the time of the Screening Visit through 30 days 
after the end of the subject’s participation in the study (last dose) and should be reported to the 
sponsor if the investigator becomes aware of them. 
8.3.3. 
Unexpected Adverse Events 
The IB 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. 
8.3.4. 
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. 
8.3.5. 
Recording Nonserious Adverse Events and Serious Adverse Events 
All AEs (both serious and nonserious) 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 nonserious (Section 8.3.2) 
• Relationship to study drug (Section 8.3.6) 
• Severity of the event (Section 8.3.7) 
• Onset date 
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 
Classification of the event as serious or nonserious determines the reporting procedures to be 
followed. 

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8.3.6. 
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 4. 
Table 4: 
Relationship of Study Drug to Adverse Event 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 AE 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 AE to a concomitant 
drug, medical history of a similar event, the subject’s disease state, other medical 
conditions, or environmental factors.  
Abbreviations: AE, adverse event 
8.3.7. 
Grading of Severity of Adverse Event 
The severity of AE will be graded using 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 
intensity grades are defined in Table 5. 
Table 5: 
Grading of Adverse Event Severity 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  

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8.3.8. 
Adverse Event Reporting 
Investigator site reporting requirements for AEs are summarized in Table 6. 
Table 6: 
Investigator Site Requirements for Reporting Adverse Events 
Event 
Recorded on the eCRF 
Reported on the SAE/Pregnancy Report 
Form to PTC Pharmacovigilance Within 
24 Hours of Awareness  
SAE 
All  
All  
Non-SAE 
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. 
8.3.9. 
Reporting Serious Adverse Events 
All SAEs occurring from the Screening Visit 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 aware of 
the event(s). In addition, the AE portion of the eCRF must also be completed. 
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 Institutional 
Review Board (IRB) or Independent Ethics Committee (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. 

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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 
PTC is responsible for notifying the relevant regulatory authorities of certain events. It is the 
Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at his or 
her site. Investigators will also be notified of all unexpected, serious, drug-related events (7/15 
Day Safety Reports) that occur during the clinical study. Each site is responsible for notifying its 
IRB or IEC of these additional SAEs. 
8.3.10. 
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 and must be reported on a Pregnancy Notification Form (see 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/CRFs (Section 8.3.9). 

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8.3.11. 
PTC Safety Reporting Requirement 
As the sponsor of the study, PTC is responsible for reporting certain safety information, 
particularly suspected unexpected serious adverse reaction (SUSAR) and other significant 
findings as required, to each investigator in an expedited manner. If notification of an 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 a SAE. This awareness date is the date the regulatory reporting clock begins, and the 
date is considered Day 0. 
8.4. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.5. 
Genetics 
Genetics are not evaluated in this study. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study. 

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9. 
STATISTICAL CONSIDERATIONS 
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods used to analyze the safety data is outlined below. Specific 
details will be provided in the statistical analysis plan. 
9.1. 
Statistical Hypotheses 
No hypotheses are planned to be tested. 
9.2. 
Analysis Sets 
Safety population: All subjects who receive at least 1 dose of vatiquinone in the study. Safety 
population will be used for all summaries in this study. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
The statistical analysis plan will be finalized prior to database lock and it will include a more 
detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses. 
All statistical methods will be descriptive in nature. For continuous variables, median, mean, 
standard deviation, minimum, maximum, and number of subjects with non-missing data will be 
presented. For categorical variables, the number (percent) of subjects in each category will be 
provided. 
By-subject listings will be created for each eCRF/CRF module. 
9.3.2. 
Subject Disposition and Baseline Characteristics 
The number of subjects who completed or discontinued from the study and the reasons of 
discontinuation will be summarized based on the safety population. 
Demographics and Baseline characteristics will also be summarized. 
9.3.3. 
Analysis of Efficacy 
Total frequency of motor seizures per 28 days is an exploratory efficacy endpoint in subjects 
previously enrolled in Study MIT-E. 
Seizure frequency will be based on the number of seizures per 28 days, calculated as the number 
of seizures over the time interval, divided by the number of the days in the interval, and 
multiplied by 28. 
Motor seizure frequency in 28 days will be summarized by visit based on the safety population. 
The change in the NPMDS score (sum of Sections 1 to 3) will be summarized by visit based on 
the safety population in subjects previously enrolled in Study MIT-E. 
Health-related quality of life, as measured by the CarerQoL-7D and PedsQL, will be summarized 
descriptively based on the safety population in subjects previously enrolled in Study MIT-E. 

