Clinical trial NCT02462603
Conditions: Parkinson's Disease
Keywords: Parkinson's Disease PD EPI-589 EPI589
Sponsor: Edison Pharmaceuticals Inc
Start date: 2016-05-17; Completion date: 2019-01-08
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Open-label study with 30-day run-in phase and adaptive design component to include more participants if deemed appropriate by investigators.

Detailed description:
This is a within-subject, controlled open-label study seeking to determine if PTC-589 can alter the biochemical signature of Parkinson's disease as assessed by peripheral blood biomarkers, central nervous system (CNS) biomarkers, and urine biomarker analysis. In addition, data on a number of disease-relevant clinical measures will be collected.

Arms: arm 1: Participants with Parkinson's disease (idiopathic and mitochondrial genetic subtype participants) will receive PTC589 at a dose of 500 milligrams (mg) (2 tablets of 250 mg each) orally twice daily (BID) for up to 3 months unless discontinued for safety or tolerability issues.
Interventions: intervention 1: PTC-589
Intervention descriptions: intervention 1: PTC-589 is a redox active molecule and will be provided in a 250 mg tablet formulation.

Protocol documents:
Prot_000.pdf: 
EPI589-15-002 
16.1 Study Information 
NCT# NCT02462603 
 
 
 
1. 
PROTOCOL AND PROTOCOL AMENDMENT 
 
 
Document Date 
Document Name 
29 September 2017 
EPI589-15-002 Protocol Amendment Version 5.0 
29 September 2017 
EPI589-15-002 Protocol Amendment SOC Version 4.0 to 5.0 
17 February 2017 
EPI589-15-002 Protocol Amendment Version 4.0 
17 February 2017 
EPI589-15-002 Protocol Amendment SOC Version 3.0 to 4.0 
10 October 2016 
EPI589-15-002 Protocol Amendment Version 3.0 
10 October 2016 
EPI589-15-002 Protocol Amendment SOC Version 2.0 to 3.0 
04 January 2016 
EPI589-15-002 Protocol Amendment Version 2.0 
04 January 2016 
EPI589-15-002 Protocol Amendment SOC Version 1.0 to 2.0 
09 September 2015 
EPI589-15-002 Protocol Amendment Version 1.0 
09 September 2015 
EPI589-15-002 Protocol Amendment SOC Version Original to 1.0 
27 April 2015 
EPI589-15-002 Protocol Version Original 
Abbreviations: SOC, summary of changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V1.0 
PTC Therapeutics Inc. - Confidential 
Page 1 of 1 


௭ 
 
 
 
 
EPI589-15-002 
A Phase 2A Safety 
and Biomarker Study of 
EPI-589 in Mitochondrial 
Subtype and Idiopathic 
Parkinson's Disease Subjects 
 
 
 
Original Protocol: 
Protocol Amendment 1.0: 
Protocol Amendment 2.0: 
Protocol Amendment 3.0: 
Protocol Amendment 4.0: 
Protocol Amendment 5.0: 
27 April 2015 
09 September 2015 
04 January 2016 
10 October 2016 
17 February 2017 
29 September 2017 
 
BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
The information contained in this document is confidential and will not be disclosed to others without 
written authorization from BioElectron except to the ex,tent necessary to obtain informed consent from 
tltose persons to wltom tile drug may be administered or for discussions with local regulatory authorities, 
Et/tics Committee/lnvestigational Review Boards, or people participating in lite conduct of the study. 


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Table of Contents 
I. PROTOCOL SYNOPSIS .................................................................................................. 6 
II. SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE ................................ 12 
A. Schedule of Dosing ...................................................................................................... 13 
III. INTRODUCTION ........................................................................................................... 14 
A. Background Information and Rationale................................................................... 14 
B. Rationale for the Study of EPI-589 in Parkinson’s Disease .................................... 15 
C. Name and Description of Investigational Product ................................................... 15 
D. Findings from Non-Clinical and Clinical Studies .................................................... 16 
D1. Non-Clinical Studies .................................................................................................. 16 
D2. Clinical Studies ........................................................................................................... 19 
E. Human Pharmacokinetics ............................................................................................ 20 
F. 
Clinical Study .............................................................................................................. 20 
G. Selection of Drugs and Dosages ................................................................................. 20 
H. Compliance Statement ................................................................................................ 20 
I. 
Relevant Literature and Data .................................................................................... 21 
IV. STUDY OBJECTIVES ................................................................................................... 22 
A. Primary Objective ...................................................................................................... 22 
B. Secondary Objectives .................................................................................................. 22 
V. INVESTIGATIONAL PLAN ......................................................................................... 23 
A. General Schema of Study Design .............................................................................. 23 
A1. Screening Phase ......................................................................................................... 23 
A2. 30-Day Run-in Phase ................................................................................................. 23 
A3. Baseline ...................................................................................................................... 23 
A4. Treatment Phase ........................................................................................................ 23 
A5. End of Treatment........................................................................................................ 24 
A6. Post-Treatment Follow-up ......................................................................................... 24 
B. Randomization and Blinding ..................................................................................... 24 
C. Study Duration, Enrollment and Number of Sites .................................................. 24 
C1. Duration of Subject Treatment ................................................................................... 24 
C2. Total Number of Study Sites/Total Number of Subjects Projected ............................ 24 
D. Study Population ......................................................................................................... 25 


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D1. Inclusion Criteria ....................................................................................................... 25 
D2. Exclusion Criteria ...................................................................................................... 25 
VI. STUDY PROCEDURES ................................................................................................. 27 
A. Screening Visit ............................................................................................................ 27 
A1. Run-in Assessments ..................................................................................................... 27 
B. Treatment Phase ......................................................................................................... 28 
B1. Baseline Assessments ................................................................................................. 28 
B2. Study Visit Assessments .............................................................................................. 28 
B3. Pharmacokinetics** ................................................................................................... 30 
B4. Early Termination Study Visit .................................................................................... 30 
C. End of Treatment Visit ............................................................................................... 30 
D. Post-Treatment Follow-up ......................................................................................... 30 
E. Unscheduled Visits ...................................................................................................... 30 
F. 
Concomitant Medication ............................................................................................ 30 
G. Prohibited Medications .............................................................................................. 31 
H. Subject Withdrawals .................................................................................................. 31 
VII. STUDY ENDPOINTS AND EVALUATIONS ............................................................. 33 
A. Primary Endpoint ....................................................................................................... 33 
B. Secondary Endpoints (Efficacy) ............................................................................... 33 
C. Secondary Endpoints (Safety) ................................................................................... 33 
D. Screening and Baseline Evaluation ........................................................................... 33 
D1. Physical Examination, height and weight .................................................................. 33 
D2. Laboratory Evaluations ............................................................................................. 34 
D3. Dose Limiting Toxicity (DLT) .................................................................................... 35 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) .................................................... 35 
E. Sample Collection Procedures, Bioanalytical Methods and Sample Shipment .... 35 
F. 
Efficacy Evaluations ................................................................................................... 36 
F1. Fasting Glutathione Cycle Biomarkers ...................................................................... 36 
F2. Study Clinical Assessments ........................................................................................ 36 
VIII. 
STATISTICAL CONSIDERATIONS ................................................................... 38 
A. Statistical Analysis ...................................................................................................... 38 
A1. Analysis Populations ................................................................................................... 38 


