Efficacy and Safety Study of Vatiquinone for the Treatment of Mitochondrial Disease Subjects With Refractory Epilepsy
Phase: PHASE2
Conditions: Mitochondrial Diseases, Drug Resistant Epilepsy, Leigh Disease, Leigh Syndrome, Mitochondrial Encephalopathy (MELAS), Pontocerebellar Hypoplasia Type 6 (PCH6), Alpers Disease, Alpers Syndrome
Sponsor: PTC Therapeutics

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CLINICAL PROTOCOL 
EFFICACY AND SAFETY STUDY OF VATIQUINONE FOR THE 
TREATMENT OF MITOCHONDRIAL DISEASE SUBJECTS WITH 
REFRACTORY EPILEPSY (MIT-E) 
PTC743-MIT-001-EP 
27 MAY 2022 
VERSION 8.0 
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 
NCT #: NCT04378075

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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.

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PROTOCOL IDENTIFIERS AND STUDY PERSONNEL 
Project Code 
PTC743-MIT 
International Nonproprietary Name 
Vatiquinone 
Therapeutic Area 
Neurology 
PTC Therapeutics Substance Identifier 
PTC743 
IND Number 
140755 
EudraCT Number 
2020-002100-39 
ClinicalTrials.gov Identifier 
NCT04378075 
Protocol Number 
PTC743-MIT-001-EP 
Protocol Version 
8.0 
Protocol Version Date 
27 May 2022 
Protocol Phase 
2b/3 
Protocol Title 
Efficacy and Safety Study of Vatiquinone for the 
Treatment of Mitochondrial Disease Subjects with 
Refractory Epilepsy (MIT-E) 
PTC 
 
 
PTC 
 
 
PTC 
 
 
PTC 
 
 
 

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

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

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TABLE OF CONTENTS 
PROTOCOL IDENTIFIERS AND STUDY PERSONNEL ...........................................................3 
PTC THERAPEUTICS PROTOCOL APPROVAL SIGNATURES..............................................4 
PRINCIPAL INVESTIGATOR AGREEMENT AND SIGNATURE............................................5 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................12 
1. 
INTRODUCTION ......................................................................................................14 
1.1. 
Background Information .............................................................................................14 
1.2. 
Name and Description of Investigational Product ......................................................14 
1.3. 
Vatiquinone Mechanism of Action .............................................................................14 
1.4. 
Findings from Nonclinical and Clinical Safety Studies .............................................18 
1.4.1. 
Nonclinical Safety Assessment Studies ......................................................................18 
1.4.2. 
Clinical Safety Studies ................................................................................................19 
1.5. 
Risk/Benefit Assessment ............................................................................................20 
1.5.1. 
Risk Assessment .........................................................................................................20 
1.5.2. 
Potential Benefits of Trial Participation .....................................................................20 
1.5.3. 
Risk-Benefit Assessment ............................................................................................20 
2. 
STUDY OBJECTIVE AND ENDPOINTS ................................................................21 
2.1. 
Objectives ...................................................................................................................21 
2.1.1. 
Primary Objective .......................................................................................................21 
2.1.2. 
Secondary Objectives .................................................................................................21 
2.1.3. 
Exploratory Objective .................................................................................................21 
2.2. 
Endpoints ....................................................................................................................21 
2.2.1. 
Primary Endpoint ........................................................................................................21 
2.2.2. 
Secondary Endpoints ..................................................................................................22 
2.2.3. 
Exploratory Endpoint ..................................................................................................22 
2.2.4. 
Safety Endpoints .........................................................................................................22 
2.2.4.1. 
Clinical Variables .......................................................................................................22 
2.2.4.2. 
Laboratory Variables ..................................................................................................22 
3. 
STUDY DESIGN .......................................................................................................23 

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3.1. 
Overall Study Design ..................................................................................................23 
3.1.1. 
Screening and Run-in Phase .......................................................................................23 
3.1.2. 
Randomization ............................................................................................................24 
3.1.3. 
Placebo-controlled Phase ............................................................................................24 
3.1.4. 
Long-term Extension Phase ........................................................................................24 
3.1.5. 
Follow-up Phase .........................................................................................................24 
3.2. 
Study Duration and Number of Sites ..........................................................................24 
3.2.1. 
Duration of Subject Treatment ...................................................................................24 
3.2.2. 
Total Number of Study Sites/Total Number of Subjects Projected ............................25 
3.3. 
Scientific Rationale for Study Design ........................................................................25 
3.4. 
Justification of Dose ...................................................................................................26 
3.5. 
End of Study Definition ..............................................................................................26 
4. 
STUDY POPULATION .............................................................................................27 
4.1. 
Overview .....................................................................................................................27 
4.2. 
Inclusion Criteria ........................................................................................................27 
4.3. 
Exclusion Criteria .......................................................................................................28 
4.4. 
Screen Failures ............................................................................................................28 
4.5. 
Strategies for Recruitment and Retention ...................................................................28 
4.6. 
Home Care Services ...................................................................................................29 
5. 
STUDY INTERVENTION ........................................................................................30 
5.1. 
Study Intervention(s) Administration .........................................................................30 
5.1.1. 
Study Intervention Description ...................................................................................30 
5.1.2. 
Dosing and Administration .........................................................................................30 
5.1.3. 
Treatment of Missed Doses ........................................................................................31 
5.2. 
Preparation/Handling/Storage/Accountability ............................................................31 
5.2.1. 
Accountability .............................................................................................................31 
5.2.2. 
Formulation, Appearance, Packaging, and Labeling ..................................................31 
5.2.3. 
Preparation ..................................................................................................................31 
5.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................31 
5.4. 
Study Intervention and Compliance ...........................................................................32 
5.5. 
Concomitant Therapy .................................................................................................32 
6. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................33 

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6.1. 
Discontinuation of Study Intervention ........................................................................33 
6.2. 
Participant Discontinuation/Withdrawal from the Study............................................33 
6.3. 
Lost to Follow-up .......................................................................................................34 
7. 
STUDY ASSESSMENT AND PROCEDURES ........................................................35 
7.1. 
Schedule of Events and Study Parameters ..................................................................35 
7.1.1. 
Screening Visit/Run-in Phase .....................................................................................38 
7.1.2. 
Placebo-controlled Treatment Phase ..........................................................................39 
7.1.2.1. 
Baseline Visit/Randomization ....................................................................................39 
7.1.2.2. 
Week 2 Visit (Day 14±1 week) ..................................................................................40 
7.1.2.3. 
Week 4 Visit (Day 28 ± 1 week) ................................................................................40 
7.1.2.4. 
Week 8 Visit (Day 56 ± 1 week) ................................................................................40 
7.1.2.5. 
Week 12 Clinic Visit (Day 84 ± 1 week)....................................................................41 
7.1.2.6. 
Week 16 Visit (Days 112 ± 1 week) ...........................................................................41 
7.1.2.7. 
Week 20 Visit (Days 140 ± 1 week) ...........................................................................42 
7.1.2.8. 
Week 24 Clinic Visit (Days 168 ± 1 week) ................................................................42 
7.1.3. 
Long-Term Extension Phase (Study Weeks 36, 48, 60, and 72 are In-Person 
Visits and Study Weeks 28, 32, 40, 44, 52, 56, 64, and 68 are Telephone 
contact ±1 week) .........................................................................................................43 
7.1.4. 
Post Treatment Follow-up Phase ................................................................................44 
7.1.5. 
Unscheduled Visits .....................................................................................................44 
7.1.6. 
Sample Collection Procedures ....................................................................................44 
7.1.7. 
Safety Considerations .................................................................................................44 
7.1.8. 
Rescue Medication Administration for Epilepsy ........................................................44 
7.1.9. 
Prohibited Medications ...............................................................................................45 
7.1.10. 
End of Treatment Visits ..............................................................................................45 
7.1.11. 
Early Termination Study Visit ....................................................................................45 
7.2. 
Efficacy Assessments .................................................................................................45 
7.3. 
PK and/or Other Assessments ....................................................................................46 
7.4. 
Safety Evaluations ......................................................................................................46 
7.4.1. 
Physical Examination, Height, Weight, and Vital Signs ............................................46 
7.4.2. 
Laboratory Evaluations ...............................................................................................47 
7.4.2.1. 
Hematology .................................................................................................................47 
7.4.2.2. 
Coagulation Panel .......................................................................................................47 

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7.4.2.3. 
Serum Chemistry ........................................................................................................47 
7.4.2.4. 
Urinalysis ....................................................................................................................48 
7.4.3. 
Urine or Serum Pregnancy Test ..................................................................................48 
7.4.4. 
Laboratory Abnormalities ...........................................................................................48 
7.4.4.1. 
Grade 3 or 4 Laboratory Abnormalities ......................................................................48 
7.4.5. 
Dose-Limiting Toxicity ..............................................................................................49 
7.4.6. 
Dose Modification Guidelines and Stopping Rules ....................................................49 
7.4.7. 
Safety Guidance ..........................................................................................................49 
7.5. 
Adverse Events and Serious Adverse Events .............................................................50 
7.5.1. 
Definition of Adverse Events .....................................................................................50 
7.5.2. 
Definition of Serious Adverse Events ........................................................................51 
7.5.3. 
Unexpected Adverse Events .......................................................................................52 
7.5.4. 
Eliciting Adverse Event Information ..........................................................................52 
7.5.5. 
Recording Nonserious AEs and SAEs ........................................................................52 
7.5.6. 
Describing Adverse Event Relationship to Study Drug .............................................53 
7.5.7. 
Grading of Severity of Adverse Event ........................................................................53 
7.5.8. 
Adverse Event Reporting ............................................................................................55 
7.5.9. 
Serious Adverse Event Reporting ...............................................................................55 
7.5.10. 
Contraception ..............................................................................................................56 
7.5.11. 
Reporting Pregnancy ..................................................................................................57 
7.5.12. 
PTC Therapeutics Safety Reporting Requirement......................................................57 
8. 
STATISTICAL CONSIDERATIONS .......................................................................58 
8.1. 
Statistical Hypotheses .................................................................................................58 
8.2. 
Sample Size Determination ........................................................................................58 
8.3. 
Population for Analyses ..............................................................................................58 
8.4. 
Statistical Analyses .....................................................................................................58 
8.4.1. 
General Approach .......................................................................................................58 
8.4.2. 
Analysis of Primary Efficacy Endpoints ....................................................................59 
8.4.3. 
Analysis of Secondary Efficacy Endpoints ................................................................59 
8.4.4. 
Analysis of Exploratory Endpoint ..............................................................................60 
8.4.5. 
Multiplicity Adjustment ..............................................................................................60 
8.4.6. 
Safety Analyses ..........................................................................................................60 
8.4.6.1. 
Subject Disposition .....................................................................................................60 

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8.4.6.2. 
Medical History and Prior Medication .......................................................................60 
8.4.6.3. 
Extent of Exposure and Treatment Compliance .........................................................60 
8.4.6.4. 
Adverse Events ...........................................................................................................60 
8.4.6.5. 
Laboratory Parameters ................................................................................................61 
8.4.7. 
Baseline Descriptive Statistics ....................................................................................61 
8.4.8. 
Planned Analyses ........................................................................................................61 
8.4.9. 
Sub-group Analyses ....................................................................................................61 
8.4.10. 
Exploratory Analyses ..................................................................................................61 
9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................62 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................62 
9.1.1. 
Informed Consent Process ..........................................................................................62 
9.1.2. 
Study Discontinuation and Closure ............................................................................62 
9.1.3. 
Confidentiality and Privacy ........................................................................................62 
9.1.4. 
Future use of Stored Specimens and Data ..................................................................63 
9.1.5. 
Safety Oversight .........................................................................................................64 
9.1.6. 
Clinical Monitoring ....................................................................................................64 
9.1.7. 
Quality Assurance and Quality Control ......................................................................65 
9.1.8. 
Data Handling and Record Keeping ...........................................................................65 
9.1.9. 
Protocol Deviations ....................................................................................................65 
9.1.10. 
Publication and Data Sharing Policy ..........................................................................66 
9.2. 
Additional Considerations ..........................................................................................67 
9.3. 
Protocol Amendment History .....................................................................................67 
9.3.1. 
Version 2.0: 27 March 2020 .......................................................................................68 
9.3.2. 
Version 3.0: 22 May 2020 ..........................................................................................69 
9.3.3. 
Version 4.0: 30 September 2020 ................................................................................70 
9.3.4. 
Version 4.1: 12 January 2021 .....................................................................................72 
9.3.5. 
Version 5.0: 31 March 2021 .......................................................................................73 
9.3.6. 
Version 6.0: 04 June 2021 ..........................................................................................76 
9.3.7. 
Version 7.0: 06 January 2022 .....................................................................................77 
9.3.8. 
Version 8.0: 27 May 2022 ..........................................................................................77 
10. 
REFERENCES ...........................................................................................................79 
APPENDIX 1. PTC743-MIT-001-EP PROHIBITED MEDICATION LIST ............................81 

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LIST OF TABLES 
Table 1: 
Weight-Based Dosing in mL of the 100 mg/mL Solution ..........................................30 
Table 2: 
Schedule of Events .....................................................................................................35 
Table 3: 
Dose Modification and Stopping Rules for Vatiquinone............................................49 
Table 4: 
Relationship of Study Drug to Adverse Event Relationship ......................................53 
Table 5: 
Grading of Adverse Event Severity Grade .................................................................53 
Table 6: 
Investigator Site Requirements for Reporting Adverse Events ..................................55 
Table 7: 
PTC743-MIT-001-EP Prohibited Medication List .....................................................81 
 
LIST OF FIGURES 
Figure 1: 
Inhibition of 15-LO by Vatiquinone ...........................................................................15 
Figure 2: 
Ferroptosis Pathway ....................................................................................................16 
Figure 3: 
Vatiquinone Dose-dependently Protected Each PCH6 Patient Fibroblast 
Culture from RSL3-induced Cell Death (EC50 Range 17 to 22 nM) ..........................17 
Figure 4: 
RSL3-Induced Formation of Oxidized Lipid Signaling Molecules in PCH6 
Patient Primary Fibroblasts .........................................................................................17 
Figure 5: 
15 LO-Dependent Lipid Oxidation Products as Measured by LC-MS/MS ...............18 
Figure 6: 
Study Design Schematic .............................................................................................23 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialized Term 
Explanation 
15-LO 
15-lipoxygenase 
15-HETE 
15-hydroxyeicosatetraenoic acid 
15-HpETE 
15-hydroperoxyeicosa-tetraenoic acid 
15(S)-HpETE 
15-OOH-arachindonic acid 
AA 
Arachidonic acid 
AE 
Adverse event 
AEDs 
Antiepileptic drugs 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BSO 
Buthionine sulfoximine 
CBC 
Complete blood count 
COVID-19 
Coronavirus disease 2019 
CRF 
Paper case report form 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DSMB 
Data Safety Monitoring Board 
EC50 
Half maximal concentration 
eCRF 
Electronic case report form 
ECG  
Electrocardiogram  
EEG 
Electroencephalogram 
GCP  
Good Clinical Practices  
Gpx4 
Glutathione peroxidase 4 
GSH 
Glutathione 
GSSG 
Glutathione disulfide 
G-Tube 
Gastrostomy tube 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF  
Informed consent form  
IEC  
Institutional Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LC-MS/MS 
Liquid chromatography with tandem mass spectroscopy 
MELAS 
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes 
MIT-E 
Mitochondrial Disease Subjects with Refractory Epilepsy 
mtDNA 
mtDNA 
MT-TK 
mitochondrially encoded tRNA lysine 
NF 
National Formulary 
NOAEL 
No observed adverse effect level 
PedsQL 
Pediatric Quality of Life Inventory™ 
PCH6 
Pontocerebellar hypoplasia type 6 
PK 
Pharmacokinetics 
POLG 
DNA polymerase subunit gamma 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RSI 
Reference Safety Information 
RSL3 
Oncogenic-RAS-selective lethal compound 3 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 

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Abbreviation or 
Specialized Term 
Explanation 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WOCBP 
Women of childbearing potential 

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1. 
INTRODUCTION 
1.1. 
Background Information 
Vatiquinone is a novel small molecule therapeutic in development for the treatment of 
mitochondrial diseases and associated disorders of oxidative stress and inflammation. 
Vatiquinone targets oxidoreductase enzymes essential to inflammation, oxidation, and cell death. 
To date, vatiquinone has been evaluated in a number of clinical trials 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. The purpose of this study is to evaluate the efficacy and safety of vatiquinone in 
patients with genetically defined mitochondrial disease and associated refractory epilepsy. 
1.2. 
Name and Description of Investigational Product 
Vatiquinone is 2-[(3R,6E,10E)-3-hydroxy-3,7,11,15-tetramethyl-6,10,14-hexadecatrienyl]-3,5,6-
trimethyl-2,5-cyclohexadiene-1,4-dione. Vatiquinone is the quinone oxidation product of alpha-
tocotrienol, one of the 8 naturally occurring forms of vitamin E. Vatiquinone is a viscous yellow 
to brown oil and will be administered as a mixture with sesame oil National Formulary (NF)/ 
United States Pharmacopeia. 
Vatiquinone is manufactured as a 100 mg/mL Oral Solution. 
The investigator will ensure that all study drugs are stored and dispensed in accordance with the 
Food and Drug Administration and local regulations concerning the storage and administration 
of investigational drugs. 
1.3. 
Vatiquinone Mechanism of Action 
1. Vatiquinone targets 15-lipoxygenase (15-LO), a key governor of ferroptosis and 
inflammation. 
• 15-LO is a key enzyme governor of the biological process of ferroptosis, which has 
been implicated in epilepsy and a number of other central nervous system diseases 
(Joshi 2015, Guiney 2017). 
• In a cell-free enzymatic assay, we have demonstrated that Vatiquinone 
dose-dependently inhibits 15-LO enzyme activity (half maximal inhibitory 
concentration [IC50]=1.9 µM) (Figure 1). 