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9.3.4. 
Analysis of Safety 
Frequencies of AEs will be tabulated by MedDRA System Organ Class, Preferred Term, 
severity, relationship to study drug, and seriousness. 
Vital signs, laboratory data, and ECG will be summarized by visit. Changes from Baseline will 
be summarized by visit, where appropriate. 
9.4. 
Interim Analysis 
No interim analysis is planned. 
9.5. 
Sample Size Determination 
The sample size for this study is based on the number of subjects in previous vatiquinone studies 
and is not based upon any formal statistical hypothesis. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Consideration 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), IB, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations 

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10.1.2. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or their legally authorized representative. Adequate time should 
be provided for the participant to read the ICF, 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. This information must be provided to the 
participant prior to undertaking any study-related procedure. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, privacy, and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants or their legally authorized representative must be reconsented to the most current 
version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative in a language in which the participant is fluent. 
10.1.3. 
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, CRFs, 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. 

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10.1.4. 
Clinical Monitoring 
In accordance with 21 CFR Part 312.56 and/or relevant International Committee on 
Harmonisation guidelines, PTC or a designee will periodically inspect all eCRFs/CRFs, 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/CRFs; 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/CRFs 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. 
10.1.5. 
Data Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, PTC, PTC’s 
representatives, a regulatory authority and/or 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. 
10.1.6. 
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/CRFs and clinic records/source documents), all original signed ICFs, 
electronic copies (ie, CD-ROM, USB) 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. 

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10.1.7. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first site open is considered the first act of recruitment and it will be the study start date. 
Study Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.8. 
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. 

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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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11. 
PROTOCOL AMENDMENT HISTORY 
11.1. 
Amendment 2 (Version 3.0): 25 January 2023 
Overall reason for Amendment 2 (Version 3.0): The overall reason for this amendment of the 
protocol was to add 2 new exploratory objectives and endpoints for subjects who were 
previously enrolled in Study MIT-E.   
All changes to the protocol are listed below in the table. Minor editorial changes (typographical 
errors, punctuation. abbreviations, etc.) have been made to the protocol but are not listed below. 
All changes in the body of the protocol were made to the corresponding sections of the synopsis. 
Protocol Section 
Amendment/Update 
Reason/ 
Rationale 
Table 1  
Revision of Table of Assessments to include the efficacy 
assessments for subjects in Study MIT-E, to clarify the visit 
windows, to clarify serum test could be performed for urinalysis 
tests, and to clarify all subjects who discontinue treatment 
prematurely were to have an ET visit.   
Update 
Section 2  
The description of vatiquinone has been updated. 
Update 
Section 2.1  
The study rationale was revised.   
Update 
Section 3  
Previous objectives were edited for clarity, and 2 new exploratory 
objectives and endpoints were added. 
Update 
Section 4.1  
The description of the study design was revised, the duration of 
treatment in this study was updated, and the description of when 
safety assessments were performed was clarified. 
Update 
Section 6.6  
The description of the potential for subjects to have access to 
vatiquinone after the study was updated.   
Update 
Section 8.1  
Previous endpoint was edited for clarity, and a description of the 
new efficacy assessments was added.   
Update 
Section 8.2.4.4  
Serum test for urinalysis was added.  
Update 
Section 9.3.3  
Previous endpoint was edited for clarity, and a description of the 
statistical plans for the new efficacy assessments was added.   
Update 
Abbreviations: Study MIT-E, Study PTC743-MIT-001-EP 
 