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B. Efficacy Analysis ......................................................................................................... 38 
B1. Efficacy Variables ...................................................................................................... 38 
C. Safety Analysis ............................................................................................................ 38 
D. Sample Size .................................................................................................................. 39 
IX. STUDY MEDICATION ................................................................................................... 40 
A. Description ................................................................................................................... 40 
B. Packaging .................................................................................................................... 40 
B1. Labeling ..................................................................................................................... 40 
B2. Dosage Form .............................................................................................................. 40 
B3. Dispensing.................................................................................................................. 40 
C. Treatment Compliance and Adherence .................................................................... 40 
D. Drug Accountability ..................................................................................................... 40 
X. SAFETY MANAGEMENT ............................................................................................ 42 
A. Clinical Adverse Events ............................................................................................. 42 
B. Adverse Event Reporting ........................................................................................... 42 
B1. Safety Guidance ......................................................................................................... 42 
C. Definition of an Adverse Event .................................................................................. 42 
C1. Adverse Event ............................................................................................................. 42 
C2. Definition of a Serious Adverse Event (SAE) ............................................................. 43 
C3. Non-serious Adverse Event ........................................................................................ 44 
C4. Definition of Relationship to Study Medication .......................................................... 44 
C5. Definition of Severity ................................................................................................. 44 
C6. Definition of Unexpected Adverse Event .................................................................... 45 
C7. Notification of SAEs ................................................................................................... 45 
C8. Follow-up Report ....................................................................................................... 46 
C9. Dose Modification Guidelines ................................................................................... 46 
D. Medical Emergencies .................................................................................................. 47 
D1. Emergency Sponsor Contact ...................................................................................... 47 
D2. Emergency Treatment ................................................................................................ 47 
XI. STUDY ADMINISTRATION ........................................................................................ 48 
A. Treatment Assignment Methods ............................................................................... 48 
B. Data Collection and Management .............................................................................. 48 


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C. Data Quality Assurance ............................................................................................. 48 
D. Retention of Study Records ....................................................................................... 49 
E. Confidentiality ............................................................................................................. 49 
F. 
Documentation of Study Results ............................................................................... 50 
G. Regulatory and Ethical Considerations .................................................................... 50 
G1. Risk Assessment .......................................................................................................... 50 
G2. Potential Benefits of Trial Participation .................................................................... 50 
G3. Risk-Benefit Assessment ............................................................................................. 50 
H. Informed Consent ....................................................................................................... 51 
XII. PUBLICATION .............................................................................................................. 52 
A. Use of Study Results ................................................................................................... 52 
XIII. 
LIST OF ABBREVIATIONS ................................................................................. 54 
XIV. 
SIGNATURE OF SPONSOR ................................................................................. 56 
A. Declaration of Sponsor ................................................................................................ 56 
XV. REFERENCES ................................................................................................................ 57 
 
 
 
 
 
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USA 
USA 
USA 
Germany 
 
I. 
PROTOCOL SYNOPSIS 
Title of study 
A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial 
Subtype and Idiopathic Parkinson’s Disease Subjects 
 
Protocol number 
EPI589-15-002 
 
IND number 
EudraCT number 
126,795 
2015-001786-10 
 
Original Protocol 
Protocol Amendment 1.0 
Protocol Amendment 2.0 
Protocol Amendment 3.0 
Protocol Amendment 4.0 
Protocol Amendment 5.0 
27 April 2015 
09 September 2015 
04 January 2016 
10 October 2016 
17 February 2017 
29 September 2017 
 
Investigative Drug 
EPI-589 
 
Study Sponsor 
 BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
Investigators and 
• 
Investigative Sites 
• 
• 
UK 
• 
• 
 
Study population 
Approximately 40 subjects with Parkinson’s disease (PD) including 20 
subjects with genetically-defined subtypes 


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Rationale for Study 
Mitochondrial pathophysiology 
It is now well appreciated that defects in mitochondrial function contribute 
to the pathophysiology of PD both in subjects with defined genetic defects 
as well as those with idiopathic forms of the disease. 
High morbidity 
Despite the available therapies for symptomatic relief, PD remains a highly 
morbid disease. There are no approved treatments for PD capable of 
modifying disease progression. 
Pre-clinical efficacy data 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 < 
100nM) and efficacy (>80% rescue from oxidative stress-induced cell 
death) in cells derived from patients diagnosed with idiopathic and familial 
PD subtypes including PINK1, parkin and LRRK2. 
 
Study objectives 
Primary Objective 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of 
drug-related serious adverse events in subjects with PD. 
Secondary Objectives 
To evaluate the effects of EPI-589 in subjects with PD on: 
 
1. Fasting glutathione cycle biomarkers as measured in blood, cerebral 
spinal fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society- 
sponsored revision of the Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale 
(NMSS), PDQ-39 and EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment 
(MoCA) and 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the 
Montgomery and Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 


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Study design 
Open-label study with 30-day run-in phase. 
 
Planned number of 
subjects 
Approximately 40 subjects (20 with genetically-defined subtypes of PD 
and 20 idiopathic PD subjects). (Adaptive design component allows 
enrollment of up to 20 additional subjects with idiopathic PD to try to 
achieve a total of 20 subjects that have a biomarker response to EPI-589.) 
 
Study duration 
3 months (85 days ± 3 days) of study treatment preceded by a 1-month 
baseline parameter run-in period. 
 
Test product, mode of 
administration, and dose 
Test product 
EPI-589 in a tablet formulation at a strength of 250 mg 
Mode of Administration 
Oral with meal 
Dose 
EPI-589 500-mg BID (morning and evening dose along with food) 
 
Reference therapy, dose, 
and mode of 
administration 
None 
 
Safety monitoring 
Clinical 
 
1. Physical exam and vital signs 
2. Evaluation of adverse events 
3. 12-lead Electrocardiogram 
4. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
 
Laboratory 
 
1. Routine serum chemistries 
2. Routine hematology tests and coagulation tests 


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Inclusion criteria (all 
subjects) 
1. Hoehn and Yahr stage ≤ 3.0 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners must agree to use 
medically accepted methods of contraception (e.g., hormonal methods, 
including oral, subcutaneous, and intrauterine; barrier methods, 
including 
condom, 
condom, or diaphragm with 
spermicidal gel) during the course of the study and for 3 months after 
the last dose of study treatment. 
4. Willingness and ability to comply with study procedures 
5. If on medications for PD drugs, then medication regimen must be stable 
for 60 days prior to enrollment 
6. Abstention from use of other investigative or non-approved drugs for 
the duration of the trial 
For Idiopathic Subjects 
7. A diagnosis of idiopathic PD confirmed by the presence of bradykinesia 
plus one or both of the following symptoms: rigidity or resting tremor; 
and with an abnormal DaTscan consistent with a dopaminergic deficit 
8. Age 40 to 75 years 
9. Within 5 years of diagnosis of Parkinson’s disease 
For Genetic Subtype Subjects 
10. A confirmed diagnosis of PD plus a genetic diagnosis consistent with 
PD, specifically PINK1, parkin, LRRK2 or other mitochondrial genetic 
subtype 
11. Age 21 to 75 years 
 
Exclusion criteria 
1.  Allergy to EPI-589 or other components of the EPI-589 tablet 
formulation 
2. Use of antioxidant supplements, specifically vitamins E and C beyond 
the recommended daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that will 


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confound the assessment of effect of study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper 
limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial of 
a device, drug or other therapy for PD 
 