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Figure 1: 
Inhibition of 15-LO by Vatiquinone 
 
Abbreviations: 15-LO, 15-lipoxygenase 
• 15-LO catalyzes the peroxidation of arachidonic acid (AA) to produce the lipid 
hydroperoxide 15-hydroperoxyeicosa-tetraenoic acid (15-HpETE), a 
pro-inflammatory and pro-ferroptotic lipid signaling molecule. 
• 15-HpETE and downstream metabolites, such as HETEs and 4-HNE, are clinical 
biomarkers that have been associated with mitochondrial disease and seizure 
disorders (Menon 2012, Sanders 2013, Abeti 2016). 
• Net: Vatiquinone is an inhibitor for the enzyme 15-LO, a key governor of fatty acid 
oxidation and inflammation that underpin neurological disease. 
2. Ferroptosis (the biochemical process regulated by 15-LO) has been demonstrated to be a 
key mechanism underpinning mitochondrial and seizure disorders. The ferroptosis 
pathway is summarized in Figure 2.  
Ferroptosis is regulated by 15-LO, and glutathione peroxidase 4 (Gpx4). Activation of 
15-LO leads to the production of the lipid signaling molecule 15-OOH-Arachindonic acid 
[15(S)-HpETE]. Glutathione peroxidase 4 reduces 15(S)-HpETE to 
15-OOH-Arachindonic acid preventing inflammation and ferroptosis. Ferroptosis is 
experimentally induced by inhibition of Gpx4 (via oncogenic-RAS-selective lethal 
compound 3 [RSL3]), depletion of glutathione (via glutamate or buthionine sulfoximine 
[BSO]), or excess AA. Vatiquinone inhibits 15-LO and prevents ferroptosis under the 
4 pro-ferroptotic conditions described above. 

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Figure 2: 
Ferroptosis Pathway 
 
Abbreviations: 15(S)-HpETE, 15-OOH-arachindonic acid; BSO, buthionine sulfoximine; 
GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; 
RSL3, oncogenic-RAS-selective lethal compound 3 
• Ferroptosis is a form of regulated cell death (Stockwell 2017) mediated by lipid 
signaling molecules produced by 15-LO (Seiler 2008, Dixon 2012, 
Friedmann Angeli 2014). 
• Under normal conditions, ferroptosis is prevented by the constitutive activity of the 
selenoenzyme, Gpx4, which utilizes glutathione (GSH) to reduce cellular lipid 
hydroperoxides [such as 15(S)-HpETE] to their benign secondary alcohols. 
• Depletion of cellular GSH, as has been observed in mitochondrial disease and seizure 
disorders (Enns 2012, Milder 2012), or inhibition of Gpx4 leads to the accumulation 
of 15(S)-HpETE and rapidly induces ferroptotic cell death (Seiler 2008, Yang 2014, 
Kagan 2017). 
• When neuronal cells are depleted of endogenous GSH by an irreversible inhibitor of 
GSH synthesis (BSO), the result is rapid cell death that can be rescued by 15-LO 
inhibition (Seiler 2008). 
• Similarly, mice lacking Gpx4 activity fail to develop parvalbumin interneurons and 
consequently suffer fatal epileptic seizures (Seiler 2008, Wirth 2010, Ingold 2018). 
• Neurons from Gpx4 null mice are protected by the administration of 15-LO inhibitors 
(Seiler 2008). 
• Net: The ferroptosis biochemical pathway, regulated by 15-LO, underpins aspects of 
pontocerebellar hypoplasia type 6 (PCH6) disease pathology including epilepsy. 
3. In vitro validation: Vatiquinone is a potent rescue agent of human cells in an in vitro test 
system mimicking ferroptosis-related disease pathology. 
• To determine the potential therapeutic benefit of vatiquinone and 15-LO inhibition, 
an in vitro ferroptosis assay was developed, employing PCH6 patient primary 
fibroblasts and Gpx4 inhibition. 

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• Primary fibroblasts were obtained from 3 PCH6 patients untreated with vatiquinone. 
• Inhibition of cellular Gpx4 activity by RSL3, an irreversible small molecule inhibitor 
(Yang 2014), led to the rapid and nearly-complete death of PCH6 patient fibroblasts. 
Figure 3: 
Vatiquinone Dose-dependently Protected Each PCH6 Patient Fibroblast Culture 
from RSL3-induced Cell Death (EC50 Range 17 to 22 nM) 
 
Abbreviations: EC50, half maximal concentration; PCH6, pontocerebellar hypoplasia type 6; RSL3, oncogenic-RAS-
selective lethal compound 3  
• Similar results were obtained with a second means of inducing ferroptosis by the 
inhibition of endogenous glutathione synthesis in the presence of excess iron (data not 
shown; vatiquinone half maximal concentration range 7-14 nM). 
• To confirm the mechanism by which vatiquinone protected cells from ferroptosis, we 
demonstrated that vatiquinone dose-dependently prevented RSL3-induced formation 
of oxidized lipid signaling molecules in PCH6 patient primary fibroblasts measured 
using the BODIPY 581/591 C11 oxidation-sensitive fluorescent lipid probe (IC50 
range 33-58 nM). 
Figure 4: 
RSL3-Induced Formation of Oxidized Lipid Signaling Molecules in PCH6 Patient 
Primary Fibroblasts 
 
Abbreviations: PCH6, pontocerebellar hypoplasia type 6; RSL3, oncogenic-RAS-selective lethal compound 3 
• Consistent with direct cellular inhibition of 15-LO, vatiquinone decreased 
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(15-HETE), in RSL3-treated PCH6 patient fibroblasts, as measured by liquid 
chromatography with tandem mass spectroscopy (LC-MS/MS). 
Figure 5: 
15 LO-Dependent Lipid Oxidation Products as Measured by LC-MS/MS 
 
Abbreviations: 15-HETE, 15-hydroxyeicosatetraenoic acid; 15-LO, 15-lipoxygenase; LC-MS/MS liquid 
chromatography with tandem mass spectroscopy; RSL3, oncogenic-RAS-selective lethal compound 3 
Net: Collectively, these in vitro mechanism of action studies in PCH6 patient primary 
fibroblasts establish that vatiquinone potently prevents lipid oxidation and ferroptotic 
cell death via inhibition of 15-LO and provides supportive rationale for use of 
vatiquinone to treat PCH6 patients. 
4. Clinical effect: In compassionate use studies of patients with mitochondrial disease in the 
United States and European Union, vatiquinone treatment has been associated with the 
following clinical effects: 
• Arrest of status epilepticus 
• Decrease in seizure frequency 
• Decrease in seizure-related hospitalizations 
• Improvement in disease-related quality of life 
Summary: Based on the vatiquinone mechanism of action, the understood biochemical 
mechanisms underpinning seizures in mitochondrial disease, the in vitro evidence of vatiquinone 
benefit and clinical data collected to date, there is a valid rationale for the study of vatiquinone in 
patients with mitochondrial disease and associated refractory epilepsy. 
1.4. 
Findings from Nonclinical and Clinical Safety Studies 
Vatiquinone has been evaluated in a comprehensive battery of nonclinical safety and toxicology 
studies. The clinical safety experience with vatiquinone has been collected in over 500 subjects 
over 523000 dosing days. Refer to the Investigator’s Brochure (IB) for additional detail. 
1.4.1. 
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 48,786 (rat) and 

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107,426 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 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.BT). 
Safety pharmacology data collected in the 28-day toxicity studies in rat and dog and during the 
6-month and 9-month toxicity studies in rat and dog, respectively, demonstrated that vatiquinone 
did not affect neurobehavioral or cardiovascular electrocardiogram (ECG) parameters 
(Studies 1660-027, 1660-028, 1660-045, and 1660-046). In addition, vatiquinone is not a potent 
inhibitor of 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 
(Study PTC743-2020-003) to assess phototoxic potential demonstrated that vatiquinone had no 
phototoxic potential when administered to the fibroblasts at concentrations up to 17,800 ng/mL 
(approximately 16 times the Cmax obtained at the highest clinical dose of 400 mg). 
1.4.2. 
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. 

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1.5. 
Risk/Benefit Assessment 
1.5.1. 
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, partial thromboplastin time [PTT]) are found to be increased to more than 1.5×upper limit 
of normal (ULN). 
1.5.2. 
Potential Benefits of Trial Participation 
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 trial, 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. 
1.5.3. 
Risk-Benefit Assessment 
The screening criteria for this trial 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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2. 
STUDY OBJECTIVE AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
The primary objective of the study is to demonstrate the effect of vatiquinone (PTC743) on 
reduction in observable motor seizure frequency in subjects with genetically confirmed 
mitochondrial disease, as assessed by a seizure diary. 
2.1.2. 
Secondary Objectives 
Secondary objectives of the study are to: 
• Demonstrate the effects of vatiquinone on seizure-related emergency room visits and 
hospitalizations 
• Demonstrate the effects of vatiquinone on occurrence of status epilepticus 
• Demonstrate the effects of vatiquinone in monthly total seizure count 
• Demonstrate the effects of vatiquinone in responder rate in motor and non-motor 
seizures 
• Demonstrate the effects of vatiquinone on number of rescue antiepileptic medications 
used 
• Demonstrate the effects of vatiquinone on health-related quality of life (using the 
CarerQoL-7D questionnaire) 
• Demonstrate the effects of vatiquinone on occurrence of seizure clusters 
• Demonstrate the safety of vatiquinone as assessed by drug-related SAEs, drug-related 
adverse events (AEs), and dose modifications  
2.1.3. 
Exploratory Objective 
The exploratory objective of the study is to demonstrate the effects of vatiquinone on 
health-related quality of life (using the Pediatric Quality of Life Inventory™ [PedsQL] 
questionnaire). 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
The primary efficacy endpoint of the study is the percent change from baseline in frequency of 
observable motor seizures per 28 days during the placebo-controlled phase. 

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2.2.2. 
Secondary Endpoints 
Key secondary efficacy endpoints of the study are as follows: 
• Number of disease-related hospitalization days  
• Occurrence or recurrence of status epilepticus 
Other Secondary endpoints are as follows: 
• Number and percent of subjects with disease-related in-patient 
hospitalization/emergency room visits 
• Number of disease-related in-patient hospitalization admissions/emergency room 
visits 
• Percent change from baseline in total seizure frequency per 28 days of all types 
• Proportion of subjects with ≥25%, ≥50%, ≥75%, and 100% reduction in motor 
seizures 
• Proportion of subjects with ≥25%, ≥50%, ≥75%, and 100% reduction in total seizures 
• Number of rescue seizure medications 
• Health-related quality of life as measured by the CarerQoL-7D questionnaire 
• Number of seizure clusters as defined by “too many to count” entries in the seizure 
diaries 
2.2.3. 
Exploratory Endpoint 
The exploratory efficacy endpoint of the study is health-related quality of life as measured by the 
PedsQL questionnaire. 
2.2.4. 
Safety Endpoints 
Safety endpoints include both clinical and laboratory variables. 
2.2.4.1. 
Clinical Variables 
• All AEs 
• Drug-related SAEs 
• Drug-related AEs 
2.2.4.2. 
Laboratory Variables 
• Complete blood count with differential 
• PT and PTT reported as international normalized ratio (INR) units 
• Electrolytes, renal function, liver function 

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3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This study will be a parallel-arm, double-blind, placebo-controlled trial, with a screening phase 
that includes a 28-day Run-in phase to establish baseline seizure frequency. The 28 days 
immediately prior to the Baseline Visit will be considered the Run-in phase. Screening is 
followed by a 24-week randomized placebo-controlled phase during which subjects will have 
been randomized to receive either vatiquinone at a dose of 15 mg/kg if body weight <13 kg, and 
200 mg if body weight ≥13 kg, TID or placebo TID. Following completion of the randomized 
placebo-controlled phase, all subjects will be offered entry into a long-term extension phase (48 
weeks) during which they will receive open-label treatment with vatiquinone and then a safety 
follow-up as needed. The study design is summarized in Figure 6. 
Figure 6: 
Study Design Schematic 
Screening/Run-in 
Placebo-Controlled Phase 
 
 
Long-Term Extension Phase  
 
 
 
Follow-Up 
 
Day -42 
Baseline Visit 
Day 0 
Week 24 
±7 days 
Week 72 
±7 days 
Follow-up 
Visit 
Week 77  
±7 days 
3.1.1. 
Screening and Run-in Phase 
During Screening, the investigator should inform each prospective subject of the nature of the 
study, explain the potential risks, and obtain written informed consent from the subject or 
parent(s)/legal guardian(s) prior to performing any study-related procedures and prior to the 
administration of study drug. 
Screening will consist of up to 42 days. During the first part of Screening (up to 14 days), 
subjects will be instructed on how to complete the seizure diaries. To ensure the accuracy of 
diary entries during the study, subjects must complete at least 5 days of diary entries that will be 
reviewed prior to the Run-in period. Following diary review, at the discretion of the investigator 
and sponsor a further diary entry training period can be implemented, until the investigator is 
satisfied that the seizures are correctly captured in the diaries, in which case the duration of 
Screening will be longer. Diary entries during this period are for training purposes and will not 
be included in the seizure count.  
The PTC Therapeutics (PTC) medical monitor will closely review the seizure entry during the 
seizure training phase of the study and notify the principal investigators via e-mail to begin 
“Run-in” phase of the study for the subject. 
The last 28 days of screening will consist of a Run-in period for minimum number of seizure 
evaluation. If subjects are deemed eligible for all other entry criteria (except for seizure count) 
during the first period of Screening (up to 14 days), they will enter the Run-in period, in which 
the frequency of seizures will be collected daily via an electronic diary and the baseline 
frequency of seizures will be assessed. Subjects will be eligible to participate in the study if they: 

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• Have ≥6 observed motor seizures occurring during the 28 days prior to the Baseline 
Visit 
• Have ≥2 observed motor seizures in each half of the 28-day Run-in period 
• Do not have a consecutive 20-day seizure free period, and 
• Have at least 80% of seizure diary data 
Eligible subjects will then enter a 24-week placebo-controlled phase. Subjects who do not meet 
the above criteria for observed motor seizures during this period will be considered screen 
failures. 
3.1.2. 
Randomization 
Randomization will take place during the Baseline Visit. Instructions for randomization are 
provided in an operations manual. Randomization will be performed globally with 1:1 
vatiquinone to placebo and will be stratified by disease subtype including: 1) Alpers/DNA 
polymerase subunit gamma (POLG); 2) Leigh syndrome; 3) Mitochondrial encephalomyopathy, 
lactic acidosis, and stroke-like episodes (MELAS); and 4) Other genetically confirmed 
mitochondrial disease secondary to mitochondrial mutation. 
3.1.3. 
Placebo-controlled Phase 
Subjects will be randomized to receive vatiquinone at a dose of 15 mg/kg if body weight <13 kg, 
and 200 mg if body weight ≥13 kg, TID or placebo TID for 24 weeks. 
3.1.4. 
Long-term Extension Phase 
Following the 24-week randomized, placebo-controlled phase, all subjects will be eligible to 
continue in a 48-week open-label treatment phase with vatiquinone at a dose of 15 mg/kg if body 
weight <13 kg, and 200 mg if body weight ≥13 kg, TID. During this phase, subjects and 
investigators will remain blinded to the treatment assignment of the placebo-controlled phase. 
3.1.5. 
Follow-up Phase 
The follow-up contact will be by telephone and should be completed 30 days (±7 days) post last 
study drug administration or termination visit, whichever is later. Adverse events and SAEs 
whether or not deemed study drug-related will be followed until resolution or until they have 
normalized. At the investigator’s discretion an office visit and additional tests may be conducted 
in order to ensure proper follow-up of an AE/SAE. 
3.2. 
Study Duration and Number of Sites 
3.2.1. 
Duration of Subject Treatment 
The maximum duration of subject treatment will be approximately 72 weeks (including 
placebo-controlled phase and extension phase). The overall study duration will be a maximum of 
approximately 78 weeks per subject. 

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3.2.2. 
Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at approximately 30 sites globally. Approximately 60 subjects will 
be enrolled. Additional sites and investigators may be added as needed to complete the study. 
3.3. 
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 Gpx4). 
Vatiquinone, a novel small molecule therapeutic in development for 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 
targeting 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. 
Therefore, the development of vatiquinone for the treatment mitochondrial disease patients with 
refractory epilepsy is based on the following rationale: 
1. Vatiquinone mechanism of action: Vatiquinone targets 15-LO, a key regulator of 
ferroptosis and inflammation. 
2. Ferroptosis and seizure disorders: Ferroptosis and inflammation have been demonstrated 
to be fundamental biochemical mechanisms underpinning mitochondrial disease and 
seizure disorders. 
3. Vatiquinone in vitro validation: Vatiquinone is a potent rescue agent of human cells in 
an in vitro ferroptosis test system mimicking mitochondrial disease and seizure disorders. 
4. Reduction in seizure severity, resolution of status epilepticus, and reduction in 
disease-related hospitalizations were recorded in patients with pontocerebellar type 6, a 
mitochondrial epileptic encephalopathy. 