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11.2. 
Amendment 1 (Version 2.0): 11 April 2022 
Overall reason for Amendment 1: All subjects rolling over to this study will follow the same visit 
scheme from Screening/Baseline Visit. The protocol was updated and redundancies removed. 
Protocol 
Section 
Amendment/Update 
Reason/ 
Rationale 
Table 1 
The current Table 1: Schedule of Assessments for Subjects from 
Studies Other than Study MIT-E:   
- Drug dispensed: An "X" was marked for "telephone visits 3 months 
after on-site visits." 
- Pre-/Post-shipment contact: An "X" was marked for "telephone 
visits" and removed for "every 6 months" visits. 
- Physical examination, ECG, and drug compliance were added for 
ET visit. 
- Header written "Telephone visit every 3 months" must was replaced 
by "Telephone Visits 3 Months After On-site Visits." 
Update 
Table 1, 
Table 2 
Revision of Table of Assessments to accommodate all subjects following 
the same scheme from Screening/Baseline 
- Table 1 and all abbreviations related to Table 1 were removed. 
- Table 2 stated: Table 1: Schedule of Assessments for Subjects 
From Studies Other Than Study MIT-E and also included the change 
mentioned in Item 6 above. 
- Table footnote ‘a’ stated: Subjects from studies other than Study 
MIT-E; includes subjects from Studies EPI743-13-023, EPI2009-1, 
and OPBGC&RS 2011-004_CA2012. On-site visit applicable to all 
subjects rolling over to this study. For subjects rolling over from Study 
MIT-E, the Screening/Baseline Visit in this study will also be the 
Week 72 in Study MIT-E. 
Update 
Table 1 
Added text below to the end of table footnote ‘c’ 
In case the subject/caregiver cannot attend Screening/Baseline Visit 
in the clinic, remote consenting can be obtained. 
Update to 
consent 
procedure 
Table 1 
Added new footnote ‘j’ to “Urine pregnancy test (WOCBP)” 
- ‘j’ A pregnancy test will be administered every 6 months throughout 
the study. If urine pregnancy test is not possible, subjects can have a 
serum pregnancy test done. 
Update to 
pregnancy 
procedure  
Section 1  
The following change was applied to accommodate all subjects following 
the same study scheme from Screening/Baseline. 
Safety assessments and seizure data for subjects previously enrolled in 
vatiquinone Study MIT-E will be performed at screening/baseline, every 
3 months for the first year after enrollment, and then every 6 months 
until vatiquinone becomes commercially available or the program is 
terminated. Safety assessments for subjects previously enrolled in 
vatiquinone studies other than Study MIT-E will be performed at 
screening/baseline and every 6 months until vatiquinone becomes 
commercially available or the program is terminated. Safety 
assessments will also be collected for all subjects at the 
End-of-Treatment Visit. 
Update to 
study 
procedures  

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Protocol 
Section 
Amendment/Update 
Reason/ 
Rationale 
Figure 2 
Revision of study scheme to reflect all subjects following the same study 
scheme from Screening/Baseline. 
 
Update 
Section 4.1  
The following change was applied to accommodate all subjects following 
the same study scheme from screening/baseline. 
Safety assessments and seizure data for subjects previously enrolled in 
vatiquinone Study MIT-E will be performed at screening/baseline, every 
3 months for the first year after enrollment, and then every 6 months 
until vatiquinone becomes commercially available or the program is 
terminated. Safety assessments for subjects previously enrolled in 
vatiquinone studies other than Study MIT-E will be performed at 
screening/baseline and every 6 months until vatiquinone becomes 
commercially available or the program is terminated. Safety 
assessments will also be collected for all subjects at the End-of-
Treatment Visit. 
Update to 
study 
procedures 
Section 4.3  
Added the following text: 
Weight-based dose adjustment exposed above is only applicable for 
subjects transitioning from Study MIT-E. Subjects transitioning from 
Studies EPI743-13-023, OPBGC&RS 2011-004_CA2012(Italy), and 
EPI2009-1 will continue the vatiquinone dosing regimen from their 
parent study. 
Clarification 
of dose 
Section 6.5 
Change to text: 
This protocol allows some alterations from the currently outlined dosing 
schedule, but the maximum daily dose will no exceed 200 mg TID, as 
described in Section 4.3. 
Update  
Section 8  
The Schedule of Assessments (Table 1 and Table 2) summarizes the 
frequency and timing of safety measurement applicable to the study. 
Every effort should be made to keep participants on the planned study 
schedule. 
Update 
Section 8.2  
The study will include the following evaluations of safety and tolerability 
according to the time points provided in the Schedule of Assessments 
(Table 1 and Table 2). 
Update 
On-site visits 
every 6 months. 
Telephone visits 
3 months after 
on-site visits. 