Treatment 
Following study enrollment, baseline assessments will be performed. 
Subjects will participate in a 30-day run-in phase to establish biomarker 
and clinical baseline measurements. EPI-589 will then be administered for 
up to 3 months (85 days ± 3 days) unless discontinued for safety or 
tolerability issues. Post-treatment follow-up will be at least 10 days and 
up to 30 days after last dose. 
Efficacy variables 
1.  Fasting blood-based glutathione biomarkers 
2. Fasting CNS biomarkers 
3. Fasting urine-based biomarkers 
4. MDS-UPDRS 
5. Non-motor Symptoms Scale (NMSS) 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. Beck Depression Inventory (BDI) 
10. Montgomery & Asberg Depression rating scale (MADRS) 
11. Timed motor tests in ON state only (for subjects on dopamine therapy) 
12. Pharmacokinetics 


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Safety variables 
Clinical 
 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
4. C-SSRS 
5. Routine serum chemistries with liver function tests 
6. Routine hematology tests with coagulation tests 
 
 
Statistical Considerations 
Data Analysis 
This is a within-subject, controlled open-label study seeking to determine 
the safety and tolerability of EPI-589 in patients with PD as well as to 
determine if EPI-589 can alter the biochemical signature of PD as assessed 
by peripheral blood biomarkers, CNS biomarkers, brain imaging 
biomarkers, and urine biomarker analysis. In addition, data on a number of 
disease-relevant clinical measures will be collected. 
 
 
 
 
 
Space Intentionally Left Blank 


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II. 
SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE 
 
 
 
Tests 
-2 to -1 Months 
DayO 
Month 1 
Month 2 
Month3 
End of Treatment 
Visit 
Post-Treatment 
Follow-up 
Screening 
Run-in 
(upto 30 
days from 
screenin2) 
Baseline (27-33 
days from run-in
Day29 
(±3 days) 
Day 57d 
(± 3 days) 
Day85 
(±3 days) 
Up to 30Days 
afte1·Last Dose•
Informed consent 
Day 1 
First 
Dosei 
Inclusion/Exclusion criteria 
Past Medical history 
Pre:wous genetic testing 
review 
Physical examh & Vital signs 
h 
Heightg & weight 
g 
• 
12-lead ECG 
• 
Hematology (including 
coagulation panel) 
a,f 
f 
f 
Semm Chemistiy 
a,f 
f 
f 
Pregnancy test" 
C-SSRS 
Monti·eal Cognitive 
Assessment 
DaTscan (for idiopathic 
subjects) 
Revised Hamilton Rating 
Scale for Depression 
Subject enrolls in study 
X 
Fasting blood-based 
glutathione cycle biomarkers 
Fasting Lumbar puncture 
(CNS biomarkers) 
Fasting Urine-based 
biomarkers 
MDS-UPDRS 
Timed motor tests (for 
subjects on dopaniine therapy) 
NMSS, PDQ-39, EQ-5D 
BDI,MADRS 
Dmg plasma concenti·ation° 
c 
c 
AE/SAE assessment 
• 
• 
• 
d 
d 
• 
Concomitant medications 
assessment 
d 
d 
• 
Post-Treatment Assessments• 
• 
a. 
Screening values can be used if done w-ithin one month of baseline and if completed under fasted conditions 
- Female subjects of childbea1mg potential must have a negative pregnancy test. 
C. 
Full plasma concenti·ation profile w-ill be obtained at Time= 0, and 0.5, I, 2, 4, 6, 8, and12 hours after dosing from the first 10 subjects to complete 
I month of therapy at each site.12 hour PK can be obtained at time 0. 
d. 
 Month 2 assessments can be done by telephone. Any new AEs and associated concomitant medications reported at Month 3 must be followed for 30 
days; this follow up may be conducted by telephone. 


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A. 
Schedule of Dosing 
 
 
 
-2 to -1 Months 
Day0 
Month 1 
Month2 
Month3 
Post-Treatment 
Dosing Schedule 
Screening 
Run-in 
(±30 days) Baseline
Day29 
(±3 days) 
Day 57d 
(±3 days) 
Day85 
(±3 days) 
Up to30 Days 
after Last Dose• 
 
EPI-589 500-mg BID (hvice daily 
with food) 
Dispense Study Drug 
Dmg Reconciliation with diaries 
e. 
AE/SAE and concomitant medication assessments conducted bytelephone for at least 10 days after last dose and if there are any ongoing or 
new AEs noted at month 3, then the follow up will be up to 30 days after last dose. Additional assessments detemiined at Investigator 
discretion. SAEs are tracked from the time ICF is signed and all other AEs are tracked from the time first dose is administered; 
f. 
TI1e baseline and all subsequent laboratory assessments should be obtained under fasting conditions. 
g. Height is measured at screening visit only. 
h. The findings from breast exam will be captured as pa1t of the screening physical exam. The findings from breast exams conducted 
within 6 months of the screening visit and those collected as pa1t of medical history, may be used for the screening physical exam. 
1. 
First dose may be taken same day as baseline visit after all baseline assessments are completed 


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III. INTRODUCTION 
A. 
Background Information and Rationale 
 
Parkinson’s disease (PD) is a highly morbid neurodegenerative movement disorder that has a 
number of neuromuscular, cognitive and neuropsychiatric manifestations as well as non- 
neurological symptoms. PD is the second most common neurodegenerative disorder with an 
estimated prevalence of 6.3 million people worldwide (EPDA). 
 
PD has long been considered a non-genetic (idiopathic) disease; however, about 5% of patients 
have an identifiable mutation. Disease onset typically occurs after age 50, however, in a subset of 
patients, disease onset can occur at a younger age. The primary motor symptoms result from 
death of dopamine-producing cells in the pars compacta region of the substantia nigra. However, 
the mechanisms underlying this cell death and disease pathology remain poorly understood. 
There is no approved treatment for PD capable of modifying disease progression. Current 
therapies partially address disease motor symptoms through levodopa or dopamine agonists or 
other agents, and other disease symptoms (e.g. neuropsychiatric symptoms), but disability tends 
to increase over time despite these treatments. 
 
The association of PD with mitochondrial pathology and high levels of oxidative stress are well 
established. Increased levels of oxidative stress have been consistently measured in post-mortem 
specimens from PD patients (Maarouf 2012, Reale 2012). The occurrence of PD-like symptoms 
in heroin addicts exposed to MPTP in the 1980s established a first link between PD and 
mitochondrial injury (Langston 1983, Dauer and Przedborski 2003). MPTP inhibits complex 1 of 
the mitochondrial respiratory chain and induces degeneration of dopaminergic cells through 
oxidative stress-mediated injury. The link between mitochondrial injury and PD was further 
strengthened by the induction of PD symptoms following exposure to another neurotoxic 
complex 1 inhibitor, rotenone (Betarbet et al 2000, Greenamyre et al. 2003), which like MPTP 
has come to be used in pre-clinical testing for its phenotypic similarities to PD. 
 
Furthermore, the identification of genetic mutations such as PINK1, parkin, LRRK2 and others 
in mitochondrial genes in familial PD patients provided the strongest link between the 
mitochondria and PD (Winklhofer and Haass 2010). Normally these genes influence oxidative 
balance and provide neural protection of the dopaminergic neurons that are affected by PD. 
PINK1 and parkin are involved in protecting against oxidative stress (OS) and overabundant 
reactive oxygen species (ROS), and are implicated in cell morphology and dynamics, as well as 
in the preferential degradation of dysfunctional mitochondria or “mitophagy” (Ashrafi et al. 
2014). Mutant LRRK2 leads to the accumulation of misfolding intracellular protein 
accumulations, cell stress and apoptosis (Giasson et al. 2006, Zhu et al. 2006). 
 