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3.4. 
Justification of Dose 
The dose of 15 mg/kg if body weight <13 kg, and 200 mg if body weight ≥13 kg, TID 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. 
3.5. 
End of Study Definition 
The study will end when the last subject has completed the follow-up visit. 

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4. 
STUDY POPULATION 
4.1. 
Overview 
The study population consists of male and female subjects <21 years of age who have genetically 
determined mitochondrial disease and associated refractory epilepsy (defined as those who were 
unsatisfactorily treated with at least 2 antiepileptic drugs [AEDs]). 
4.2. 
Inclusion Criteria 
To be eligible for enrollment in the study, subjects must meet all of the following inclusion 
criteria: 
1. Evidence of signed and dated informed consent/assent document(s) indicating that the 
subject (and/or his/her parent/legal guardian) has been informed of all pertinent aspects of 
the trial 
2. Age <21 years at time of randomization 
3. Subject or parent/legal guardian is able and willing to complete seizure diaries for the 
duration of the study 
4. Subjects with genetic confirmation of inherited mitochondrial disease with associated 
epilepsy phenotype (Alpers/POLG, Leigh syndrome, MELAS), or other genetically 
confirmed mitochondrial diseases secondary to mitochondrial mutations (Pontocerebellar 
Hypoplasia Type 6 [PCH6], nuclear DNA RARS2 mutation) or myoclonic epilepsy with 
ragged red fibers (MERRF, mitochondrial DNA [mtDNA] mitochondrially encoded 
tRNA lysine [MT-TK] mutation) are eligible. 
5. Despite treatment with at least 2 AEDs: 
• Have ≥6 observed motor seizures occurring during the 28 days prior to the Baseline 
Visit 
• Have ≥2 observed motor seizures in the first 14 days and ≥2 in the second 14 days of 
the Run-in period 
• Do not have a consecutive 20-day seizure free period and 
• Have at least 80% of seizure diary data 
• No changes to the AED regimen will be allowed (except weight-based dose 
adjustments) during the first 24-week period. 
6. Documented medical history of epilepsy associated with mitochondrial disease for at 
least 6 months prior to screening except for subjects who are <2 years of age at the time 
of screening (subjects <2 years of age can be considered for enrollment if all other 
screening criteria are met due to the potential for rapid progression in these subjects). 
7. Consent to abstain from non-approved therapies for 30 days prior to the Screening Visit 
and for the duration of the study 
8. Stable dose regimen of antiepileptic therapies 30 days prior to the Screening Visit 

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9. Stable regimen of dietary supplements 30 days prior and, if on a ketogenic diet, stable 
ketogenic diet 90 days prior to the Screening Visit and for duration of the study 
10. Electroencephalogram (EEG) at Screening or historical EEG up to 6 months prior to 
screening for diagnostic confirmation of epilepsy 
4.3. 
Exclusion Criteria 
Subjects will be excluded from enrollment if any of the following exclusion criteria apply: 
1. Allergy to vatiquinone or sesame oil 
2. Aspartate transaminase (AST) or alanine transaminase (ALT) ≥3×ULN at time of 
screening 
3. INR >ULN at time of screening 
4. Serum creatinine ≥1.5×ULN at time of screening 
5. Participation in another interventional clinical trial 60 days prior to randomization or for 
the duration of this clinical trial 
6. Previously received vatiquinone 
7. Concomitant treatment with drug(s) that have not received regulatory agency approval 
for the treatment of mitochondrial diseases and use of artisanal (non-Epidiolex 
cannabidiol) cannabidiol therapies  
8. Concomitant treatment with idebenone 
9. Ongoing treatment with strong cytochrome P450 (CYP) inhibitors such as itraconazole or 
strong CYP inducers such as rifampin. Treatment with these agents must be completed at 
least 4 weeks prior to enrollment. During the study, subjects should not use 
grapefruit/grapefruit juice or St John’s wort extract.  
10. Pregnant or lactating subjects or those male or female sexually active subjects who are 
unwilling to comply with proper birth control methods as defined in Section 7.5.10 from 
the time consent is signed until 30 days after treatment discontinuation. Females of 
childbearing potential must have a negative pregnancy test at Screening and during the 
Baseline Visit.  
11. Comorbidities that may confound study results (eg, fat malabsorption syndrome, other 
mitochondrial disorders) in the opinion of the investigator. 
4.4. 
Screen Failures 
Any subject that does not meet inclusion or exclusion criteria within the defined screening 
window prior to randomization, will be considered a screen failure. Screen failures can be 
rescreened after consultation with the medical monitor. 
4.5. 
Strategies for Recruitment and Retention 
Subjects will be recruited via existing populations with mitochondrial diseases at identified 
investigational sites or via referrals. 

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4.6. 
Home Care Services 
If for unforeseen reasons subjects are unable to travel to the study site, with approval from both 
the Principal Investigator and PTC medical monitor, they may be offered an opportunity to have 
study visits performed in their home. 
In order to conduct the home visits, the subject must agree to utilize home care services. 
A licensed nurse will then contact the subject to schedule the visits. 
The home care nurse, the home care agency, and the home care services provider may have 
access to the subject’s personal data including their individually identifiable protected health 
information, such as the subject’s name, address, or phone number. This type of information will 
only be used as necessary to schedule and conduct the home visits and will not be provided to the 
sponsor. 

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5. 
STUDY INTERVENTION 
5.1. 
Study Intervention(s) Administration 
5.1.1. 
Study Intervention Description 
Vatiquinone oral solution is manufactured at 100 mg/mL for oral administration. Subjects will 
receive vatiquinone at a dose of 15 mg/kg if body weight <13 kg, and 200 mg if body weight 
≥13 kg, TID (Table 1). At each study visit the subjects are weighed; any change in weight of 
≥10% from baseline should result in dose adjustment. Weights ending in decimals ≥0.5 should 
be rounded up to the next whole number for dosing calculation.  
For this study, placebo will consist of sesame oil NF, with a colorant added to match vatiquinone 
oral solution. During the phase of the study where subjects are to receive placebo, a volume of 
placebo equal to the volume of active received when assigned to vatiquinone treatment will be 
provided to each subject. 
Table 1: 
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 
5.1.2. 
Dosing and Administration 
Drug dosing will occur according to the schedule described in Sections 7.1.2 and 7.1.3. 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 dosing can be found in the Pharmacy Manual. 

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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. 
5.1.3. 
Treatment of Missed Doses 
If a dose is missed, or if the subject vomits after receiving a dose, the dose should not be “made 
up.” The subject will be required to skip that dose and wait until the next scheduled dose. 
5.2. 
Preparation/Handling/Storage/Accountability 
5.2.1. 
Accountability 
Adequate records of study drug receipt and disposition will be maintained by the (Institution’s) 
Pharmacy Records of receipts, investigational drug orders, dispensing records, and disposition 
forms. The study monitor will assess drug accountability and will request to review the 
Pharmacy Records and investigator study file to assure the study medication is prescribed by the 
investigator or designee for the purpose of this study. 
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. 
5.2.2. 
Formulation, Appearance, Packaging, and Labeling 
Vatiquinone oral solution, 100 mg/mL, is a solution of vatiquinone drug substance in super 
refined, preservative free sesame oil. At room temperature, it 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. The placebo oral solution is packaged in 
the same container/closure as the active substance and is also a yellow to orange clear liquid. 
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. 
5.2.3. 
Preparation 
No preparation is required; vatiquinone is provided as a ready-to use oral solution. 
5.3. 
Measures to Minimize Bias: Randomization and Blinding 
Subjects meeting the eligibility criteria for the randomized placebo-controlled phase will be 
randomized at the Baseline Visit to either vatiquinone treatment or placebo group. Subjects who 
withdraw from the study after being assigned a subject number will retain that subject number. 
Randomization will be stratified by disease subtype including: 1) Alpers/POLG, 2) Leigh 
syndrome, 3) MELAS, and 4) Other genetically confirmed mitochondrial disease secondary to 
either nuclear or mitochondrial DNA mutation. 

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The investigators, study subjects, and sponsor will be blinded as follows: the sponsor will be 
blinded to the randomized treatment until the study is unblinded after all subjects complete the 
placebo-controlled phase; subjects and investigators remain blinded to the treatment received 
during the placebo-controlled phase until after all subjects complete the open-label phase. An 
independent Data Safety Monitoring Board (DSMB) will monitor the study until completion of 
the placebo-controlled phase of the study. 
Under normal circumstances, the blind will not be broken. The blind may be broken by the 
principal investigator only if specific emergency treatment would be dictated by knowing the 
treatment assignment. The investigators have the ability to unblind via the Interactive Response 
Technology system.  
5.4. 
Study Intervention and Compliance 
Study medication 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. 
5.5. 
Concomitant Therapy 
Any medication taken by a subject 30 days prior to Baseline Visit and during the course of the 
study and the reason for use of the medication will be recorded on the electronic case report form 
(eCRF)/paper case report form (CRF). During Screening, each subject will be instructed to report 
the use of any medication to the investigator. Subjects will also be instructed about the 
importance of not taking any 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 
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. 

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6. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
6.1. 
Discontinuation of Study Intervention 
Subjects receive study treatment until treatment discontinuation for one of the reasons listed 
below. However, subjects may discontinue study treatment or withdraw their consent to 
participate in the study at any time without prejudice. 
The following conditions require subject discontinuation from all study treatment: 
1. At their own request or at the request of their legally authorized representative 
2. 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 
3. Spontaneous bleeding in a subject 
4. At the specific request of a regulatory agency for termination of treatment of an 
individual subject or all subjects under the protocol 
5. Subject participation in another clinical study using an investigational agent or 
investigational medical device 
6. Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use medically accepted methods of contraception (Section 7.5.10) 
7. If a subject becomes pregnant 
8. Significant noncompliance with the protocol in the opinion of the investigator or the 
sponsor 
9. Use of prohibited concomitant medication 
6.2. 
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 7.5.8. 
Evaluations should be performed on all subjects who participate but do not complete the study 
according to protocol. Dropouts may be replaced at the request of the sponsor. 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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6.3. 
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 trial is ongoing. 

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7. 
STUDY ASSESSMENT AND PROCEDURES 
7.1. 
Schedule of Events and Study Parameters 
Table 2: 
Schedule of Events 
Procedures 
Screeninga Baseline 
Placebo-controlled Phase 
Long-term Extension Phase 
Follow-
up 
Phaseb 
Day 
-42 to 0 
Day 
-28  
Day 0 
up to 
+7 
days 
Week 
2c±7 
days 
Week 
4 & 8 
±7 
days 
Week 
12 
±7 
days 
Week 
16 & 
20c 
±7 
days 
Week 
24 
±7 
days 
Week 
28 & 
32c  
±7 
days 
Week 
36 
±7 
days 
Week 
40 & 
44c 
±7 
days 
Week 
48 
±7 
days 
Week 
52 & 
56c 
±7 
days 
Week 
60 
±7 
days 
Week 
64 & 
68c 
±7 
days 
Week 
72 
±7 
days 
Week 
77 
±7 days 
Informed consent 
X 
 
 
X 
 
Medical history 
X 
 
 
 
Genetic confirmation of 
mitochondrial disease 
X 
 
 
 
Inclusion/exclusion 
criteria  
X 
 
 
 
12-lead ECG 
X 
 
Xd 
Xd 
Xd 
Xd 
 
EEG 
Xe 
 
 
X 
X 
 
Height, weight, oxygen 
saturation 
Xf 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam and vital 
signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
(including CBC w/diffs) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation panel 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistry 
Xh 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood samples for PK 
analysisi 
 
 
X 
X 
X 
X 
 
Train caregiver on diary 
completion and 
hospitalization log 
Xj 
 
 
 
AE/SAE assessmentk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xl 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
 
X 
 

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Procedures 
Screeninga Baseline 
Placebo-controlled Phase 
Long-term Extension Phase 
Follow-
up 
Phaseb 
Day 
-42 to 0 
Day 
-28  
Day 0 
up to 
+7 
days 
Week 
2c±7 
days 
Week 
4 & 8 
±7 
days 
Week 
12 
±7 
days 
Week 
16 & 
20c 
±7 
days 
Week 
24 
±7 
days 
Week 
28 & 
32c  
±7 
days 
Week 
36 
±7 
days 
Week 
40 & 
44c 
±7 
days 
Week 
48 
±7 
days 
Week 
52 & 
56c 
±7 
days 
Week 
60 
±7 
days 
Week 
64 & 
68c 
±7 
days 
Week 
72 
±7 
days 
Week 
77 
±7 days 
Seizure and dosing diary 
distribution 
X 
 
 
 
Seizure and dosing diary 
collection/review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Total hospital 
admissions and total 
hospital days for 
disease-related issues 
log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CarerQoL-7D 
 
 
X 
X 
X 
X 
X 
X 
 
PedsQL 
 
 
X 
X 
X 
 
Initiate dosing diary entry 
 
 
X 
 
In-office dosing PO with 
food 
 
 
Xm 
Xm 
Xm 
Xm 
 
Dispense study drug 
 
 
Xm 
X 
Xn 
X 
X 
X 
 
Return of study drug 
bottles and drug 
reconciliation with dosing 
diary 
 
 
 
X 
X 
X 
X 
X 
X 
 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; COVID-19, coronavirus 
disease 2019; ECG, electrocardiogram; EEG, electroencephalogram; eCRF, electronic case report form; PedsQL, Pediatric Quality of Life Inventory™; 
PK, pharmacokinetics; SAE, serious adverse event; w/diffs, with differentials 
a Screening will be conducted and completed in a maximum of 42 days (up to 14 days Screening and 28 days Run-in period) prior to the Baseline Visit. Before 
the Run-in period subjects will be trained in diary completion. The Run-in phase and initiation of the seizure diary completed during this phase of the study, will 
contain a minimum of 28 consecutive days of seizure data collected prior to the Baseline Visit. Ideally the subject will be instructed to start entering diary 
information the day after Screening, so that the requisite number of days can be collected prior to the Baseline Visit. Laboratory tests from within 30 days of 
Screening are acceptable for entry to the study. 
b The follow-up visit will be conducted via telephone 30 days (±7 days) after last dose or termination visit. 
c Telephone call only. 
d ECG measurement will be performed at 4 hours postdose during each visit, time-matched to PK blood collection. Electrocardiogram should be performed 
approximately within 10 minutes preceding the 4-hour PK blood collection. 
e EEG for epilepsy confirmation if historical EEG up to 6 months prior to screening for confirmation of epilepsy is not provided. 
f Height will only be collected at the Screening Visit; all subsequent visits will collect weight and oxygen saturation only. Any change in weight of ≥10% from 
Baseline should result in dose adjustment. Weights ending in decimals ≥0.5 should be rounded up to the next whole number for dosing calculation. 

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g Female subjects of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy text at all other indicated 
timepoints. If a subject cannot perform a urine pregnancy test at any timepoint, a serum pregnancy test should be performed. 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. 
h ALT, AST, and creatinine are the only chemistries required at the Screening Visit. 
i Blood will be drawn for PK assessment predose and 1, 3, 4, and 8 hours postdose (prior to the next dose of vatiquinone) at Baseline and Week 24, and only 
4 hours postdose at Weeks 48 and 72. For subjects weighing less than 10 kg, PK blood draw can be reduced to 2 timepoints per visit at the Baseline and Week 24 
visits. Recommended timepoints are 0 (predose) hour and 4 hours postdose. 
j During the Screening Visit, the subject’s caregiver will be trained on how to capture information in the seizure diary and hospital admissions log. 
k Serious adverse events will be assessed 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. 
l The follow-up contact will be by telephone and should be completed 30 days (±7 days) post last study drug administration or termination visit, whichever is later. 
Adverse events and SAEs will be followed until resolution or until they have normalized. At the investigator’s discretion an office visit and additional tests may be 
conducted in order to ensure proper follow-up of an AE/SAE. 
m First dose for the placebo-controlled phase of the study will be taken the same day as the Baseline Visit. Study drug will be dispensed during the Baseline Visit 
and at each subsequent in-person visit. Drug may be delivered via delivery service if needed. 
n From Week 24 onwards, vatiquinone will be dispensed to all subjects entering the long-term extension phase. Vatiquinone will be dispensed after completing 
the Week 24 assessments. The subjects will enter the open-label phase of the study and receive vatiquinone for the dose after the visit. 
 