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Protocol 
Section 
Amendment/Update 
Reason/ 
Rationale 
Section 8.2.2  Complete physical exams will be conducted (excluding genital/rectal 
exam) at protocol specified study visits. The physical examination will 
consist of an examination of the following: general appearance, skin, 
head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest, heart, abdomen, and extremities (Table 1 and Table 2). 
Standing height (in cm) will be measured at Screening/Baseline Visit. 
Weight (kg) will be measured at Screening/Baseline Visit, every 3 
months, End-of-Treatment Visit, and at the Early Termination Visit (6 
weeks after discontinuation of study drug), if applicable. As noted in 
Table 1 and Table 2, when not at the clinical site, weight will be collected 
by telephone. Weight will be measured in ordinary indoor clothing (ie, 
street clothes, scrubs) with shoes off. 
Vital signs measurements (including systolic and diastolic blood 
pressure, pulse rate, 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). Vital signs will be monitored at the 
Screening/Baseline Visit, every on-site treatment visit, End-of-Treatment 
Visit, and at the Early Termination Visit (6 weeks after discontinuation of 
study drug), if applicable (Table 1 and Table 2). 
Update 
Section 8.2.3  12-lead ECG will be measured at Screening/Baseline Visit, every on-site 
treatment visit, and End-of-Treatment Visit as noted in Table 1 and 
Table 2. 
Update 
Section 8.2.4  Hematology, serum chemistry, and urinalysis will be collected as noted 
in Table 1 and Table 2 to assess safety. Subjects will have 
approximately 15 mL of blood drawn per visit over the course of the 
study. The total amount of blood drawn will vary per subject depending 
on the duration of study participation. 
Update 
Section 8.2.5  Urine or serum pregnancy test will be measured on all female subjects 
of childbearing potential as noted in Table 1 and Table 2. At-home urine 
pregnancy test kits will be provided; subjects will be required to perform 
the test at home 30 days after the last dose of study drug and self-report 
the results via telephone. 
Update 
Abbreviations: ECG, electrocardiogram; ET, early termination; WOCBP, woman of childbearing potential  

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12. 
REFERENCES 
Aycicek, A and Iscan, A. The effects of carbamazepine, valproic acid and phenobarbital on the 
oxidative and antioxidative balance in epileptic children. Eur Neurol 2007;57(2):65-69. 
CTFG. (2020). "Clinical Trial Facilitation Group: Recommendations related to contraception and 
pregnancy testing in clinical trials." Retrieved 08 March 2021, from 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Versio
n_1.1_updated.pdf. 
Hamed, SA, Abdellah, MM and El-Melegy, N. Blood levels of trace elements, electrolytes, and 
oxidative stress/antioxidant systems in epileptic patients. J Pharmacol Sci 2004;96(4):465-473. 
Saneto, RP. Epilepsy and Mitochondrial Dysfunction: A Single Center’s Experience. Journal of 
Inborn Errors of Metabolism and Screening 2017;5. 
Verrotti, A, Lattanzi, S, Brigo, F and Zaccara, G. Pharmacodynamic interactions of antiepileptic 
drugs: From bench to clinical practice. Epilepsy Behav 2020;104(Pt A):106939. 
 

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