The importance of oxidative stress in PD pathology is further substantiated by the measurement 
of decreased levels of reduced glutathione in the brains of patients with PD (Holmay et al. 2013). 
Glutathione levels are low at very early stages of PD and correlate with disease severity 
(Riederer et al. 1989), and experimental induction of glutathione depletion leads to mitochondrial 
complex I dysfunction (Jha et al, 2000;). Reduced glutathione is an essential intermediary 


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metabolite that serves as the primary native cellular antioxidant. In a state of high oxidative 
stress, elevated levels of ROS outstrip the supply of glutathione (GSH) resulting in depletion of 
GSH and ROS-mediated cell death. 
 
Given the important role of oxidative stress and mitochondrial pathology in PD, a redox-active 
therapy that could target key pathways in cellular OS response pathways may hold promise for 
the treatment of PD. 
 
B. 
Rationale for the Study of EPI-589 in Parkinson’s Disease 
 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 <100nM ) and efficacy 
(>80% rescue from oxidative stress-induced cell death) in cells derived from patients diagnosed 
with idiopathic and familial PD genetic subtypes including PINK1, parkin and LRRK2. 
In these cell-based assays, primary fibroblasts from patients (and control) were pre-incubated 
with and without test compound, then treated with L-buthionine-(S,R)-sulfoximine (BSO), a 
GSH synthesis inhibitor, to initiate depletion of cellular GSH. GSH depletion has been shown to 
lead to OS and disruption of calcium homeostasis resulting in loss of the mitochondrial 
membrane potential and cell death. Under these conditions, the control cells are resistant to the 
stress and the fibroblast cells from patients with disease indications die within 36 to 48 hours. 
Pretreatment of cells with EPI-589 prior to initiation of GSH depletion potently protected against 
oxidative stress-mediated cell death, with EC50 response concentrations of 16 to 52 nM. (Table 
1). 
Table 1: 
Cell Line Rescue with EPI-589 in Parkinson’s Disease Genetic Subtypes 
 
EPI-589 EC50 (nM range) 
PINK1 
26-36 
LRRK2 
16-18 
parkin 
42-52 
 
C. 
Name and Description of Investigational Product 
The IUPAC name of EPI-589 is: 
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide. 
 
A common chemical name of EPI-589 is (R)-troloxamide quinone. EPI-589 is derived from 
resolved (R)-Trolox®, a derivative of vitamin E in the form of a pale yellow to yellow solid. The 
EPI-589 drug product will be provided in a 250-mg tablet formulation. 
 
The Investigator will ensure that all study drugs are stored and dispensed in accordance with the 
Food and Drug Administration (FDA) and local regulations concerning the storage and 
administration of investigational drugs. 


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D. 
Findings from Non-Clinical and Clinical Studies 
D1. Non-Clinical Studies 
 
EPI-589 is an orally available compound that has been demonstrated in vitro and in vivo to cross 
the blood-brain-barrier. In 28-day, 91-day, 6-month, and 9-month repeat-dose toxicity studies in 
rat and cynomolgus monkey, the no observed adverse effect level (NOAEL) was 300 mg/kg/day, 
corresponding to terminal combined mean Cmax values of 37,717 to 56,500 ng/mL (rat) and 
14,300 to 24,500 ng/mL (monkey), and terminal combined mean area under the plasma 
concentration-time curve (AUC) values of 149,495 to 297,000 ng.h/mL (rat) and 47,300 to 
124,000 ng.h/mL (monkey) (Studies 1660-038, 1660-039, 1660-063, 1660-064, 1660-079, and 
1660-080). 
 
The dose-limiting drug-associated toxicity observed in the 28-day, 3-month, and 9-month 
(monkey) animal studies was hemolysis in rat and significant acute toxicity leading to 
moribundity with indication of skeletal, renal, liver, and lymphoid tissue effects in monkey. All 
clinical program investigators have been required to monitor hematology parameters and clinical 
chemistry parameters for kidney, liver, and muscle function in all EPI-589 subjects. To date, no 
dose-limiting toxicities have been reported with EPI-589 in humans. 
 
A phase 1 clinical study demonstrated that healthy young and elderly subjects administered 
500 mg EPI-589 BID for 14 days showed mean Cmax values of 1,890 to 1,960 ng/mL and mean 
AUC values of 10,480 to 11,000 ng.h/mL (Study EPI589-14-01). These plasma concentrations 
are well below the 300 mg/kg/day NOAEL exposure values in monkey, the most sensitive 
toxicity species, corresponding to repeat-dose exposure safety margins of approximately 7- to 
12- fold for the mean Cmax and 4- to 8-fold for the mean AUC. 
 
During the 9-month repeat-dose toxicity study in monkey, animals were administered 60, 100, 
300, or 500 mg/kg/day EPI-589 PO (Study 1660-080). The NOAEL was 300 mg/kg/day. 
Monkeys that received 500 mg/kg/day showed significant test-article related moribundity after 
receiving only three or four doses resulting in three animals being euthanized on Days 4, 5, and 7 
and the remaining animals being euthanized on Day 11. Animals exhibited significant elevations 
in AST and ALT values, and microscopic findings in multiple sites in the skeletal muscle, 
kidney, liver, and lymphoid tissues. The primary cause of morbidity in the three animals 
euthanized on Days 4, 5, and 7 was myofiber degeneration and degenerative changes in kidney 
(3/3 animals). The toxicity observed following administration of three to four doses of 
500 mg/kg/day EPI-589 were similar and consistent with toxicity observed following 
administration of two doses of 1,000 mg/kg/day during the 28-day toxicity study (Study 1660- 
038), likely due to similar exposures between the two doses. The margin of exposure between 
healthy young and elderly humans exposed to 500 mg BID EPI-589 (relevant clinical dose) for 
14 days (Study EPI589-14-01) and monkeys exposed to EPI-589 PO on Day 1 is approximately 
26-fold for the mean Cmax and 21-fold for the mean AUClast at 500 mg/kg, and approximately 29- 
fold for the mean Cmax and 27-fold for the mean AUClast at 1,000 mg/kg. 


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During the 6-month repeat-dose toxicity study in rat, animals were exposed to up to 300 
mg/kg/day EPI-589 PO (Study 1660-079). The NOAEL was 300 mg/kg/day. Rats exposed to 
300 mg/kg/day exhibited mild test-article related effects on hematology parameters consistent 
with hemolysis and compensating reticulocytosis. These findings were not considered adverse. 
 
During the 91-day repeat-dose toxicity studies, rat and monkey were exposed to up to 
300 mg/kg/day EPI-589 PO (Studies 1660-063 and 1660-064). The NOAEL for the rat study was 
300 mg/kg/day and the no observed effect level (NOEL) for the monkey study was 
300 mg/kg/day. Male rats exposed to 300 mg/kg/day and female rats exposed to 
≥ 100 mg/kg/day exhibited mild test-article related effects on hematology parameters consistent 
with hemolysis and bone marrow regeneration. These findings were not considered adverse. 
 