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7.1.1. 
Screening Visit/Run-in Phase 
Screening evaluations will be performed within a 42-day period (up to 14 days initial screening 
then 28 days Run-in) prior to the Baseline Visit. The investigator should inform each prospective 
subject of the nature of the study, explain the potential risks, and obtain written informed consent 
from the subject or parent(s)/legal guardian(s) prior to performing any study-related procedures 
and prior to the administration of study drug. 
Screening (Day -42 to Day 0) evaluations will consist of the following: 
1. Administer informed consent (Assent) 
2. Assessment of eligibility 
3. Chart review- previous medical history 
4. Genetic confirmation of mitochondrial disease 
5. Review inclusion and exclusion criteria 
6. 12-lead ECG 
7. EEG-diagnostic confirmation of epilepsy (historical EEG, up to 6 months prior to 
screening for, is acceptable) 
8. Height, weight, and oxygen saturation 
9. Physical Examination including vital signs 
10. Serum pregnancy test: women of childbearing potential (WOCBP) must have a negative 
serum pregnancy test (see Section 7.4.3) 
11. Laboratory assessments for coagulation, serum chemistry (ALT, AST, and creatinine 
only), and urinalysis (see Section 7.4.2) 
12. The subject’s caregiver will be trained on how to capture information in dosing diary, 
seizure diary, and hospital admissions log. The subjects will begin entering information 
in seizure diary daily and hospital admissions log during the Run-in phase. However, the 
subjects will begin entering information in dosing diary only after first dose. 
13. SAE assessment 
14. Concomitant medications assessment (last 30 days prior to screening) 
During the first Screening Visit (occurring before Run-in), subjects will be instructed on how to 
complete the seizure diaries. To ensure the accuracy of diary entries during the study, subjects 
must complete at least 5 days of diary entries that will be reviewed prior to the Run-in period. 
Following diary review, at the discretion of the investigator and sponsor, a further diary entry 
training period can be implemented, until the investigator is satisfied that the seizures are 
correctly captured in the diaries, in which case the duration of Screening will be longer. Diary 
entries during this period are for training purposes and will not be included in the seizure count. 
The PTC medical monitor will closely review the seizure entry during the seizure training phase 
of the study and notify the principal investigators via e-mail to begin “Run-in” phase of the study 
for the subject. Seizures will be documented in an electronic seizure diary provided to each 
subject. Run-in will be a minimum of 28 days prior to the Baseline Visit. 

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7.1.2. 
Placebo-controlled Treatment Phase 
If the subject has the required frequency of observable motor seizures during Run-in, meets all 
inclusion/exclusion criteria, and is willing to participate in the study, the subject will return for 
the baseline assessment and initiation of treatment with vatiquinone at a dose of 15 mg/kg if 
body weight <13 kg, and 200 mg if body weight ≥13 kg, administered TID or placebo TID. In 
addition to the assessments listed below, all hospitalizations, total number of hospital days, total 
intensive care unit days and use of rescue antiepileptic medications will be tracked and recorded. 
7.1.2.1. 
Baseline Visit/Randomization 
The following assessments and procedures will be performed at Baseline Visit: 
1. Review of all previous screening testing performed on the subject 
2. 12-lead ECG at 4 hours postdose time-matched to pharmacokinetic (PK) blood 
collection; ECG should be performed approximately within 10 minutes preceding the 
4-hour PK blood collection 
3. Weight and oxygen saturation 
4. Physical Examination including vital signs 
5. Urine or serum pregnancy test: WOCBP must have a negative urine or serum pregnancy 
test (see Section 7.4.3) 
6. Laboratory assessments for hematology, coagulation, serum chemistry, and urinalysis 
(see Section 7.4.2) 
7. Randomization 
8. The study drug will be administered at Baseline Visit by site staff or caregiver will be 
trained to administer the first dose on site 
9. Blood samples drawn for PK analysis predose and 1, 3, 4, and 8 hours postdose (prior to 
the next dose of vatiquinone). For subjects weighing less than 10 kg, PK blood draw can 
be reduced to 2 timepoints per visit. Recommended timepoints are 0 (predose) hour and 
4 hours postdose. 
10. AE/SAE assessment 
11. Concomitant medications assessment 
12. Review of seizure diary  
13. Calculation of total hospital admissions and total hospital days for disease-related issues 
from the time of the Screening Visit 
14. CarerQoL-7D questionnaire 
15. PedsQL questionnaire 
16. Dispense study drug 
During the Baseline Visit, study medication will be dispensed to the subject according to the 
randomization. First dose for the study drug will be taken the same day as Baseline Visit and PK 
samples collected during the Baseline Visit. 

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Subjects randomized to the treatment arm will be required to take study drug in a formulation 
mixed with sesame oil NF. Subjects in the placebo group will receive sesame oil with a colorant, 
which will have similar appearance and consistency as vatiquinone. In case the subject has a 
gastrostomy tube or nasogastric tube (G-tube or nasogastric tube) installed, vatiquinone or 
placebo will be administered using an amber oral dispenser into the G-tube with liquid food. If 
the subject is able to swallow, vatiquinone or placebo can be administered using an amber oral 
dispenser along with food. 
7.1.2.2. 
Week 2 Visit (Day 14±1 week) 
1. AE/SAE assessment 
2. Concomitant medications assessment 
3. Review of seizure and drug diaries 
4. Calculation of total hospital admissions and total hospital days for disease-related issues 
7.1.2.3. 
Week 4 Visit (Day 28 ± 1 week) 
The following assessments and procedures will be performed at Week 4. A home health visit 
option may be performed at Week 4 if an in-person visit is not feasible due to travel or 
coronavirus disease 2019 (COVID-19) restrictions, etc. 
1. Weight and oxygen saturation 
2. Physical Examination including vital signs 
3. Urine pregnancy test: WOCBP must have a negative urine pregnancy test (see 
Section 7.4.3). If a subject cannot perform a urine pregnancy test, a serum pregnancy test 
should be performed. 
4. Laboratory assessments for hematology, coagulation, serum chemistry, and urinalysis 
(see Section 7.4.2) 
5. AE/SAE assessment 
6. Concomitant medications assessment 
7. Review of seizure and dosing drug diaries 
8. Calculation of total hospital admissions and total hospital days for disease-related issues 
9.  CarerQoL-7D questionnaire 
7.1.2.4. 
Week 8 Visit (Day 56 ± 1 week) 
The following assessments and procedures will be performed at Week 8. A home health visit 
option may be performed at Week 8 if an in-person visit is not feasible due to travel or 
COVID-19 restrictions, etc. 
1. Weight and oxygen saturation 
2. Physical Examination including vital signs 

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3. Urine pregnancy test: WOCBP must have a negative urine pregnancy test (see 
Section 7.4.3). If a subject cannot perform a urine pregnancy test, a serum pregnancy test 
should be performed. 
4. Laboratory assessments for hematology, coagulation, serum chemistry, and urinalysis 
(see Section 7.4.2) 
5. AE/SAE assessment 
6. Concomitant medications assessment 
7. Review of seizure and dosing drug diaries 
8. Calculation of total hospital admissions and total hospital days for disease-related issues 
9.  CarerQoL-7D questionnaire 
7.1.2.5. 
Week 12 Clinic Visit (Day 84 ± 1 week) 
The following assessments and procedures will be performed at Week 12 (± 1 week): 
1. Weight and oxygen saturation 
2. Physical Examination including vital signs 
3. Urine pregnancy test: WOCBP must have a negative urine pregnancy test (see 
Section 7.4.3). If a subject cannot perform a urine pregnancy test, a serum pregnancy test 
should be performed. 
4. Laboratory assessments for hematology, coagulation, serum chemistry, and urinalysis 
(see Section 7.4.2) 
5. AE/SAE assessment 
6. Concomitant medications assessment 
7. Review of seizure and dosing drug diaries 
8. Calculation of total hospital admissions and total hospital days for disease-related issues 
9.  CarerQoL-7D questionnaire 
10. Drug reconciliation of returned study drug bottles with dosing diaries 
11. Dispense study drug 
7.1.2.6. 
Week 16 Visit (Days 112 ± 1 week) 
Week 16 assessments can be conducted by telephone and must include review of: 
1. AE/SAE assessment 
2. Concomitant medications assessment 
3. Review of seizure and dosing drug diaries 
4. Calculation of total hospital admissions and total hospital days for disease-related issues 

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7.1.2.7. 
Week 20 Visit (Days 140 ± 1 week) 
Week 20 assessments can be conducted by telephone and must include review of: 
1. AE/SAE assessment 
2. Concomitant medications assessment 
3. Review of seizure and dosing drug diaries 
4. Calculation of total hospital admissions and total hospital days for disease-related issues 
7.1.2.8. 
Week 24 Clinic Visit (Days 168 ± 1 week) 
The following assessments and procedures will be performed at Week 24 (±1 week): 
1. 12-lead ECG at 4 hours postdose time-matched to PK blood collection; ECG should be 
performed approximately within 10 minutes preceding the 4-hour PK blood collection 
2. Weight and oxygen saturation 
3. Physical Examination including vital signs 
4. Urine pregnancy test: WOCBP must have a negative urine pregnancy test (see 
Section 7.4.3). If a subject cannot perform a urine pregnancy test, a serum pregnancy test 
should be performed. 
5. Laboratory assessments for hematology, coagulation, serum chemistry, and urinalysis 
(See Section 7.4.2) 
6. Blood samples drawn for PK analysis predose and 1, 3, 4, and 8 hours postdose (prior to 
the next dose of vatiquinone). For subjects weighing less than 10 kg, PK blood draw can 
be reduced to 2 timepoints per visit. Recommended timepoints are 0 (predose) hour and 
4 hours 
7. EEG 
8. AE/SAE assessment 
9. Concomitant medications assessment 
10. Review of seizure and dosing drug diaries 
11. Calculation of total hospital admissions and total hospital days for disease-related issues 
12. CarerQoL-7D questionnaire 
13. PedsQL questionnaire 
14. Drug reconciliation of returned study drug bottles with dosing diaries 
15. Informed consent if subject is continuing in Long-Term Extension phase 
16. Dispense study drug if subject is continuing in Long-Term Extension phase 

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7.1.3. 
Long-Term Extension Phase (Study Weeks 36, 48, 60, and 72 are In-Person 
Visits and Study Weeks 28, 32, 40, 44, 52, 56, 64, and 68 are Telephone contact 
±1 week) 
The subjects who are interested in continued treatment with vatiquinone will continue in the 
long-term extension phase of the study. In-person visits will occur every 12 weeks (±1 week) and 
there will be every 4 weeks (±1 week) telephone contact with the subject in between the 
in-person visits. Study medication will be dispensed at each in-person visit and will be sufficient 
to reach the next 12-week in-person visit. 
The following assessments and procedures will be performed at each of the in-person visits 
under the long-term extension phase: 
1. 12-lead ECG at 4 hours postdose time-matched to PK blood collection (Weeks 48 and 
72 only; ECG should be performed approximately within 10 minutes preceding the 
4-hour PK blood collection) 
2. Weight and oxygen saturation 
3. Physical examination including vital signs 
4. Urine pregnancy test: WOCBP must have a negative urine pregnancy test (see 
Section 7.4.3). If a subject cannot perform a urine pregnancy test, a serum pregnancy test 
should be performed. 
5. Laboratory assessments for hematology, coagulation, serum chemistry, and urinalysis 
(see Section 7.4.2) 
6. Blood samples drawn for PK analysis 4 hours postdose at Study Weeks 48 and 72 
7. EEG at Week 72 
8. AE/SAE assessment 
9. Concomitant medications assessment 
10. Review of seizure and dosing drug diaries 
11. Calculation of total hospital admissions and total hospital days for disease-related issues 
12.  CarerQoL-7D questionnaire will be collected at Study Week 48 and Study Week 72 
13. PedsQL questionnaire (Week 72) 
14. Drug reconciliation of returned study drug bottles with dosing diary (Study Weeks 36, 
48, 60, and 72) 
15. Dispense study drug (Weeks 36, 48, and 60) 
The following assessments will be conducted at each of the telephone contacts and must include 
review of: 
1. AE/SAE assessment 
2. Concomitant medications assessment 
3. Seizure and drug diaries 

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4. Calculation of total hospital admissions and total hospital days for disease-related issues 
7.1.4. 
Post Treatment Follow-up Phase 
The follow-up contact will be by telephone and should be completed 30 days (±7 days) post last 
study drug administration or termination visit, whichever is later. Adverse events and SAEs 
whether or not deemed study drug-related will be followed until resolution or until they have 
normalized. At the investigator’s discretion an office visit and additional tests may be conducted 
in order to ensure proper follow-up of an AE/SAE. Subjects will be closely monitored for 
possible rebound effects following discontinuation of study drug. Additionally, subjects who are 
WOCBP will be required to perform an at-home pregnancy test (study-provided) 30 days after 
the last dose of study drug and self-report the results via telephone. 
7.1.5. 
Unscheduled Visits 
If a subject returns to the clinic outside of the normal study visit windows, assessments will be 
made at the investigator’s discretion. All study relevant unscheduled visit assessments will be 
recorded in the eCRF using the supplemental visit eCRF pages. 
7.1.6. 
Sample Collection Procedures 
Blood samples for clinical laboratory measurements should be collected and processed according 
to the central laboratory collection manual guidance or if collection is for local laboratory 
according to study site laboratory’s standard procedure. 
7.1.7. 
Safety Considerations 
Based on the known clinical manifestations of mitochondrial diseases, PTC expects that many 
AEs could occur during the course of the trial that are known to be associated with disease 
natural history. 
Both the preclinical and clinical safety profiles of vatiquinone have been favorable. To date, in 
over 523000 patient treatment days with vatiquinone there have been 7 SAEs assessed by the 
investigators to be probably or possibly drug-related. 
Specific dose modification guidelines for INR are provided in Section 7.4.6. 
Nonetheless, specific or supportive care as chosen by the investigator may be considered. 
7.1.8. 
Rescue Medication Administration for Epilepsy 
Use of rescue medications for epilepsy will be collected throughout the study and analyzed as a 
secondary study endpoint. 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 

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7.1.9. 
Prohibited Medications 
Subjects will be required to maintain a stable regimen of mitochondrial disease supplements 
from screening throughout the trial. 
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 inhibitors such as itraconazole have been demonstrated to significantly 
increase the plasma concentrations of vatiquinone (up to 2-fold). Cytochrome P450 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 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.  
No changes to the AED regimen (except for weight-based dose adjustments) will be allowed 
during the first 24-week period. 
The use of artisanal (non-Epidiolex cannabidiol) cannabidiol therapies should continue to be 
excluded due to uncertainty regarding the quality and quantity of cannabidiol in the artisanal 
product. 
7.1.10. 
End of Treatment Visits 
End of treatment visit takes place at Study Week 72 and includes the assessments listed in 
Section 7.1.2.1. Subjects who have an ongoing AE/SAE at the time of study completion will be 
followed for up to 30 days, until the event resolves, or until the sponsor and the Investigator 
agree that further follow-up is not medically necessary. 
7.1.11. 
Early Termination Study Visit 
Subjects who terminate from the study after receiving first dose and prior to the completion of all 
scheduled visits should have the end of treatment visit assessments completed as soon as 
possible. Early termination study visit will include the assessments listed in Section 7.1.2.1. 
Subjects who have an ongoing AE/SAE at the time of study completion will be followed for up 
to 30 days, until the event resolves, or until the sponsor and the Investigator agree that further 
follow-up is not medically necessary. 
7.2. 
Efficacy Assessments 
Efficacy assessments will include numbers of motor and non-motor seizures, which should be 
recorded at least daily in the electronic diary. 

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The number of emergency room visits, use of rescue seizure medications, and health-related 
quality of life as measured by the CarerQoL-7D and PedsQL questionnaires, will also be 
captured in the electronic diary or recorded on the appropriate page of the eCRF. 
7.3. 
PK and/or Other Assessments 
Blood samples for PK assessments will be drawn predose and 1, 3, 4, and 8 hours postdose (prior 
to the next dose of study drug) at Baseline and Week 24, and 4 hours postdose at Week 48 and 
Week 72. For subjects weighing less than 10 kg, PK blood draw can be reduced to 2 timepoints 
per visit at the Baseline and Week 24 visits. Recommended timepoints are 0 (predose) hour and 
4 hours postdose. The collection of these drug concentration values will serve 2 purposes: (1) to 
assess the consistency of systemic drug concentrations at specific timepoints around the time to 
maximum plasma concentration to confirm the durability of drug exposure and (2) be potentially 
incorporated in a structural model (from prior PK profiles) that can help to quantitate selected 
pharmacodynamic relationships such as safety and disease improving effects. 
7.4. 
Safety Evaluations 
Safety will be evaluated by physical examinations, vital signs assessments, 12-lead ECGs, EEGs, 
routine clinical laboratory tests (including blood chemistry, hematology, coagulation, and 
urinalysis as described below), and AE assessments from baseline through study completion. 
Serious adverse events will be collected from the time of obtaining informed consent through the 
end of the follow-up phase. 
If at any time during the treatment phase of the study, in the opinion of the investigator, a finding 
of an AE precludes continuation of treatment with study drug at the dose level at which the AE 
was observed, the dose and/or dose regimen for the study drug may be reduced or terminated 
altogether at the discretion of the investigator. The investigator will inform the sponsor of any 
discontinuations of treatment with vatiquinone and the DSMB will be notified of all AEs and 
SAEs. The investigator may solicit advice of the sponsor at any time to ensure the safety and 
well-being of participating subjects. 
7.4.1. 
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. 
Medical history and demographics including age, gender, and race, will be collected at the 
Screening Visit. Weight (lb or kg) will be measured in ordinary indoor clothing (ie, street clothes, 
scrubs, etc) with shoes off. Height will be recorded in centimeters or inches. 
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. 