During the 28-day repeat-dose toxicity studies, rat and monkey were exposed to up to 
1,000 mg/kg/day EPI-589 PO (Studies 1660-039 and 1660-038). The NOAEL for both studies 
was 300 mg/kg/day. Rats exposed to 1,000 mg/kg/day exhibited adverse test-article related 
effects on hematology parameters consistent with hemolysis and bone marrow regeneration, mild 
to moderately enlarged spleens, and increased organ weights with some organs showing 
corresponding microscopic pathology. The majority of these findings were resolved following 
the 28-day recovery period. Monkeys exposed to 1,000 mg/kg/day showed significant test-article 
related moribundity after receiving only two doses resulting in half the animals in the high dose 
group being euthanized on Days 3 and 4 and the remaining animals being euthanized on Day 9. 
Animals exhibited significant elevations in aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) values, and microscopic findings in multiple sites in the skeletal muscle, 
kidney, liver, lymphoid tissues, and heart. The primary cause of morbidity in five animals 
euthanized on Days 3 and 4 was renal tubular degeneration and necrosis (2/5 animals) or was not 
able to be determined (3/5 animals). 
Development and reproductive toxicology studies were conducted in rat and rabbit at doses up to 
1,000 mg/kg/day EPI-589 PO (Studies 1660-069, 1660-067, and 1660-068). The NOAEL for 
reproductive toxicity in rat was demonstrated to be 1,000 mg/kg/day (Study 1660-069). The 
NOAEL for developmental toxicity in rat and rabbit during the embryofetal studies was deemed 
to be 300 mg/kg/day (Studies 1660-067 and 1660-068). 
Rats exposed to 1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, and decreased fetal body weights. There was no teratogenic potential in rat at 
doses up to 1,000 mg/kg/day. Rabbits exposed to 1,000 mg/kg/day exhibited decreased maternal 
body weights, decreased food consumption, decreased number of viable fetuses, decreased litter 
size, increased postimplantation loss, increased resorptions (early and late), and increased fetal 
skeletal malformations. The margin of exposure between healthy young and elderly humans 
exposed to 500 mg BID EPI-589 (relevant clinical dose) for 14 days (Study EPI589-14-01) and 
rabbits exposed to 300 or 1,000 mg/kg/day EPI-589 is approximately 22-fold and 84-fold, 
respectively. Based on these data, EPI-589 is not anticipated to increase the risk of adverse 
developmental or reproductive outcomes in humans when used in accordance with dosing 
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EPI-589 was negative for mutagenic response in the in vitro Ames bacterial reverse mutation 
assay (Study AD58AS.502ICH.BTL); equivocal for the induction of structural and negative for 
the induction of numerical chromosomal aberrations in the in vitro chromosome aberration assay 
in Chinese hamster ovary (CHO) cells (Study AD58AS.331ICH.BTL); and negative in the in 
vivo micronucleus assay in rat (Study AD58AS.125012ICH.BTL). These data indicate a low 
clinical mutagenicity risk. 
 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, EPI-589 did not 
significantly affect off-target molecular targets (Study EPI-BA-186). In safety pharmacology 
studies, EPI-589 did not significantly affect ion channel current in the human ether-a-go-go- 
related gene (hERG) assay (Study 130719.FEK); did not adversely affect electrocardiogram 
(ECG) parameters during the 28-day, 3-month, or 39-week repeat-dose toxicology studies in 
monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for animals administered 500 
or 1,000 mg/kg/day and up to Day 91 data collected for animals administered up to 300 
mg/kg/day) (Studies 1660-038, 1660-064, and 1660-080); and did not change respiratory 
function or adversely impact neurobehavioral function in rat at doses up to 1,000 mg/kg (Studies 
1660-051, 1660-050, and 1660-063). 
 
EPI-589 is approximately 60% protein bound in human plasma (Study MC14M-0067). EPI-589 
did not significantly induce cytochrome P450 (CYP) enzymes (Study MC12M-0037) and 
exhibited weak direct inhibition of CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (both 
midazolam and testosterone as probe substrates) with estimated IC50 (µM) values and R values 
based on free plasma concentrations (shown in parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 
34 (1.21), and 53 (1.13), respectively (Study MC14M-0020). EPI-589 is metabolized by 
reductases in the liver cytosol and microsomal subcellular fractions, and to a lesser extent by the 
family of CYP enzymes (Study MC14M-0018). EPI-589 is an inhibitor of the BCRP efflux 
transporter, possibly an inhibitor of the MATE1, OATP1B3, MATE2-K, OCT1, OATP1B1, 
OCT2 and OAT3 uptake transporters (in order of increasing inhibitory potential), and possibly a 
substrate of the MDR1 and BCRP efflux transporters (Edison-04-25Feb2014). 
 
An in vivo primary pharmacodynamic study demonstrated that EPI-589 significantly reduced 
disease progression as measured by standard functional outcomes of rotarod test and forelimb 
deformity score as compared with vehicle controls in the gold standard in vivo wobbler mouse 
model of ALS. These EPI-589 effects were superior to riluzole. In addition, EPI-589 had 
synergistic effects with riluzole when co-administered. These results indicate that EPI-589, alone 
or in combination with riluzole, may have beneficial effects on the progression of neuromuscular 
dysfunction in ALS patients (Study R-PH-EPI-589-002). 


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In vitro primary pharmacodynamics studies demonstrated EPI-589 is a potent rescue agent in 
cellular models of diseases of energy metabolism and oxidative stress. In vitro cellular models 
utilizing primary human fibroblasts from patients with ALS, Parkinson’s disease and other 
diseases characterized by high levels of oxidative stress, or striatal cells derived from mouse 
models of Huntingdon’s disease were used to assess the potential of EPI-589 to mitigate the 
harmful effects of oxidative stress (Studies EPI-BA-000216, EPI-BA-000363, and 
EPI-BA-000362). Pretreatment of patient cells with EPI-589 potently protected against oxidative 
stress-mediated cell death in a concentration dependent manner. Furthermore, EPI-589 
normalized 3-nitrosotyrosine (3NT) levels, a biomarker of oxidative stress, and increased 
glutathione levels in mouse striatal cells under oxidative stress conditions. 
 
The nonclinical laboratory studies conducted in accordance with the United States Food and 
Drug Administration (FDA) Good Laboratory Practice (GLP) Regulations 21 Code of Federal 
Regulations (CFR) Part 58 were conducted in conformance with the principles of OECD-GLP in 
the United States, a country that is part of the OECD Mutual Acceptance of Data process. 
 
D2. Clinical Studies 
 
Phase I Study EPI589-13-022 evaluated the pharmacokinetics, safety and tolerability of single 
ascending oral doses (SADs) of EPI-589 in healthy subjects and a preliminary evaluation of 
safety and tolerability data was performed. Sixteen AEs were reported in the 36 subjects who 
received administration of EPI-589. Ten subjects (27.8%) who received EPI-589 (and 2 subjects, 
20% on placebo) reported AEs that were assessed as related. All were mild and resolved during 
the study, with the exception of a common cold (1 subject) and cold sore (1 subject). None of the 
vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant change 
compared to baseline. From all preliminary data available from this SAD study it may be 
concluded that there is no objection to proceed with treatment with 50 mg, 100 mg, 250 mg or 
500 mg of EPI-589. 
 
Phase I Study EPI589-14-01 evaluated the pharmacokinetics, safety and tolerability of multiple 
ascending oral doses (MAD) of EPI-589 in healthy subjects, and an evaluation of safety and 
tolerability data was performed. No severe or serious adverse events were observed. Twenty-six 
subjects (65.0%) on EPI-589, and 8 subjects (80%) on placebo reported AEs. Twenty-four of 34 
AEs were considered by the Investigator to be related to EPI-589. Nineteen subjects (47.5%) on 
EPI-589, and 6 subjects (60%) on placebo reported AEs that were assessed as related. All 
adverse events were mild, except for 1 AE which was moderate (unrelated brain contusion). All 
AEs were resolved during the study, with the exception of one, which was a common cold. None 
of the vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant 
change compared to baseline. From all preliminary data available from the MAD study it may be 
concluded that there is no objection to proceed with treatment with 250-mg, or 500-mg doses of 
EPI-589. 


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E. 
Human Pharmacokinetics 
 
EPI-589 was fast absorbed following oral administration in SAD Study EPI589-13-022. The 
median Cmax was attained approximately within 1 hour under fasted conditions after dosing. The 
median Tmax values were attained in 0.50 to 1.00 hours over the dose range of 50 to 1000 mg 
under fasted conditions and 3.01 hours at the 500 mg dose level under fed conditions. Mean half- 
life ranged from 5.55 to 10.7 hours over the dose range of 50 to 1000 mg under fasted conditions 
and 4.91 hours at the 500 mg dose level under fed conditions. Half-life was independent of the 
dose levels over the dose range of 50 to 1000 mg under fasted conditions. The rate of EPI-589 
absorption, as measured by Cmax, was decreased by 24.07% under fed conditions at the 500 mg 
dose level. The extent of absorption as measured by AUCs (AUC0-t or AUC0-inf) was not affected 
under fed conditions in the 500 mg dose groups. 
 
In MAD study EPI589-14-01, EPI-589 was rapidly absorbed following oral administration and 
the median Cmax was attained within 1 hour (0.50 to 0.76 hours) under fasted conditions after 
single or multiple dosing among these five cohorts. The mean half-life of EPI-589 ranged from 
5.64 to 8.47 hours among these five cohorts. In general, the mean values of the time to peak 
concentration (Tmax), half-life (t½), apparent terminal constant (λz), accumulation ratio (AR), 
percent fluctuation (%F) and accumulation index (AI) of EPI-589 were similar among the five 
cohorts of various ages and smoking status. No significant effects of age or smoking on EPI-589 
pharmacokinetics were observed in this study. Dose proportionality existed in the exposures 
(AUC0-tau, Cmax, Cmin and Cavg) over the dose range of 250 to 500-mg BID EPI-589 under fasted 
conditions. 
 
F. 
Clinical Study 
 
EPI589-15-002: A Phase 2A Safety and Biomarker Study of EPI-589 in in Mitochondrial 
Subtype and Idiopathic Parkinson’s Disease Subjects. 
 
G. 
Selection of Drugs and Dosages 
 
The study drug in this trial is EPI-589: common chemical name (R)-troloxamide quinone. 
 
Each tablet contains 250 mg of EPI-589. The study dose is 500-mg BID, to be maintained in the 
absence of treatment-emergent toxicity. EPI-589 tablets must be taken morning and evening with 
meals. 
 
H. 
Compliance Statement 
 
This study will be conducted in full accordance with all applicable research policies and 
procedures, the EU Clinical Trials Directive, all applicable EU and US federal and local laws 
and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312 and 314, and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonization (ICH). Any episode of noncompliance will be documented. 


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The investigators will perform the study in accordance with this protocol, will obtain consent and 
will report AEs in accordance with local institutional policies and procedures and all EU and US 
federal requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the study. 
 
I. 
Relevant Literature and Data 
 
Literature references have been provided in Section XV. Additional information can be found in 
the Investigator’s Brochure. 
 
 
 
 
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IV. STUDY OBJECTIVES 
A. 
Primary Objective 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
B. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with PD on: 
 
1. Fasting glutathione cycle biomarkers as measured in blood, cerebral spinal fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society-sponsored revision of 
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale (NMSS), PDQ-39 and 
EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment (MoCA) 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the Montgomery & Asberg 
Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 
 
 
 
 
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V. 
INVESTIGATIONAL PLAN 
A. 
General Schema of Study Design 
 
Following study enrollment, baseline assessments will be performed. Subjects will participate in 
a 30-day run-in phase to establish biomarker and clinical baseline measurements. EPI-589 will 
then be administered for up to 3 months (85 days ± 3 days) unless discontinued for safety or 
tolerability issues. 
 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. Given that the investigational drug 
targets an enzyme key to glutathione synthesis and that glutathione depletion has been found to 
be associated with PD, we are seeking to determine the safety and potential biochemical benefit 
of EPI-589 in PD subjects as assessed by glutathione cycle biomarkers. If we determine that 
there are a subset of idiopathic PD patients—whether due to disease stage or baseline biomarker 
profile—who are more likely to be EPI-589 responsive, we will seek to enroll additional 
numbers of these subjects in the adaptive phase so that we can increase the number of likely 
biomarker responsive subjects. EPI-589 will be administered for up to 3 months (85 days ± 3 
days) unless discontinued for safety or tolerability issues. 
 
A1. 
Screening Phase 
 
Suitable candidates for the trial will receive a short overview of the study by the Investigator’s 
staff and, if interested, will undergo Screening. The Investigator will inform each prospective 
subject of the nature and details of the study, explain the potential risks and must obtain written 
informed consent from the subject or their legally authorized representative prior to performing 
any study related procedures. 
 
A2. 
30-Day Run-in Phase 
 
Once eligibility is confirmed, the subject will be enrolled in the study and the run-in scans, CNS, 
blood-based biomarker, urine-based biomarker and clinical measurements will be collected. 
 
A3. 
Baseline 
 
Baseline assessments, scans, blood-based biomarker, urine biomarker, and clinical measurements 
will be collected. 
 
A4. 
Treatment Phase 
 
EPI-589 dosing will start on Day 1. Subjects will self-administer EPI-589 at a dose of 500-mg 
BID (morning and evening dose along with food). 
 
Blood-based biomarker, urine biomarker, and clinical measurements will be collected at Day 29 
(± 3 days) and Day 85 (± 3 days). 


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USA. 
Germany 
USA 
USA 
 
A5. 
End of Treatment 
 
End of treatment data will be collected at the last study visit Day 85 (± 3 days). 
 
AEs reported as ongoing at Day 85 (± 3 days) and/or any concomitant medications associated 
with such events 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. 
 
A6. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days after last dose and if there are any ongoing or 
new AEs noted at month 3, then the follow up will be up to 30 days after last dose. AE/SAE and 
concomitant medication assessments conducted by telephone. Additional assessments to be 
determined at Investigator discretion. 
 
 
B. 
Randomization and Blinding 
 
This is an open-label study. 
 
C. 
Study Duration, Enrollment and Number of Sites 
C1. Duration of Subject Treatment 
 
Subjects will participate in a 30-day run-in phase to establish biomarker and clinical baseline 
measurements. EPI-589 will then be administered for 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. A post-treatment follow-up will be conducted at 
least 10 days and up to 30 days after last dose. 
 
C2. Total Number of Study Sites/Total Number of Subjects Projected 
 
This study will be conducted at five study sites: 
• 
UK 
• 
• 
• 
• 
Approximately 40 subjects with PD are projected: 
• 20 with genetically-defined subtypes 
• 20 PD idiopathic PD 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects to achieve a higher number of subjects in 


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whom we could understand the biochemical effects of the investigative drug and its potential 
clinical impact as assessed by the same study protocol and outcome metrics. 
 