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Vital sign measurements (pulse rate, blood pressure, and respiration rate) will be obtained in the 
sitting position (after the subject has been sitting for 5 minutes, if the subject is capable of sitting 
for 5 minutes). 
7.4.2. 
Laboratory Evaluations 
The maximum total quantity of blood that will be collected during a subject’s participation in the 
MIT-E study will be approximately 100 mL for subjects weighing 10 kg or more and 
approximately 88 mL for subjects weighing less than 10 kg. The maximum volume that will be 
collected per visit will be approximately 8 mL for safety laboratory assessments and 18 mL 
during PK visits for subjects weighing 10 kg and over.  
The maximum volume that will be collected per visit will be approximately 8 mL for safety 
laboratory assessments and approximately 12 mL during PK visit for subjects weighing less than 
10 kg.  
The maximum total volume (if a subject is rescreened) that could be withdrawn is approximately 
107 mL in the case of a subject weighing 10 kg or more and approximately 95 mL in the case of 
a subject weighing less than 10 kg. 
Refer to Section 7.1 (Table 2), Section 7.1.2.1, Section 7.1.2.8 , and Section 7.3 for modified PK 
collection for subjects weighing less than 10 kg. Urine will also be collected at specified 
timepoints for analysis.  
The following variables will be collected at various times to assess safety. 
7.4.2.1. 
Hematology 
1. Erythrocytes: red blood cell count, hematocrit, hemoglobin, mean corpuscular volume 
2. Leukocytes: white blood cell count and differential (basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils) 
3. Platelets: platelet count 
7.4.2.2. 
Coagulation Panel 
1. PT with INR and PTT 
7.4.2.3. 
Serum Chemistry 
1. Liver: Alkaline phosphatase, ALT (serum glutamic-pyruvic transaminase), AST 
(serum glutamic-oxaloacetic transaminase), bilirubin (total, direct), gamma-glutamyl 
transferase, and lactic dehydrogenase 
2. Renal: blood urea nitrogen and creatinine 
3. Electrolytes: sodium, potassium, chloride, carbon dioxide, calcium, magnesium, 
phosphate 
4. General: total protein, albumin, glucose 
5. Lipids: cholesterol (total) and triglycerides 

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7.4.2.4. 
Urinalysis 
1. pH 
2. Protein 
3. Glucose 
4. Ketones 
5. Blood 
6. Bilirubin 
7.4.3. 
Urine or Serum Pregnancy Test 
Both men and women should be counseled to abstain from sexual activity or use an acceptable 
method of birth control (Section 7.5.10) while participating in this clinical research study and for 
30 days afterwards. They are required to use acceptable methods of birth control. Female 
subjects who become pregnant should be immediately discontinued from the study if they have 
not yet received study drug. If a subject is found to be pregnant after she has received study drug, 
she should discontinue dosing, complete all end of study procedures, and be followed to 
determine the outcome of the pregnancy. Generally, follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. See Section 7.5.11 for rules regarding reporting 
pregnancies. 
Human chorionic gonadotropin beta subunit will be measured on all female subjects of 
childbearing potential at Screening, Baseline, Weeks 4, 8, and 12 and every 12 weeks thereafter 
throughout the study. If a subject cannot perform a urine pregnancy test at any timepoint, a 
serum pregnancy test should be performed. 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. 
7.4.4. 
Laboratory Abnormalities 
Laboratory values will be collected throughout the study to assess for safety. The investigator 
must review and assess all laboratory results in a timely manner, and determine whether the 
abnormal laboratory values, if any, are clinically significant or not clinically significant, and 
whether there are associated signs and symptoms. The investigator must make the determination 
whether the clinically significant abnormal laboratory values are AEs. 
An abnormal laboratory finding in absence of any other signs or symptoms is not necessarily an 
AE. If the abnormal laboratory finding is accompanied by signs or symptoms, report the signs 
and symptoms as the AE in lieu of the abnormal laboratory value. If a diagnosis is available, 
report the diagnosis. Clinically significant laboratory abnormalities after taking study medication 
that reflect a meaningful change from the screening value(s) and that require active management 
are to be considered by the investigator as AEs (eg, abnormalities that require study treatment 
dose modification, discontinuation, more frequent follow-up assessments, etc). 
7.4.4.1. 
Grade 3 or 4 Laboratory Abnormalities 
Diagnoses associated with any CTCAE Version 5.0 Grade 3 or 4 laboratory abnormalities will 
be recorded as AEs on the eCRF. Repeated and verified laboratory tests that meet at least 

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Grade 3 AE requirements will be reported to the Institutional Review Board/Institutional Ethics 
Committee (IRB/IEC) per institutional requirements. The recorded AEs should indicate the 
underlying abnormality or diagnosis (eg, renal insufficiency) if known, as opposed to the 
observed deviation in laboratory results (eg, elevated creatinine). Any additional relevant 
laboratory results obtained by the investigator during the study will be supplied to the sponsor. 
7.4.5. 
Dose-Limiting Toxicity 
No dose-limiting toxicities or other drug-related laboratory abnormalities were reported in prior 
clinical studies. In preclinical studies, prolongation of PT was identified as the NOAEL. 
Coagulation parameters (PT [can be measured as INR] and PTT) will be monitored throughout 
this study. 
7.4.6. 
Dose Modification Guidelines and Stopping Rules 
In the event that any subject develops any AE ≥Grade 3 per CTCAE criteria version 5.0 in 
severity that is deemed related to treatment with study drug and not related to the underlying 
disease, the Principal Investigator should contact PTC’s medical monitor to discuss dose 
modification options up to and including discontinuation of the administration of study drug. 
In the event that any subject develops or is diagnosed with an allergy to vatiquinone or sesame 
oil after initiating treatment with study drug, administration of study drug will be discontinued. 
In the event that any subject develops elevated INR ≥Grade 2 in severity (>1.5×ULN) per 
CTCAE criteria version 5.0 thought to be related to treatment with study drug, administration of 
study drug will be reduced to 66%. Should the INR toxicity not resolve to at least Grade 1 in 
severity within 2 weeks of the initial dose reduction, administration of study drug may either be 
further reduced or discontinued (Table 3). 
Once a subject’s dose is reduced due to elevated INR thought to be related to study drug 
administration, their dose should not be re-escalated. 
Table 3: 
Dose Modification and Stopping Rules for Vatiquinone 
Qualifying Event 
Example Guidelines for Management 
Recommendation 
If Resolved to ≤Grade 1 
If Not Resolved to 
≤Grade 2 After 14 Days 
INR ≥Grade 2 or 
>1.5xULN thought to 
be related to study 
drug and confirmed 
within 24-48 hours 
Reduce dose by 1/3 
from TID to BID 
Re-evaluate 7 days 
after dose reduction 
Continue on-study at 
2/3 dose.* 
*Once a subject is dose 
reduced, do not 
re-escalate. 
Consider withdrawing the 
subject after consultation 
with the study medical 
monitor. 
Abbreviations: AE, adverse event; DSMB, Data Safety Monitoring Board; INR, International Normalized Ratio; 
ULN, upper limit of normal 
The investigator is responsible for decisions on dose holds, reductions, or interruptions for any clinically significant 
AE. The DSMB is responsible for determining dose modification or stopping actions for any other safety event. 
7.4.7. 
Safety Guidance 
PTC may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations. If a subject dies during participation in the study or during a 
recognized follow-up period, PTC should be provided with a copy of any post-mortem findings, 
including histopathology. 

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7.5. 
Adverse Events and Serious Adverse Events 
7.5.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not it is considered related to the drug. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease in a study 
subject who is administered study drug in this study. 
For this protocol, untoward medical occurrences that should be reported as AEs include the 
following: 
• All AEs during the course of treatment with study drug administration 
• All AEs resulting from medication misuse, abuse, withdrawal, or overdose, of study 
drug 
• All AEs resulting from medication errors such as dispensing or administration error 
outside of what is described in the protocol 
• Apparently unrelated illnesses, including worsening of a preexisting illness 
• Injury or accidents. Note that if a medical condition is known to have caused the 
injury or accident (a fall secondary to dizziness), the medical condition (dizziness) 
and the accident (fall) should be reported as 2 separate AEs. The outcome of the 
accident (hip fracture secondary to the fall) should be recorded in source documents. 
• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test) 
• Laboratory or ECG abnormalities that require clinical intervention or further 
investigation (beyond ordering a repeat [confirmatory] test) unless they are associated 
with an already reported clinical event. Laboratory abnormalities associated with a 
clinical event should be captured in the source documents. Laboratory abnormalities 
not requiring clinical intervention or further investigation will be captured as part of 
overall laboratory monitoring, and should not be reported as AEs. 
• 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 7.5.2 any hospitalization occurring as the 
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Each AE is to be classified as serious or nonserious by the investigator using medical and 
scientific judgment. 
7.5.2. 
Definition of Serious Adverse Events 
An SAE is an untoward medical occurrence or effect associated with the use of a study drug at 
any dose, regardless of whether it is considered to be related to the study drug, which results in 
one of the following: 
• Results in death. This includes all deaths on treatment or within 30 days after last 
study drug administration, including deaths due to disease progression. Any death 
occurring later than 30 days following the last dose need not be reported as an SAE 
unless it is a result of an event that started within the period covered by the on-study 
definition. The reported AE should be the event that caused the death. In addition, 
any AE resulting in death that occurs subsequent to the AE reporting period and that 
the investigator assesses as possibly related to the study drug should also be reported 
as serious. 
• Is life-threatening. This refers to an event in which the subject was at risk of death at 
the time of the event. It does not include an event that, had it occurred in a more 
severe form, hypothetically might have caused death. 
• Requires hospitalization or prolongation of existing hospitalization (excluding 
hospitalizations for administration of the study drug, procedures required by the study 
protocol, or treatment-related diagnostic procedures; other planned hospitalizations; 
or hospitalizations related only to progression of disease).  
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should also usually be considered 
serious. 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. 
Additionally, hospitalization should be used as an indicator of the seriousness of the 
AE and should only be used for situations where the AE truly fits this definition and 
not for hospitalizations associated with less serious events (eg, a hospital visit where a 
subject is admitted for observation or minor treatment [eg, hydration] and released in 
less than 24 hours). Furthermore, hospitalization for pharmacokinetic sampling, is not 
an AE, and therefore is not to be reported either as a routine AE or in an expedited 
report. 
• Results in persistent or significant disability or incapacity or substantial disruption of 
the ability to conduct normal life functions. 
• 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 

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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). 
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. 
7.5.3. 
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. 
7.5.4. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject/parent(s)/legal guardian/legally acceptable representative. In addition, each study 
subject/parent(s)/legal guardian/legally acceptable representative will be questioned about AEs at 
each scheduled clinic visit after study drug administration or during any telephone contact with 
the subject/parent(s)/legal guardian/legally acceptable representative. The type of question asked 
should be open-ended, for example, “How have you been feeling?” or a similar type of query. 
7.5.5. 
Recording Nonserious AEs and SAEs 
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 should be employed. In addition, the following information should be recorded: 
• Indication of whether the event is serious or nonserious (see Section 7.5.2) 
• Relationship to study drug (see Section 7.5.6) 
• Severity of the event (see Section 7.5.7) 
• Onset date 
• Resolution date, or date of death 
• Action taken 
• Outcome of the event 

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Classification of the event as serious or nonserious determines the reporting procedures to be 
followed. 
7.5.6. 
Describing Adverse Event Relationship to Study Drug 
The investigator should provide an assessment of the relationship of the AE to the study drug, 
ie, whether there is a reasonable possibility that the study drug caused the AE, using the 
considerations outlined in Table 4. 
Table 4: 
Relationship of Study Drug to Adverse Event Relationship 
Relationship  Description 
Probable  
A clinical event in which a relationship to the study drug seems probable because of 
such factors as consistency with known effects of the drug; a clear temporal 
association with the use of the drug; improvement upon withdrawal of the drug; 
recurrence upon rechallenge with the drug; lack of alternative explanations for the 
event.  
Possible  
A clinical event occurring coincident with administration of the study drug and which 
may or may not be explained by concurrent disease or other drugs or chemicals. 
Information on drug withdrawal or rechallenge may be lacking.  
Unlikely  
A clinical event with a temporal relationship to the study drug exposure that does not 
preclude causality but for which there is a clear alternate cause that is more likely to 
have caused the 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.  
Abbreviation: AE, adverse event 
7.5.7. 
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 
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  

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Grade 5  
Fatal  
Sign or symptom results in death  

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7.5.8. 
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  
Serious AE 
All  
All  
Non-Serious AE 
All  
None  
Exposure to the study 
drug during pregnancy or 
breastfeeding, and 
occupational exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure 
Exposure during pregnancy, exposure via 
breastfeeding, occupational exposure 
(regardless of whether associated with an 
AE) 
Abbreviations: AE, adverse event; eCRF, electronic case report form; SAE, serious adverse event 
All AEs should be followed up by the investigator until they are resolved, or the investigator 
assesses them as chronic or stable. The investigator should consider protocol guidelines and use 
his/her discretion in ordering additional tests as necessary to monitor the resolution of such 
events. In the event of additional investigations, the PTC Pharmacovigilance Department or 
designee should be informed via e-mail or fax. A subject withdrawn from the study because of 
an AE must be followed by the investigator until clinical recovery is complete and laboratory 
results have returned to normal, or until progression has been stabilized. Follow-up may need to 
continue after the subject has discontinued from the study, and additional investigations may be 
requested by the PTC medical monitoring team. 
The first day of AE reporting will coincide with the date of signing of informed consent and 
including a minimum of 30 calendar days after the last administration of study drug. 
7.5.9. 
Serious Adverse Event Reporting 
All SAEs occurring from the 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 IRB/IEC (if 
required by local regulations) within 24 hours. 
Follow-up information to the SAE should be clearly documented as “follow-up” in the SAE 
report form and must also be faxed or e-mailed to the same party. All follow-up SAE report 
forms for the event must be signed by the investigator. Any source documents (eg, progress 
notes, nurses’ notes, laboratory and diagnostic test results, discharge summaries) provided to the 
sponsor should be redacted so that the subject’s name, address, and other personal identity 
information are obscured. Only the subject’s study number and initials are to be provided 
(in regions where the provision of such information is permitted). The information in the AE 
portion of the eCRF and the SAE report form(s) must match or be reconciled. Where the same 
data are collected, the forms must be completed in a consistent manner. For example, the same 
AE term should be used on both forms. 

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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 
7.5.10. 
Contraception 
Women of childbearing potential includes any female who has experienced menarche and who 
has not undergone successful surgical sterilization (eg, hysterectomy, bilateral tubal ligation, 
bilateral oophorectomy) or is not postmenopausal. Postmenopausal is defined as ≥12 months 
with no menses without an alternative medical cause. Women who are using an active method of 
birth control, who are practicing abstinence or whose partner is sterile (eg, vasectomy), are 
considered to be WOCBP. 
Males subjects and subjects who are WOCBP must use 2 forms of effective contraception 
simultaneously from the time consent is signed until 30 days after treatment discontinuation in a 
manner such that risk of failure is minimized. Periodic and/or temporary abstinence such as 
declaration of abstinence during study participation or fertility awareness- based methods to 
prevent pregnancy (including but not limited to symptothermal and ovulation estimation by 
either calendar day or salivary/cervical secretions) are not considered effective methods of birth 
control; however, true (absolute) sexual abstinence (ie, in line with the preferred and usual 
lifestyle of the subject) may be permitted. Effective methods of birth control approved for use in 
this study are as follows: 
• Implants (eg, Norplant® system) 
• Injectable (eg, Depo-Provera®) 
• Transdermal patch 
• Combined oral contraceptives 
• Barrier methods (condoms and diaphram with spermicide) - note: double barrier 
method is required if no other methods of birth control are in use. 
• Intrauterine devices (eg, ParaGard®, Mirena®)  
Prior to study enrollment, male subjects and WOCBP must be advised of the importance of 
avoiding pregnancy during trial participation. During the trial, all WOCBP will be instructed to 
contact the investigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual period). 

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7.5.11. 
Reporting Pregnancy 
PTC should be notified in the event that a female subject in the study, or a female partner of a 
male subject in the study, becomes pregnant on-study or within 30 days of the last administration 
of study drug 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 (see Section 7.5.9). 
7.5.12. 
PTC Therapeutics Safety Reporting Requirement 
In compliance with local requirements, PTC shall immediately notify the investigators of any 
new or emerging safety information, which impacts the benefit-risk ratio of the drug, once 
confirmed by the executive safety review board. This will include any urgent measures that need 
to be taken with respect to the protocol. 
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 appropriate per local reporting requirements, to each investigator in an expedited 
manner. If notification of a SUSAR requiring expedited reporting to investigators is received, 
PTC or its designated representative will contact each investigational site participating in this 
study by e-mail, fax, and/or overnight mail such that the investigator can promptly notify the site 
IRB/IEC per their local requirements. The initial expedited safety report will be provided as 
required according to local regulations (eg, within 15 days) after the earliest date PTC or an 
agent of PTC (eg, a site monitor) becomes aware of an SAE. This awareness date is the date the 
regulatory reporting clock begins, and the date is considered Day 0. 