D. 
Study Population 
D1. Inclusion Criteria 
 
1. Hoehn and Yahr stage ≤ 3.0 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners must agree to use medically accepted 
methods of contraception (e.g., hormonal methods, including oral, subcutaneous, and 
intrauterine; barrier methods, including 
condom, 
condom, or diaphragm with 
spermicidal gel) during the course of the study and for 3 months after the last dose of 
study treatment. 
4. Willingness and ability to comply with study procedures 
5. If on medications for PD drugs, then medication regimen must be stable for 60 days prior 
to enrollment 
6. Abstention from use of other investigative or non-approved drugs for the duration of the 
trial 
 
For Idiopathic Subjects 
7. A diagnosis of idiopathic PD confirmed by the presence of bradykinesia plus one or both 
of the following symptoms: rigidity or resting tremor; and with an abnormal DaTscan 
consistent with a dopaminergic deficit 
8. Age 40 to 75 years 
9. Within 5 years of diagnosis of Parkinson’s disease 
 
For Genetic Subtype Subjects 
10. A confirmed diagnosis of PD plus a genetic diagnosis consistent with PD, specifically 
PINK1, parkin, LRKK2 or other mitochondrial genetic subtype 
11. Age 21 to 75 years 
 
D2. Exclusion Criteria 
 
1. Allergy to EPI-589 or other components of the EPI-589 tablet formulation 
2. Use of antioxidant supplements, specifically vitamins E and C beyond the recommended 
daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that will confound the 
assessment of effect of study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 


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10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial of a device, drug or 
other therapy for PD 
 
 
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VI. STUDY PROCEDURES 
A. 
Screening Visit 
 
Screening evaluations will be performed within two months of first dose. The Investigator will 
inform each prospective subject of the nature of the study, explain the potential risks, and must 
obtain written informed consent from the subject prior to performing any study-related 
procedures and prior to the administration of study drug. Screening evaluations consist of the 
following: 
1. Assessment of eligibility 
2. Medical history, chart review 
3. Receipt and review of previous testing including genetic tests 
4. Physical examination* including vital signs 
5. Height** and weight 
6. 12-lead ECG 
7. Laboratory assessments for hematology, coagulation, and serum chemistry*** (See 
Sections VII.D2.a and VII.D2.b) 
8. Urine pregnancy test (women of childbearing potential must have a negative urine 
pregnancy test; see Section VII.D2.c) 
9. MDS-UPDRS 
10. MoCA 
11. DaTscan (for idiopathic subjects only) 
12. Revised Hamilton Rating Scale for Depression 
13. SAE assessments 
14. Concomitant medications assessment (last 60 days prior to enrollment) 
*Breast exam is at screening physical exam only. 
** Height is measured at screening visit only. 
***Screening values can be used if done within one month of baseline and if completed 
under fasted conditions 
 
A1. 
Run-in Assessments 
 
If the subject is eligible for the study following all screening procedures and is still willing to 
participate in the study, the subject must return to the clinic within one month for Run-in 
assessments. These will be performed 30 days (± 3 days) prior to baseline after eligibility is 
confirmed and subject is enrolled in the study. Run-in evaluations consist of the following: 
1. Fasting blood-based glutathione cycle biomarkers 
2. Fasting CNS biomarkers (lumbar puncture) 
3. Fasting urine biomarkers 
4. Timed motor tests (for subjects on dopamine therapy) 
5. AE/SAE assessments 
6. Concomitant medications review 


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B. 
Treatment Phase 
After the Run-in phase, the subject must return to the clinic within 30 days (± 3 days) for 
baseline assessments. In-clinic study visits are scheduled at Month 1 and Month 3. The Month 2 
study assessments can be conducted via telephone. End of treatment assessments will be 
conducted at the Month 3 study visit. Pharmacokinetic sampling takes place at Month 1 and 
Month 3. The baseline and all subsequent laboratory assessments should be obtained under 
fasting conditions. 
 
B1. 
Baseline Assessments 
 
The following will be assessed or performed at this visit. 
1. Physical examination including vital signs 
2. Height and weight* 
3. 12-Lead ECG* 
4. Fasting blood-based GSH cycle biomarkers 
5. Fasting urine-based biomarkers 
6. Laboratory assessments for hematology, coagulation and serum chemistry* 
7. Urine pregnancy test (females of child bearing potential) 
8. C-SSRS (Columbia Suicide Severity Rating Scale) 
9. MDS-UPDRS 
10. NMSS, PDQ-39, EQ-5D 
11. BDI, MADRS 
12. Timed motor tests (for subjects on dopamine therapy) 
13. AE/SAE assessments 
14. Concomitant medications review 
* Screening results for these assessments may be used if obtained within 1 month of Baseline 
and if they are completed under fasted conditions. The baseline laboratory assessments 
should be obtained under fasting conditions. 
 
B2. 
Study Visit Assessments 
 
• Month 1 Clinic Visit (Day 29 ± 3 days): 
 
The following will be assessed or performed at the Month 1 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry* 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Fasting blood-based GSH cycle biomarkers 
8. Fasting urine-based biomarkers 
9. MDS-UPDRS 


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10. Pharmacokinetics**: a full plasma drug concentration profile will be obtained from the 
first 10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 
6, 8, and 12 hours after dosing.12 hour time point may be obtained at 0 hour. 
11. AE/SAE assessments 
12. Concomitant medications review 
* The laboratory assessments should be obtained under fasting conditions. 
• Month 2 Visit (Day 57 ± 3 days) 
 
Month 2 assessments can be conducted by telephone and must include review of: 
1. AE/SAE assessments 
2. Concomitant medication 
 
• Month 3 Clinic Visit (Day 85 ± 3 days) 
 
The following will be assessed or performed at the Month 3 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry* 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Fasting blood-based GSH cycle biomarkers 
8. Fasting urine-based biomarkers 
9. Fasting CNS biomarkers 
10. MDS-UPDRS 
13. Pharmacokinetics**: a full plasma drug concentration profile will be obtained from the 
first 10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 
6, 8, and 12 hours after dosing. 12 hour time point may be obtained at 0 hour. 
11. AE/SAE assessments 
12. Concomitant medications review 
13. MoCA 
14. NMSS, PDQ-39, EQ-5D 
15. BDI, MADRS 
16. Timed motor tests (for subjects on dopamine therapy) 
 
* The laboratory assessments should be obtained under fasting conditions. 


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B3. 
Pharmacokinetics** 
 
Plasma concentration samples will be collected from 20 subjects (10 idiopathic and 10 with 
genetically defined subtypes) at the following time points: 
 
• Month 1 (Day 29 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
• Month 3 (Day 85 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
 
** 12 hour PK can be obtained at time 0 
 
The pharmacokinetics samples collection will be monitored as subjects are enrolling and sponsor 
will alert each principal investigator once the required samples for each subtype are obtained. 
 
B4. 
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. 
 
C. 
End of Treatment Visit 
 
End of treatment visit takes place at Month 3 (Day 85 ± 3 days) and includes the assessments 
listed in Section VB2 Study Visit Assessments. 
 
Subjects who have an ongoing AE at the time of study completion will be followed for up to 30 
days, until the event resolves, or until the Sponsor and the Investigator agree that further follow- 
up is not medically necessary. 
 
D. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose, with 
AE/SAE and concomitant medication assessments conducted by telephone. Additional 
assessments to be determined at Investigator discretion. 
 
E. 
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 case report form (CRF) using the supplemental visit CRF pages. 
 
F. 
Concomitant Medication 
 
Any medication taken by a subject ≤ 60 days prior to enrollment and during the course of the 
study and the reason for use of the medication will be recorded on the CRF. During screening, 
each subject will be instructed to report the use of any medication to the Investigator. Subjects 


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will also be instructed about the importance of not taking any medication throughout the study 
(including over-the-counter [OTC] medications) without consulting the Investigator. 
 