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8. 
STATISTICAL CONSIDERATIONS 
This is a randomized, placebo-controlled trial of vatiquinone in pediatric subjects with 
genetically confirmed mitochondrial disease and associated refractory epilepsy. The primary 
endpoint of this study will be the percent change from baseline in the frequency of observable 
motor seizures per 28 days in the placebo-controlled phase.  
A formal statistical analysis plan (SAP) will be finalized before the unblinding of the study. 
Detailed discussion of statistical methods, including estimand and missing data handling, will be 
specified in the SAP.  
8.1. 
Statistical Hypotheses 
The null hypothesis is that there is no difference in the effect of vatiquinone versus placebo in 
percent change from baseline in observable motor seizures per 28 days during the double-blind 
period. 
8.2. 
Sample Size Determination 
It is planned to randomize 30 subjects per arm in this study. Sixty subjects (30 subjects in each 
treatment group) will provide a power of 81% to detect a 40% treatment difference with common 
standard deviation of 50% at a two-sided significance level of 0.05 based on the Wilcoxon 
Rank-Sum Test. The 40% treatment difference is based on 10% and 50% decrease in the placebo 
treatment group and PTC743 treatment group, respectively, for percent change from baseline in 
motor seizure frequency per 28 days. 
8.3. 
Population for Analyses 
• Intent-to-treat (ITT) population will include all subjects who were randomized and 
received at least one dose of treatment. In the event that a subject received study drug 
different from the one to which he/she was randomized, the subject’s efficacy data 
will be analyzed “as randomized.” ITT Analysis population will be used in the 
statistical analyses of the efficacy endpoints. 
• Safety population will include subjects who were randomized and received at least 
one dose of treatment. In the event that a subject received study drug different from 
the one to which he/she was randomized, the subject’s safety data will be analyzed 
“as treated.” The Safety Analysis population will be used in the statistical analyses for 
safety. 
8.4. 
Statistical Analyses 
8.4.1. 
General Approach 
For continuous variables, median, mean, standard deviation, minimum, maximum, and number 
of subjects with non-missing data will be provided for each treatment group, and for overall 
treatment group for assessment prior to randomization. For categorical variables, the number 
(percent) of subjects in each category will be provided. 

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In general, data will be presented by treatment groups separately for double-blind period and 
open-label extension period. In addition, vatiquinone experience from both double-blind and 
open-label extension period will be combined and summarized. In this summary, baseline for 
subjects on placebo in the double-blind period will be the last observation prior to the first 
vatiquinone dose. 
8.4.2. 
Analysis of Primary Efficacy Endpoints 
Efficacy analyses will be based on the ITT population. Seizure frequency will be based on the 
number of seizures per 28 days, calculated as (the number of seizures over the time interval 
multiplied by 28) and divided by the number of days in the interval. Only “valid days” will be 
used in the calculations of seizures frequency per 28 days. A “valid day” is defined as the day 
where seizure counts information is present. 
The percent change in the motor seizure frequency per 28 days in the double-blind period will be 
the primary efficacy endpoint. 
For this analysis, first both the pre-randomization period motor seizure frequencies per 28 days 
as well as percent change in the double-blind period per 28 days will be rank transformed 
separately. The analysis of covariance will then be conducted on this rank transformed data with 
treatment, and stratifying factor (4 levels) and the ranked pre-randomization phase seizure 
frequency per 28 days as a covariate. P values will be computed using contrasts between active 
and placebo treatment groups. 
Due to an expected irregular distribution of seizure frequency, median will be the primary 
statistic of interest for the primary endpoint. Hodges-Lehmann estimator and 95% confidence 
interval for this estimator will be displayed for understanding the treatment effect size. 
A sensitivity analysis will be performed excluding all subjects with <25 days of valid days 
entered in the diary. 
8.4.3. 
Analysis of Secondary Efficacy Endpoints 
Change from baseline in number of disease-related hospitalization days per 28 days and change 
from baseline in occurrence/recurrence of status epilepticus per 28 days are the two key 
secondary endpoints. The treatment groups will be compared using Wilcoxon Rank-Sum Test. 
Number of disease-related hospitalization days and number of occurrence/recurrence of status 
epilepticus will be tabulated by frequency and percent as well. 
Percent change from baseline in total seizure frequency per 28 days will be analyzed in a similar 
way to the primary endpoint.  
Response rates (25%, 50%, 75%, and 100%) for motor seizure and total seizure will be tabulated 
by treatment groups and treatment will be compared by Cochran-Mantel-Haenszel test adjusting 
for stratifying factor. 
Number of disease-related emergency room visits and in-patient hospitalizations, number of 
rescue seizure medications, and seizure clusters will be tabulated by frequency and percent. In 
addition, change from baseline in disease-related emergency room visits and in-patient 
hospitalizations per 28 days, and change from baseline in seizure clusters per 28 days will be 
summarized. 

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Health-related quality of life, as measured by the CarerQoL-7D questionnaire, will be 
summarized descriptively. 
8.4.4. 
Analysis of Exploratory Endpoint 
Health-related quality of life, as measured by the PedsQL, will be summarized descriptively 
8.4.5. 
Multiplicity Adjustment 
A sequential method will be used to adjust for multiple comparison. The primary endpoint will 
be first tested at 0.05 level. If the p-value is less than 0.05 the first key secondary endpoint, 
number of hospitalization days, will be tested at 0.05 level. If the p-value for the primary 
endpoint is >0.05 then the number of hospitalization days will not be tested. The same procedure 
will be applied to the endpoint of occurrence or recurrence of status epilepticus. 
8.4.6. 
Safety Analyses 
8.4.6.1. 
Subject Disposition 
The disposition of subjects, including the number of subjects screened, the number of 
randomized subjects, the number of randomized subjects who received at least 1 dose of study 
drug, and the number of subjects who prematurely discontinue study drug as well as the reason 
for the premature termination will be tabulated. The number of subjects enrolled in the 
open-label extension study will also be tabulated. 
8.4.6.2. 
Medical History and Prior Medication 
Medical history and prior medication information will be summarized. 
8.4.6.3. 
Extent of Exposure and Treatment Compliance 
The extent of exposure to vatiquinone treatment is defined as the last dose date minus the first 
dose date +1 day. Compliance will be assessed in terms of the percentage of drug actually taken 
relative to the amount that should have been taken during the study. Exposure and compliance 
will be summarized descriptively. 
8.4.6.4. 
Adverse Events 
Summary information (the number and percent of subjects by treatment) will be tabulated for: 
• Treatment-emergent adverse events (TEAEs) 
• Treatment-related AEs 
• TEAEs by severity 
• SAEs 
• AEs leading to discontinuation 
Summaries will be presented by treatment groups and categorized by System Organ Class and 
Preferred Term. The frequencies of AEs displayed will be the crude rates that represent the 
number of subjects experiencing AEs divided by the total number of subjects. 

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8.4.6.5. 
Laboratory Parameters 
Changes in clinical laboratory tests from Baseline (last measurement prior to randomization) and 
laboratory marked abnormalities using pre-defined abnormality criteria will be descriptively 
summarized. 
8.4.7. 
Baseline Descriptive Statistics 
Demographic and baseline characteristics of subjects will be summarized descriptively by means 
and standard deviations for continuous variables, and frequency distribution for categorical 
variables. Summaries will be performed based on all randomized subjects. 
8.4.8. 
Planned Analyses 
Two analyses will be conducted, Period 1 at Week 24 (the end of placebo-controlled period) and 
Period 2 at Week 72 (the end of long-term extension period), respectively. All formal statistical 
conclusions will be drawn from data collected in the double-blind treatment period, and all 
statistical type I error will be spent on the hypothesis tests performed on these data. 
8.4.9. 
Sub-group Analyses 
Percent change from baseline in motor seizure frequency per 28 days, percent change from 
baseline in total seizure frequency per 28 days, and response rates (25%, 50%, 75%, and 100%) 
for motor seizure and total seizure will be summarized descriptively by disease subtype 
(Alpers/POLG; Leigh syndrome; MELAS; and Other). 
8.4.10. 
Exploratory Analyses 
No exploratory analyses are planned. 

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9. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations 
9.1.1. 
Informed Consent Process 
By signing the protocol, the investigator assures that informed consent/assent will be obtained 
from each subject prior to study entry and that the informed consent/assent will be obtained in 
accordance with current regulations. 
The investigator or sub-investigator will give each subject full and adequate verbal and written 
information regarding the objectives and procedures of the study and the possible risks involved. 
An informed consent/assent document will be provided to each subject in a language in which 
the subject is fluent. This information must be provided to the subject prior to undertaking any 
study-related procedure. Adequate time should be provided for the subject to read the informed 
consent, to understand the risks and benefits of participating in the study, and to ask any 
questions that the subject may have about the study. The subject should be able to ask additional 
questions as and when needed during the conduct of the study. The subject’s signature on the 
informed consent form should be obtained at the investigator site in the presence of the 
investigator or a qualified representative (eg, sub investigator). Where applicable, the subject 
will sign an age-appropriate assent form. 
Each subject will be given a copy of the signed consent/assent form. The original signed 
informed consent forms will be retained by the investigator with the study records. 
The written subject information must not be changed without prior approval by PTC and the 
IRB/IEC. 
9.1.2. 
Study Discontinuation and Closure 
PTC reserves the right to discontinue the study prior to inclusion of the intended number of 
subjects. The investigator, after consultation with the PTC medical monitor, reserves the right to 
discontinue the study at the investigator site for safety reasons at any time. 
After a decision to terminate the study, investigators must contact all subjects who are continuing 
their participation in the study and must do so within a time period set by PTC. As directed by 
PTC, all study materials must be collected and all electronic data entry forms completed to the 
greatest extent possible. 
9.1.3. 
Confidentiality and Privacy 
Research records will be collected and stored in a manner that protects the confidentiality of 
subject information. The names and identities of all research subjects will be kept in strict 
confidence and will not appear on eCRFs, paper 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 informed consent form must include 
appropriate statements explaining these requirements. 

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By signing this protocol, the investigator affirms to PTC that the investigator will maintain, in 
confidence, information furnished by PTC and will divulge such information to the IRB/IEC 
under an appropriate understanding of confidentiality with such board. 
9.1.4. 
Future use of Stored Specimens and Data 
As part of the current study, blood, plasma, and serum will be collected and stored. 
Sample processing will be performed by a laboratory under the direction of the sponsor. 
Processing, analysis, and storage will be performed at a secure laboratory facility to protect the 
validity of the data and maintain subject privacy. 
Samples will only be used for the purposes described in this protocol. Laboratories contracted to 
perform the analysis on behalf of the sponsor will not retain rights to the samples beyond those 
necessary to perform the specified analysis and will not transfer or sell those samples. The 
sponsor will not sell the samples to a third party. 
Samples will be stored until the completion of the study (defined as submission of the clinical 
study report to the appropriate regulatory agencies). At the end of the storage period, samples 
will be destroyed. Samples may be stored longer if a health authority (or medicinal product 
approval agency) has active questions about the study. In this special circumstance, the samples 
will be stored until the questions have been adequately addressed. 
No subject-identifying information (eg, initials, date of birth, government identifying number) 
will be associated with any of the biologic samples. All samples will be single coded. The 
sponsor will take steps to ensure that data are protected accordingly, and confidentiality is 
maintained as far as possible. Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection. 
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research. These include: 
• Contract Research Organizations (CROs) retained by the sponsor 
• IECs or IRBs that have responsibility for this research study 
• National regulatory authorities or equivalent government agencies 
At the end of the analysis, results may be presented in a final report which can include part or all 
of the coded data, in listing or summary format. Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of the 
population in the study, and no identified individual results will be disclosed. 
Given the research nature of the planned analyses, it will not be possible to return individual data 
to subjects. The results that may be generated are not currently anticipated to have clinical 
relevance to the subjects or their family members. Therefore, these results will not be disclosed 
to the subjects or their physicians. 

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9.1.5. 
Safety Oversight 
External oversight for this trial will be provided by a DSMB. The primary responsibility of the 
DSMB is to protect the safety and welfare of subjects participating in this clinical trial and to 
ensure the integrity of the clinical trial. 
Specifically, for this study, the DSMB will be responsible for: 
• Examining accumulated safety data, PK, and compliance data in order to make 
recommendations concerning continuation, termination, or modification of the trial 
based on the safety of the interventions under study 
• Reviewing major study design modifications proposed by PTC or the investigators 
prior to implementation of those modifications 
• Reviewing the general progress of the study as regards accrual, protocol violations, 
and study conduct 
The DSMB may review the safety data at any time as warranted by emerging results. Based on 
review of the safety data, the DSMB can recommend continuation of the study unchanged, study 
interruption, study termination, modification of the trial, or alteration in the DSMB monitoring 
plan. Further information regarding the DSMB review process is provided in the DSMB charter 
(see Study Manual). 
9.1.6. 
Clinical Monitoring 
In accordance with 21 Code of Federal Regulations Part 312.56 and/or relevant International 
Council for Harmonisation guidelines, PTC or a designee will periodically inspect all eCRFs, 
study documents, research facilities, and clinical laboratory facilities associated with this study at 
mutually convenient times, before, during, and after completion of the study. As required by 
applicable regulations (Responsibilities of Sponsors and Investigators), the monitoring visits 
provide PTC with the opportunity to evaluate the progress of the study; verify the accuracy and 
completeness of data in the eCRFs; ensure that all protocol requirements, relevant regulations, 
and investigator’s obligations are being fulfilled; and resolve any inconsistencies in the study 
records. This includes inspection of all documents and records required to be maintained by the 
investigator, including but not limited to medical records (office, clinic, or hospital) for the 
subjects in this study. The names and identities of all research subjects will be kept in strict 
confidence and will not appear on eCRFs or other records provided to or retained by PTC. The 
investigator/institution guarantees direct access to source documents by PTC and appropriate 
regulatory authorities. 
It is important that the investigator and relevant institutional personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 

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9.1.7. 
Quality Assurance and Quality Control 
To ensure compliance with Good Clinical Practices (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 International Council for Harmonisation, and any 
applicable regulatory requirements. The investigator should contact the sponsor immediately if 
contacted by a regulatory agency about an inspection. 
9.1.8. 
Data Handling and Record Keeping 
To enable evaluations and/or audits from regulatory authorities or PTC, the investigator agrees to 
keep accurate and complete records, including the identity of all participating subjects (sufficient 
information to link eCRFs and clinic records/source documents), all original signed informed 
consent forms, electronic copies (ie, CD-ROM, USB, etc.) or paper copies of the data that have 
been captured in the electronic data capture for each subject (eCRFs), and detailed records of 
study drug disposition. All records and documents pertaining to the study will be maintained by 
the investigator until notification is received from PTC that the records no longer need to be 
retained. 
The investigator must obtain written permission from PTC before disposing of any records. The 
investigator will promptly notify PTC in the event of accidental loss or destruction of any study 
records. If the investigator relocates, retires, or for any reason withdraws from the study, the 
study records may be transferred to an acceptable designee, such as another investigator, another 
institution, or to PTC as applicable. 
9.1.9. 
Protocol Deviations 
A protocol deviation is defined as any intentional or unintentional change to, or noncompliance 
with, the approved protocol procedures or requirements. Deviations may result from the action or 
inaction of the subject, investigator, or site staff. Examples of deviations include, but are not 
limited to: 
• Failure to adhere to study exclusion and inclusion criteria 
• Failure to comply with dispensing or dosing requirements 
• Use of medications that are specifically prohibited in the protocol 
• Missed or out-of-window visits 
• Drug dosing not administered within the time frame specified in the protocol 
• Failure to adhere to test requirements, including vital signs, laboratory tests, physical 
examinations, PK blood draws, medical history, etc.-either tests not done, incorrect 
tests done, or not done within the time frame specified in the protocol 

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• Procedural deviations such as incorrect storage of study drug, failure to update the 
Informed Consent Form (ICF) when new risks become known, or failure to obtain 
IRB approvals for the protocol and ICF revisions 
Major deviations are any deviations that impact subject eligibility (ie, protocol 
inclusion/exclusion violations), subject safety or a subject’s ability to continue in the clinical 
trial. 
At the outset of the study, a process for defining and handling protocol deviations will be 
established with the CRO. This will include determining which deviations will be designated 
major; thus, requiring immediate notification to the PTC medical monitor and the sponsor. 
Prospective deviations (eg, protocol waivers) are prohibited per PTC policy. 
The investigator is responsible for seeing that any known protocol deviations are recorded 
handled as agreed. 
9.1.10. 
Publication and Data Sharing Policy 
The information developed during the conduct of this clinical study is considered confidential by 
PTC. This information may be disclosed as deemed necessary by PTC. 
PTC intends that the data from this study will be presented and published. The PTC staff under 
the direction of the PTC Chief Medical Officer or designee in collaboration with the investigator 
will be responsible for writing presentations and manuscripts for publication. Investigators will 
not be allowed to publish or present the data from this study without prior agreement with PTC. 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the Clinical Study Site Agreement, any 
public disclosure (including publicly accessible websites) related to the protocol or study results, 
other than study recruitment materials and/or advertisements, is the sole responsibility of the 
sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
Data from all sites participating in the study will be pooled and analyzed by the sponsor or the 
sponsor’s designee. The first publication of the study results shall be made in conjunction with 
the results from other study sites as a multicenter publication. If a multicenter publication is not 
forthcoming within 24 months of completion of the study at all sites, the investigator may 
publish or present the results generated at his or her site. 

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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. 
Furthermore, 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. 
9.2. 
Additional Considerations 
Not applicable. 
9.3. 
Protocol Amendment History 
Version 1.0: 26 March 2019 
Version 2.0: 27 March 2020 
Version 3.0: 22 May 2020 
Version 4.0: 30 September 2020 
Version 4.1: 12 January 2021 
Version 5.0: 31 March 2021 
Version 6.0: 04 June 2021 
Version 7.0: 06 January 2022 
Version 8.0: 27 May 2022 

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9.3.1. 
Version 2.0: 27 March 2020 
Overall reason for Version 2.0: The overall reason for Version 2.0 of the protocol was to 
change the name of the study sponsor, subsequently the drug name, and to incorporate health 
authorities’ feedback on the previous version of the protocol. 
Item 
No. 
Protocol 
Section 
Version 2/Update 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical error, punctuation, tenses, 
abbreviations) were incorporated to provide clarity. The sponsor 
name was updated from BioElectron to PTC and the protocol was 
moved into the PTC template. Standard template sections in the 
BioElectron template were replaced with those from the PTC 
template. The synopsis was updated to be consistent with 
changes in the protocol.  
Update 
2 
Section 1.5.1 
Anticoagulation in the nonclinical toxicology studies was added to 
explain the reason for monitoring coagulation parameters. 
Clarification 
3 
Section 2.1.2 
The secondary objectives were expanded to include the effects of 
vatiquinone on the monthly seizure count, the responder rate in 
motor and non-motor seizures, seizure clusters, and to change 
the quality of life questionnaire to the CarerQoL-7D. 
Update 
4 
Section 2.2  
Endpoints were updated to align with the objectives and 
2 endpoints were designated key endpoints. 
Update 
5 
Section 3.1.1  The Screening and Run-in Phase were combined, and 
clarification was added that the 28 days prior to Baseline Visit is 
the Run-in phase. Clarification was added that if subjects do not 
meet the entry criteria regarding number of seizures, they will be 
considered screen failures.  
Clarification 
6 
Section 3.2.2  The number of study sites was increased from 10 to 12.  
Update 
7 
Section 3.4  
A section justifying the chosen dose was added.  
Update 
8 
Section 4.2  
Inclusion criteria were expanded for clarification. 
Clarification 
9 
Section 4.3  
INR ≥1.5 ULN and ongoing treatment with CYP inhibitors were 
included in the exclusion criteria. 
Update 
10 
Section 4.4  
Section added per PTC template. 
Update 
11 
Section 4.5  
Section added per PTC template. 
Update 
12 
Section 6.3  
Section added per PTC template. 
Update 
13 
Section 7  
The requirement for laboratory assessments to be performed 
under fasting conditions was removed.  
Update 
14 
Section 7.3  
Blood samples for PK assessments were detailed in this section 
and added to the schedule of events (Section 7.1) and wherever 
appropriate throughout the protocol.  
Update 
15 
Section 7.5  
This section was updated per PTC template, including definitions 
and standard reporting procedures for AEs and SAEs.  
Update 
16 
Section 8  
Section added per PTC template. 
Update 
Abbreviations: AE, adverse events; CYP, cytochrome P450; INR, International Normalized Ratio; 
PTC, PTC Therapeutics; SAE, serious adverse events; ULN, upper limit of normal 

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9.3.2. 
Version 3.0: 22 May 2020 
Overall reason for Version 3.0: The overall reasons for Version 3.0 of the protocol were to add 
urinalysis assessment and an additional PK timepoint and to give additional training for seizure 
diaries, if needed. 
Item 
No. 
Protocol 
Section 
Version 3/Update 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical error, punctuation, tenses, 
abbreviations) were incorporated to provide clarity. The synopsis 
was updated to be consistent with changes in the protocol.  
The study name (MIT-E) was added to the study title. 
Update 
2 
Protocol 
Identifiers 
and Study 
Personnel 
The EudraCT number was added. 
Update 
3 
Section 
2.1.2 and 
2.2.3.1 
Dose-limiting toxicities were removed from the secondary objectives 
and endpoints. 
Update 
4 
Sections 
3.1, 3.4, 
5.1.1 and 
7.1.2 
The dose regimen description was clarified. 
Clarification 
5 
Sections 
3.1.1 and 
7.1.1 
An extension to the Screening period, at the discretion of the 
investigator, was added, if further training on seizure diaries in 
necessary. 
Update 
6 
Section 
4.2 
Inclusion criterion “Subject or parent/legal guardian is able and 
willing to complete seizure diaries for the duration of the study” was 
added. 
Inclusion criterion #6 was amended to remove the word “symptoms” 
after epilepsy. 
Inclusion criterion #10 was amended to remove the 30-day window 
for historical EEG. 
Update and 
clarification 
7 
Section 
4.3 
Exclusion criterion #9 was amended to prohibit the use of grapefruit 
juice and St John’s wort extract. 
Exclusion criterion #8 was added prohibiting treatment with 
idebenone. 
Clarification 
and update 
8 
Section 
4.6 
Home Care Services section was added. 
Update 
9 
Sections 
7.1 and 
7.4.2 
Urinalysis assessments were added. 
Update 
10 
Sections 
7.1 and 
7.3 
PK assessment timepoints were changed to Predose, 1h, 3h, 4h, 
and 8h postdose. 
Update 
11 
Section 
7.1 
ECG and EEG assessments were reduced. EEG will only be 
required at Screening if no historical EEG is available. 
A +7-day window was added to the Screening Visit. 
Update 
12 
Section 
7.1.9 
Prohibition of cannabidiol containing therapies was removed. 
Grapefruit juice and St John’s wort extract were specifically added 
as CYP inducers or inhibitors. 
Update 
13 
Section 
7.4.2.4 
Urinalysis parameters were detailed. 
Update 

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Item 
No. 
Protocol 
Section 
Version 3/Update 
Reason/ 
Rationale 
14 
Sections 
7.4.5 and 
7.4.6 
Dose-limiting toxicity text was clarified and a window for 
confirmation of elevated INR was added. 
Clarification 
Abbreviations: CYP, cytochrome P450; ECG, electrocardiogram; EEG, electroencephalogram; INR, International 
Normalized Ratio; MIT-E, Mitochondrial Disease Subjects with Refractory Epilepsy 
9.3.3. 
Version 4.0: 30 September 2020 
Overall reason for Version 4.0: The overall reasons for Version 4.0 of the protocol were to 
revise the ECG collection schedule so as to time match it with the 4-hour postdose PK, to add 
PK samples to 4 hours postdose at Weeks 48 and 72, to revise the definition of compliance with 
study drug dosing, to separate the secondary endpoints into key and other endpoints, and 
refinement of statistical considerations.  
Item 
No. 
Protocol 
Section 
Version 4/Update 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical error, punctuation, 
tenses, abbreviations) were incorporated to provide clarity. 
The synopsis was updated to be consistent with changes in 
the protocol.  
The study name (MIT-E) was added to the study title. 
Update 
2 
Section 3.1.2 
Number of subjects to be allocated to the Alpers/POLG 
(DNA polymerase subunit gamma); Leigh syndrome; and 
Mitochondrial encephalomyopathy, lactic acidosis, and 
stroke-like episodes categories revised from 15 subjects to 
6 subjects each. 
Update 
3 
Section 4.2  
Clarification of inclusion criterion 4 to include mitochondrial 
disease secondary to either nuclear or mitochondrial DNA 
mutation with associated epilepsy phenotype. 
Clarification added to exclusion criterion 5 indicating that no 
changes to the AED regimen will be allowed during the first 
24-week period of the study. 
Revision of inclusion criterion 8 to indicate stable dose 
regimen of antiepileptic therapies for 30 days (revised from 
60 days) prior to the Baseline Visit 
Clarification that electroencephalogram at Screening or 
historical EEG for diagnostic confirmation of “epilepsy” 
(revised from “seizures”) will be required in inclusion 
criterion 10.  
Update and 
clarifications 
4 
Section 4.3  
Clarification that, in addition to grapefruit juice, grapefruit will 
also be excluded. 
Clarification 
5 
Section 5.4  
Revision of compliance from 80% - 100% to 80% - 120%. 
Update 

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Item 
No. 
Protocol 
Section 
Version 4/Update 
Reason/ 
Rationale 
6 
Section 7.1 
Update to include return of study drug bottles and 
reconciliation with dosing diary at each visit from Weeks 4 to 
72 
Addition of new footnote (“d”): ECG measurement will be 
performed at 4h postdose, time-matched to PK blood 
collection. 
Revision of the EEG footnote (“e” to reflect EEG for epilepsy 
confirmation must be obtained if historical EEG confirmation 
of epilepsy is not provided. 
Addition to PK footnote for 4h postdose sample at Weeks 48 
and 72. 
Updates 
and 
clarification 
7 
Section 7.1, 
Section 7.1.2.1, 
Section 7.1.2.7, 
Section 7.3, and 
Section 7.4.2 
Revisions to note modified PK sample collection for subjects 
weighing less than 10 kg 
Update 
8 
Section 7.1.2.1, 
Section 7.1.2.7, 
and Section 7.1.3 
Addition to ECG collection indicating that ECG will be 
obtained at 4 hours postdose during each visit, 
time-matched to PK blood collection. 
Update 
9 
Section 7.1.2.2, 
Section 7.1.2.3, 
Section 7.1.2.4, 
Section 7.1.2.5, 
Section 7.1.2.6, 
Section 7.1.2.7, 
and Section 7.1.3 
Addition of review of study drug diary to occur along with 
review of seizure diary 
 
10 
Sections 7.1.3 
and Sections 7.3 
Addition to PK collection indicating that 4h postdose sample 
will be collected at Weeks 48 and 72. 
Update 
11 
Section 7.1.9  
Clarification that, in addition to grapefruit juice, grapefruit will 
also be excluded 
Addition of statement that no changes to the AED regimen 
will be allowed during the first 24-week period. 
Update and 
clarification 
12 
Section 8  
Revision of primary endpoint description to reflect percent 
change from baseline in the motor seizure frequency per 
28 days in the double-blind period for consistency with 
Section 8.4.2. 
Revision to SAP language to indicate analysis to be 
completed prior to database lock instead of prior to last 
subject completing the placebo-controlled phase. 
Update and 
clarification 
13 
Section 8.4.1 
Addition of text regarding presentation of data by treatment 
groups for the double-blind and open-label extension 
periods.  
Clarification 
14 
Section 8.4.2  
Removal of text regarding other seizure frequency based 
continuous endpoints (to focus on primary endpoint only).  
Clarification 
15 
Section 8.4.3  
Revision of language regarding analysis of secondary 
efficacy endpoints to separate key secondary endpoints 
from the other secondary endpoints. 
Clarification 
16 
Section 8.4.8 
Addition of text to indicate that response rates for motor 
seizure and total seizure will be summarized descriptively by 
disease subtype. 
Clarification 
Abbreviations: AED, antiepileptic drug; ECG, electrocardiogram; EEG, electroencephalogram; 
PK, pharmacokinetics; POLG, polymerase subunit gamma; SAP, statistical analysis plan 

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9.3.4. 
Version 4.1: 12 January 2021 
Overall reason for Version 4.1: The overall reasons for Version 4.1 of the protocol were to 
incorporate administrative letters, add a dedicated contraception section, and revise the study 
calendar to add in-person visits. 
Item 
No. 
Protocol 
Section 
Version 4.1/Update 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical error, punctuation, 
tenses, abbreviations) were incorporated to provide clarity. 
The synopsis was updated to be consistent with changes in 
the protocol.  
Update 
2 
Section 3.1.1 
Section 7.1.1 
Clarification added that the sponsor/PTC medical monitor 
will review patient seizure diary entries prior to the run-in 
phase 
Clarification 
3 
Section 4.3 
Revision of exclusion criterion 3 from INR ≥1.5×ULN to INR 
≥ULN at the time of screening 
Addition to exclusion criterion 10 of cross-reference to 
Section 7.5.10  
Update 
4 
Section 6.1 
Addition of spontaneous bleeding and use of prohibited 
concomitant medications as criteria for discontinuation of 
study intervention 
Addition of cross-reference to Section 7.5.10 to 
discontinuation criterion 6 (refusal of sexually active fertile 
subjects [excluding subjects who have been sterilized] to use 
medically accepted methods of contraception) 
Update 
5 
Section 7.1 
Addition of a week 2 telephone visit and change from 
telephone to in-person visits at weeks 4 and 8 
Removal of return of study drug bottles and reconciliation 
with dosing diary from visits at Weeks 28 and 32, Weeks 40 
and 44, Weeks 52 and 56, and Weeks 64 and 68 (telephone 
visits) 
Revision of footnote d to clarify window for ECG collection 
Added clarification in footnote f that weights ending in 
decimals >0.5 should be rounded up to the next whole 
number for dosing calculation 
Addition of statement in footnote g that at-home pregnancy 
test will be provided to be taken at 30 day follow-up and 
self-reported via telephone 
Footnote j added to indicate that SAEs will be assessed from 
the time of the Screening Visit  
Footnotes k and l re-lettered to footnotes l and m, 
respectively 
Updates 
and 
clarifications 
6 
Section 7.1.2.1 
Addition to ECG assessment to indicate that ECG should be 
performed approximately within 10 minutes preceding the 
4-hour PK blood collection 
Clarification that hospitalizations and hospital days for 
disease-related issues will be collected from the time of the 
Screening Visit 
Clarification 
7 
Section 7.1.2.2 
Week 2 visit added  
Update 
8 
Section 7.1.2.3 
Section 7.1.2.4 
Revisions of Week 4 and Week 8 from telephone to 
in-person visits and related revisions of assessments 
Updates 
9 
Section 7.1.2.2 
through 
Section 7.1.2.7 
Section numbers revised to 7.1.2.3 through 7.1.2.8 due to 
addition of new Section 7.1.2.2  
Updates  

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Item 
No. 
Protocol 
Section 
Version 4.1/Update 
Reason/ 
Rationale 
10 
Section 7.1.2.8 
Addition to ECG assessment to indicate that ECG should be 
performed approximately within 10 minutes preceding the 
4-hour PK blood collection 
Clarification 
11 
Section 7.1.3 
Addition to ECG assessment to indicate that ECG should be 
performed approximately within 10 minutes preceding the 
4-hour PK blood collection 
Clarification that drug reconciliation of returned study drug 
bottles with dosing diary will occur every 12 weeks during 
the long-term extension phase 
Clarification 
12 
Section 7.1.4 
Addition of statement indicating that WOCBP will be required 
to perform a study-provided at-home pregnancy test 30 days 
after the last dose of study drug and self-report the results 
via telephone  
Update 
13 
Section 7.1.9 
Addition of the guidelines for use of CYP inducers during 
study treatment 
Clarification 
14 
Section 7.4.3 
Cross-reference to newly added Section 7.5.10 added 
Cross-reference to previous Section 7.5.10 updated to 
Section 7.5.11 
Clarification added that pregnancy test will be conducted at 
Weeks 4.8, 12 and every 12 weeks thereafter. 
Addition of statement that at-home urine pregnancy test kits 
will be provided and 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 
Updates 
15 
Section 7.5.2 
Revision of language regarding reporting adverse events 
leading to hospitalization as SAEs  
Addition of statement that SAEs will be assessed from the 
time of the Screening Visit  
Updates 
16 
Section 7.5.9 
Clarification that SAEs will be collected from the Screening 
Visit through 30 days following the last dose of study drug 
Clarification 
17 
Section 7.5.10 
Addition of new section (Contraception) 
Update 
18 
Section 7.5.12 
Section 7.5.11 renumbered to Section 7.5.12 due to addition 
of new Section 7.5.10 
Update 
Abbreviations: CYP, cytochrome P450; ECG, electrocardiogram; INR, international normalized ratio; 
SAE, serious adverse event; ULN, upper limit of normal; WOCBP, women of childbearing potential 
9.3.5. 
Version 5.0: 31 March 2021 
Overall reason for Version 5.0: The overall reasons for Version 5.0 of the protocol were to add 
PedsQL questionnaire at Weeks 24 and 72; revise the number of study sites from approximately 
12 to approximately 30; clarify that historical EEG may be within 6 months prior to the 
Screening Visit; revise inclusion and exclusion criteria to clarify genetic confirmation of 
mitochondrial disease, clarify use of AEDs, clarify AST and ALT range for subjects with 
underlying Alpers-Huttenlocher syndrome/POLG subtypes, and clarify exclusion of artisanal 
(non-Epidiolex cannabidiol) cannabidiol; add a weight-based dosing table for study drug; and 
clarify that the SAP will be finalized prior to unblinding of the study and revise the text 
regarding the sample size and statistical powering. 

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Item 
No. 
Protocol 
Section 
Version 5/Update 
Reason/ 
Rationale 
1 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical error, punctuation, tenses, 
abbreviations) were incorporated to provide clarity. The 
synopsis was updated to be consistent with changes in the 
protocol.  
Renumbering of Tables 1 through 6 to Tables 2 through 7 due 
to addition of a weight-based dosing table as Table 1. 
Update 
2 
Section 1.4  
Update of number of subjects who have been treated with 
vatiquinone and exposure (in dosing days)  
Update 
3 
Section 1.4.1  
Addition of brief summary of in vitro phototoxicity study 
Update 
4 
Section 1.4.2  
Update of number of patients who have been treated with 
vatiquinone and exposure (in dosing days) 
Revision of age range from 22 days to 70 years to <1 year to 
70 years 
Revision of largest duration of vatiquinone exposure 
Update and 
clarification 
5 
Section 2.1.3  
Addition of section to add an exploratory objective (PedsQL) 
Update 
6 
Section 2.2.3  
Addition of section to add an exploratory endpoint (PedsQL) 
Update 
7 
Section 3.2.2  
Revision of number of study sites from approximately 12 to 30 
Update 
8 
Section 4.2  
Revision of Inclusion Criterion #4 to include subjects with 
genetic confirmation of inherited mitochondrial disease with 
associated epilepsy phenotype (Alpers/POLG, Leigh syndrome, 
MELAS), or other genetically confirmed mitochondrial disease 
secondary to mitochondrial mutations (PCH6, nuclear DNA 
RARS2 mutation), or MERRF, mtDNA MT-TK mutation are 
eligible. 
Removal of the word “ongoing” from the phrase “Despite 
ongoing treatment with at least 2 AEDS” from Inclusion Criterion 
#5 per administrative letter dated 23 February 2021and 
clarification that weight-based adjustments to the AED regimen 
will be allowed 
Update of “Baseline Visit” to “Screening Visit” in Inclusion 
Criteria 7, 8, and 9 
Clarification added to inclusion Criterion #10 that historical EEG 
may be up to 6 months prior to screening 
Update and 
clarification 
9 
Section 4.3  
Revision to exclusion Criterion #2 per administrative letter dated 
09 February 2021 to clarify that AST and ALT can be ≥2×the 
ULN if hepatic transaminases may be associated with the 
underlying mitochondrial disorders like Alpers-Huttenlocher 
syndrome/POLG subtypes and that, in these cases, the AST or 
ALT ≥3×ULN at time of screening will be exclusionary  
Addition to exclusion Criterion #7 to exclude use of artisanal 
(non-Epidiolex cannabidiol) cannabidiol as per administrative 
letter dated 25 November 2020 
Update  
10 
Section 5.1.1  
Addition of Table 1 (Weight-Based Dosing in mL of the 
100 mg/mL Solution)  
Update 
11 
Section 5.1.3  
Addition of section for treatment of missed doses 
Update 
12 
Section 5.3  
Clarification that the study will be unblinded after all subjects 
complete the placebo-controlled phase of the study  
Updated disease subtype #4 to “Other genetically confirmed 
mitochondrial disease secondary to either nuclear or 
mitochondrial DNA mutation” 
Clarification 
13 
Section 5.5  
Addition of guidelines for immunizations as concomitant therapy 
Update 

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Item 
No. 
Protocol 
Section 
Version 5/Update 
Reason/ 
Rationale 
14 
Section 7.1 
(Table 2) 
Addition of PedsQL at baseline and Weeks 24 and 72 
Revision to indicated that EEG will only be done at screening 
and Week 72 
New row inserted to include coagulation panel separately from 
hematology 
Revision to indicate that seizure diary distribution will only occur 
at screening 
Revision to footnote “e” to indicate that historical EEG may be 
up to 6 months prior to screening 
Clarification added in footnote “j” for consistency with SAE 
reporting requirements in Section 7.5.9 
Clarification to footnote “m” to indicate that vatiquinone will be 
dispensed after completing the Week 24 assessments and that 
the subjects will enter the open-label of the study and receive 
vatiquinone for the dose after the visit 
Update and 
clarification 
15 
Section 7.1.1  
Addition of clarification that historical EEG may be done within 
6 months prior to screening  
Clarification 
16 
Section 7.1.2.1  
Section 7.1.2.8  
Section 7.1.3  
Addition of PedsQL questionnaire at baseline and Weeks 24 
and 72 
Update 
17 
Section 7.1.2.3  
Section 7.1.2.4  
Deletion of drug reconciliation of returned study drug bottles 
with dosing diaries for consistency with return of study drug 
bottles being returned every 12 weeks only 
Clarification 
18 
Section 7.1.3  
Clarification that dispense study drug will occur during the 
long-term extension phase will occur on weeks 36, 48, and 60 
Clarification 
19 
Section 7.1.7  
Update of vatiquinone exposure in patient dosing days 
Update 
20 
Section 7.1.9  
Addition of exclusion of the use of artisanal (non-Epidiolex 
cannabidiol) cannabidiol per administrative letter dated 
25 November 2020 
Clarification that weight-based adjustments to the AED regimen 
will be allowed 
Update and 
clarification 
21 
Section 7.2  
Addition of the PedsQL as an efficacy assessment 
Update 
22 
Section 7.4.2  
Separation of coagulation panel into its own subsection from the 
hematology subsection 
Clarification 
23 
Section 7.5.12  Revision of adverse event reporting requirements to include 
SUSAR language 
Clarification 
24 
Section 8  
Revision of paragraph regarding the SAP to indicate that the 
SAP will be finalized prior to unblinding of the study 
Clarification 
25 
Section 8.2  
Revision of text regarding sample size and statistical powering 
Removal of statistical power table  
Clarification 
and update 
26 
Section 8.4.4  
Addition of section for Analysis of Exploratory Endpoint due to 
the addition of PedsQL questionnaire 
Update 
Abbreviations: AED, antiepileptic drug; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
EEG, Electroencephalogram; MELAS, Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; 
MERRF, myoclonic epilepsy with ragged red fibers; mtDNA, mitochondrial DNA; MT-TK, mitochondrially encoded 
tRNA lysine; PedsQL, Pediatric Quality of Life Inventory™; PCH6, Pontocerebellar Hypoplasia Type 6; 
POLG, DNA polymerase subunit gamma; SAE, serious adverse event; SAP, Statistical Analysis Plan; 
SUSAR, suspected unexpected serious adverse reaction; ULN, upper limit of normal 

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9.3.6. 
Version 6.0: 04 June 2021 
Overall reason for Version 6.0: The overall reasons for Version 6.0 were to clarify that male 
subjects must use contraception and that all subjects must use contraceptive measures from the 
time consent is signed until 30 days after treatment discontinuation and to add an appendix of 
prohibited medications.  
Section 
Version 6.0/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. 
Editorial revisions (eg, typographical error, punctuation, tenses, and 
abbreviations) were incorporated to provide clarity. The synopsis was 
updated to be consistent with changes in the protocol.  
Update 
Section 4.3  
Revision to exclusion criterion 2 to increase aspartate transaminase 
and alanine transaminase to ≥3×upper limit of normal and remove 
exception for underlying diseases 
Revision of exclusion criterion 9 to specify that “strong” cytochrome 
P450 inhibitors or inducers are prohibited 
Revision of exclusion criterion 10 to specify that male subjects must 
also use contraception and addition of requirement for use of 
contraception for all subjects from the time consent is signed until 
30 days after treatment discontinuation 
Addition of exclusion criterion 11 to indicate that subjects with 
comorbidities that may confound study results (eg, fat malabsorption 
syndrome, other mitochondrial disorders) in the opinion of the 
investigator will be excluded 
Update and 
clarification 
Section 7.1  
Removal of the option of choosing the time for the post-dose sample 
and specify 4 hours postdose to be done with the 4-hour ECG (for 
subjects weighing <10 kg)  
Removal of hematology panel at the Screening Visit 
Revision of chemistry laboratory assessments to include only alanine 
aminotransferase, aspartate aminotransferase, and creatinine at the 
Screening Visit  
Added electroencephalogram at Week 24 
Update 
Section 7.1.2.1  
Section 7.1.2.8  
Section 7.3  
Removal of the option of choosing the time for the post-dose sample 
and specify 4 hours postdose to be done with the 4-hour ECG (for 
subjects weighing <10 kg)  
Clarification  
Section 7.1.2.8  Added electroencephalogram at Week 24 
Update 
Section 7.1.3  
Removed all timepoints except for 4 hours postdose for PK at Weeks 
48 and 72 
Clarification 
Section 7.4.2  
Revision of total blood volume to be drawn over the course of the study 
and addition of weight-based volumes 
Addition of cross-reference to Table 2 and revision of cross-reference 
from Section 7.1.2.7 to Section 7.1.2.8  
Update and 
Clarification 
Section 7.5.10  
Revision to specify that male subjects must also use contraception and 
addition of requirement for use of contraception for all subjects from the 
time consent is signed until 30 days after treatment discontinuation 
Clarification 
Section 7.5.12  
Revision of section title to indicate “Safety Reporting Requirement” 
Addition of text to indicate notification by PTC to investigators of any 
new or emerging safety information 
Clarification 
Section 9.3.4  
Revision of item numbers 4 through 18 due to previously missing 
number 4 
Clarification 
Appendix 1 
Addition of appendix of prohibited medications 
Update 

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9.3.7. 
Version 7.0: 06 January 2022 
Overall reason for Version 7.0: The overall reason for Version 7.0 was to incorporate feedback 
from health authorities. 
Section 
Version 7.0/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. 
The synopsis was updated to be consistent with changes in the 
protocol. Editorial revisions (eg, typographical errors, punctuation, 
tenses, and abbreviations) were incorporated to provide clarity. 
Update 
Section 4.2  
Inclusion criterion #2 was updated to include subjects <21 years of 
age. 
Inclusion criterion #6 was updated to “Documented medical history of 
epilepsy associated with mitochondrial disease for at least 6 months 
prior to screening except for subjects who are <2 years of age at 
the time of screening (Subjects <2 years of age can be 
considered for enrollment if all other screening criteria are met 
due to the potential for rapid progression in these subjects)”.  
Update 
Section 4.3  
Exclusion criterion #3 which read, “INR ≥ULN at time of screening”, 
was revised to read “INR >ULN at time of screening”. 
Update 
Section 5.1.1  
Section 7.1 
It was corrected that weights ending in decimals ≥0.5 (instead of 
>0.5, as stated previously) should be rounded up to the next whole 
number for dosing calculation. 
Update 
Section 7.1  
Section 7.1.2.8  
It was specified that informed consent for subjects entering the long-
term extension phase would be completed at Week 24. 
Update 
Section 7.1.3  
It was clarified that EEG is to be collected at Week 72, as already 
specified in Table 2. 
Clarification 
Section 7.4.1  
The text was updated to specify that weight could also be collected in 
lb and height could also be collected in inches. 
Update 
Section 7.4.2  
The total volume of blood collected as written in V6.0 is incorrect and 
has now been corrected. 
Update 
9.3.8. 
Version 8.0: 27 May 2022 
Overall reason for Version 8.0: The overall reason for Version 8.0 was to remove “a minimum 
number of 6 subjects” per mitochondrial disease subtype category and clarify the blinding of the 
investigators, study subjects, and sponsor during the placebo-controlled and open-label phases of 
the study. 
Section 
Version 8.0/Update 
Reason/ 
Rationale 
Protocol 
The version number and date were updated throughout. 
The synopsis was updated to be consistent with changes in the 
protocol. Editorial revisions (eg, typographical errors, punctuation, 
tenses, and abbreviations) were incorporated to provide clarity. 
Relevant updates to the study personnel and approval signatures 
pages were made. 
Update 
Section 3.1.2   
The following text was removed: “A minimum of 6 subjects 
(approximately) will be allocated to category 1), 2), and 3), 
respectively.” 
Update 

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Section 
Version 8.0/Update 
Reason/ 
Rationale 
Section 5.3  
The blinding of the investigators, study subjects, and sponsor was 
clarified with the following text: “The investigators, study subjects, and 
sponsor will be blinded as follows: the sponsor will be blinded to the 
randomized treatment until the study is unblinded after all subjects 
complete the placebo-controlled phase; subjects and investigators 
remain blinded to the treatment received during the placebo-
controlled phase until after all subjects complete the open-label 
phase. An independent Data Safety Monitoring Board (DSMB) will 
monitor the study until completion of the placebo-controlled phase of 
the study.” 
Clarification 
Section 7.1  
The following clarifying text was added to footnote “g” of Table 2 : “If 
a subject cannot perform a urine pregnancy test at any timepoint, a 
serum pregnancy test should be performed.” 
Clarification 
Section 7.1.2 
Section 7.1.3  
The following clarifying text was added to the relevant timepoints: “If a 
subject cannot perform a urine pregnancy test, a serum pregnancy 
test should be performed.” 
Clarification 
Section 7.4.3  
The following text was added for clarification: “If a  subject cannot 
perform a urine pregnancy test at any timepoint, a serum pregnancy 
test should be performed.” 
Clarification 
 

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10. 
REFERENCES 
Abeti, R, Parkinson, MH, Hargreaves, IP, Angelova, PR, Sandi, C, Pook, MA, et al. 
'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'. 
Cell Death Dis 2016;7:e2237. 
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. 
Dixon, SJ, Lemberg, KM, Lamprecht, MR, Skouta, R, Zaitsev, EM, Gleason, CE, et al. 
Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149(5):1060-1072. 
Enns, GM, Kinsman, SL, Perlman, SL, Spicer, KM, Abdenur, JE, Cohen, BH, et al. Initial 
experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab 
2012;105(1):91-102. 
Friedmann Angeli, JP, Schneider, M, Proneth, B, Tyurina, YY, Tyurin, VA, Hammond, VJ, et al. 
Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 
2014;16(12):1180-1191. 
Guiney, SJ, Adlard, PA, Bush, AI, Finkelstein, DI and Ayton, S. Ferroptosis and cell death 
mechanisms in Parkinson's disease. Neurochem Int 2017;104:34-48. 
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. 
Ingold, I, Berndt, C, Schmitt, S, Doll, S, Poschmann, G, Buday, K, et al. Selenium Utilization by 
GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell 2018;172(3):409-
422.e421. 
Joshi, YB, Giannopoulos, PF and Pratico, D. The 12/15-lipoxygenase as an emerging therapeutic 
target for Alzheimer's disease. Trends Pharmacol Sci 2015;36(3):181-186. 
Kagan, VE, Mao, G, Qu, F, Angeli, JP, Doll, S, Croix, CS, et al. Oxidized arachidonic and 
adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 2017;13(1):81-90. 
Menon, B, Ramalingam, K and Kumar, RV. Oxidative stress in patients with epilepsy is 
independent of antiepileptic drugs. Seizure 2012;21(10):780-784. 
Milder, J and Patel, M. Modulation of oxidative stress and mitochondrial function by the 
ketogenic diet. Epilepsy Res 2012;100(3):295-303. 
Sanders, LH and Timothy Greenamyre, J. Oxidative damage to macromolecules in human 
Parkinson disease and the rotenone model. Free Radic Biol Med 2013;62:111-120. 
Saneto, RP. Journal of Inborn Errors of Metabolism and Screening 2017;5:1-12. 
Seiler, A, Schneider, M, Forster, H, Roth, S, Wirth, EK, Culmsee, C, et al. Glutathione 
peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-
mediated cell death. Cell Metab 2008;8(3):237-248. 
Stockwell, BR, Friedmann Angeli, JP, Bayir, H, Bush, AI, Conrad, M, Dixon, SJ, et al. 
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. 
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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. 
Wirth, EK, Conrad, M, Winterer, J, Wozny, C, Carlson, BA, Roth, S, et al. Neuronal 
selenoprotein expression is required for interneuron development and prevents seizures and 
neurodegeneration. Faseb j 2010;24(3):844-852. 
Yang, WS, SriRamaratnam, R, Welsch, ME, Shimada, K, Skouta, R, Viswanathan, VS, et al. 
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APPENDIX 1. PTC743-MIT-001-EP PROHIBITED MEDICATION LIST 
Table 7: 
PTC743-MIT-001-EP Prohibited Medication List 
Prohibited Medications  
Examples 
Anticoagulants  
• 
heparin 
• 
warfarin 
• 
aspirin 
• 
clopidogrel 
• 
apixaban 
• 
dabigatran 
• 
edoxaban 
• 
enoxaparin 
• 
rivaroxaban 
CYP3A4 strong inducers 
• 
apalutamide 
• 
carbamazepine 
• 
enzalutamide 
• 
mitotane 
• 
phenytoin 
• 
rifampin 
• 
St. John’s wort 
CYP3A4 strong inhibitors 
• 
boceprevir 
• 
cobicistat 
• 
danoprevir and ritonavir 
• 
elvitegravir and ritonavir 
• 
grapefruit juice (any grapefruit product) 
• 
indinavir and ritonavir 
• 
itraconazole 
• 
ketoconazole 
• 
lopinavir and ritonavir 
• 
paritaprevir and ritonavir and (ombitasvir and/or 
dasabuvir) 
• 
posaconazole 
• 
ritonavir 
• 
saquinavir and ritonavir 
• 
telaprevir 
• 
tipranavir and ritonavir 
• 
telithromycin 
• 
troleandomycin 
• 
voriconazole 
• 
clarithromycin 
• 
idelalisib 
• 
nefazodone 
• 
nelfinavir 
Investigational medications for MIT-E 
 
Idebenone 
 

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Prohibited Medications  
Examples 
Artisanal (non-Epidiolex cannabidol) 
 
Abbreviations: CYP3A4, cytochrome P450 3A4 
Note: This list is neither comprehensive, nor final. In general, study subjects should not be taking any strong 
CYP3A4 inhibitors or inducers, anticoagulants, or any investigational medications.