G. 
Prohibited Medications 
 
The following are prohibited while the subject is on study treatment: 
1. Use of antioxidants, specifically vitamins E and C beyond the recommended daily 
allowance. However if the subjects are on high doses of Vitamin E and C and are eligible 
to participate , they are allowed a 2 weeks washout period prior to enrollment 
2. Participation 3 months prior to and for the duration of the study in a trial of a device, drug 
or other therapy for PD 
 
H. 
Subject Withdrawals 
 
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 adverse event that is deemed related to treatment with EPI-589 
and in the Investigator’s or the Sponsor’s medical judgment continuation of treatment 
would be detrimental to the subject. 
3. At the specific request of a regulatory agency for termination of treatment of an 
individual subject or all subjects under the protocol 
4. Subject participation in another clinical study using an investigational agent or 
investigational medical device 
5. Use of prohibited medications such as vitamins E and C beyond the recommended daily 
allowance. 
6. Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use medically accepted methods of contraception 
7. If a subject becomes pregnant. 
8. Significant noncompliance with the protocol in the opinion of the Investigator or the 
Sponsor 
In all cases, the reason for withdrawal must be recorded in the 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 
X.B. 
 
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. 


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Every effort will be made to follow subjects who have an ongoing AE at the time of withdrawal 
until the event resolves, or until the Sponsor and the Investigator agree that further follow-up is 
not medically necessary. 
 
 
 
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VII. STUDY ENDPOINTS AND EVALUATIONS 
A. 
Primary Endpoint 
 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of drug-related serious 
adverse events in subjects with PD. 
 
B. 
Secondary Endpoints (Efficacy) 
 
1. Fasting blood-based biomarkers 
2. Fasting CNS-based biomarkers 
3. Fasting urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests as ON state only (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Secondary Endpoints (Safety) 
 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Routine serum chemistries with liver function tests 
4. C-SSRS 
5. Routine hematology tests with coagulation tests 
6. Electrocardiogram 
 
D. 
Screening and Baseline Evaluation 
D1. Physical Examination, height and weight 
 
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. 
 
Vital sign measurements (pulse rate, blood pressure and respiration rate) will be obtained in the 
sitting position (after the subject has been sitting for five minutes). 


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The findings from breast exam will be captured as part of the screening physical exam. The 
findings from breast exams conducted within 6 months of the screening visit and those collected 
as part of medical history, may be used for the screening physical exam. 
 
Medical history and demographics including age, gender, race, will be collected at screening 
visit. Weight (kg) will be measured in ordinary indoor clothing (i.e., street clothes, scrubs, etc.) 
with shoes off. Height will be recorded in centimeters (cm) and need not be repeated after 
screening visit. 
 
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. 
 
D2. Laboratory Evaluations 
 
Subjects will have less than 100 mL of blood drawn over the course of the study. 
The following variables will be collected at various times (as detailed in Section I). 
a. Hematology 
 
a. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
volume (MCV) 
b. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils).The differential can be recorded as an absolute 
value or percentages. 
c. Platelets: platelet count 
d. Coagulation: prothrombin time (PT) with INR, and partial thromboplastin time (PTT) 
 
b. Serum chemistry 
 
a. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total and 
direct), gamma-glutamyl transferase (GGT), and lactic dehydrogenase (LDH) 
b. Renal: blood urea nitrogen (BUN), and creatinine 
c. Electrolytes: sodium, potassium, chloride and bicarbonate 
d. General: creatine phosphokinase (CPK), total protein, albumin, calcium, magnesium, 
glucose, phosphate 
e. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL), cholesterol, and triglycerides 


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c. Urine pregnancy test 
1. Human chorionic gonadotropin (HCG) beta subunit will be measured on all female 
subjects of childbearing potential. 
 
Laboratory tests that result in significantly abnormal values should be repeated for verification. 
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, or to monitor the course of an AE, should be obtained when clinically indicated. 
In particular, if a clinically significant abnormal result is observed that is not resolved by the 
final study visit, repeat tests should be performed to document resolution or stability of the 
abnormality. 
 
Diagnoses associated with any NIH Common Terminology Criteria for Adverse Events (CTC 
v4.03) Grade 3 or 4 laboratory abnormalities will be recorded as adverse events (AEs) on the 
CRF. The recorded event should indicate the underlying abnormality or diagnosis (e.g., renal 
insufficiency) if known, as opposed to the observed deviation in laboratory results (e.g., elevated 
creatinine). Any additional relevant laboratory results obtained by the Investigator during the 
study will be supplied to the Sponsor. 
 
D3. Dose Limiting Toxicity (DLT) 
 
There were no DLTs noted in the phase 1 study; the dose-limiting (NOAEL) in nonclinical studies, 
as described in the protocol were increased LFTs (ALT, AST), rhabdomyolysis (elevated CPK), 
renal dysfunction (likely secondary to rhabdo), and marrow toxicity (most notably hemolysis). 
Therefore for this study, any increased LFT, BUN/Cr or CPK (or CK) should be considered related 
to study drug and should be designated as a DLT. If there is a DLT, a dose reduction will be 
attempted. Contact the medical monitor for further instructions. 
 
D4.  Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a semi-structured tool for assessing suicidal ideation (Questions 1-5) and 
behavior (Questions 6-10) through a series of questions. 
 
E. 
Sample Collection Procedures, Bioanalytical Methods and Sample Shipment 
 
Subject samples will be identified by unique sample codes. 
 
Blood, urine, and cerebral spinal fluid samples will be collected for determination of levels of 
GSH cycle markers. Additional information about the collection, handling, storage, and 
shipment of the GSH cycle marker samples will be provided separately prior to start of the study. 


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F. 
Efficacy Evaluations 
F1. 
Fasting Glutathione Cycle Biomarkers 
 
Blood, urine, and CNS levels of oxidized and reduced GSH as well as GSH metabolites will be 
used to evaluate EPI-589 target engagement and ability to correct a key biochemical aspect of 
disease pathology. 
 
F2. 
Study Clinical Assessments 
 
The investigator or sub-investigator should be the primary administrator of these assessments, 
though they may delegate this study procedure to another qualified staff member on their team. 
It is recommended that the same administrator conduct this assessment on the same patient(s) 
throughout the study to ensure consistency when at all possible. 
 
a. Parkinson’s Disease Rating (MDS-UPDRS) 
 
The MDS-UPDRS is a tool for monitoring the impact of PD, the degree of disability caused, and 
complications from treatment. Part I evaluates nonmotor experiences of daily living; Part II 
evaluates motor experiences of daily living; Part III is a motor examination and includes the 
Hoehn and Yahr scale; Part IV examines motor complications (e.g., motor fluctuations and 
dyskinesias). 
 
Several questions from Part I and all questions from Part II are designed to be amenable to a 
patient/caregiver questionnaire format; the remaining interview (Part I and Part III) and 
examination (Part IV) are designed with the expectation they can be completed within 30 
minutes. Each item is measured on a five-point scale. 
 
b. Non-motor Symptoms (NMSS) 
 
Non-motor symptoms are evaluated using the NMSS which is divided into 30 questions in 9 
different domains including such symptoms as dribbling saliva, constipation, depression, sleep 
disorders, apathy, hallucinations and dementia. Symptoms are quantified based on their severity 
(using a scale of 0 to 3) and frequency (using a scale of 0 to 4). The final cumulative scores are 
derived from adding up the product of the frequency score times severity score for each of the 30 
questions. 
 
c. Parkinson’s Disease Questionnaire (PDQ-39) 
 
PDQ-39 is a self-administered questionnaire for patients with PD that has 39 questions relating 
to eight key areas of health and daily activities, including both motor and non-motor symptoms. 
It is scored on a scale of 0 to 100, with lower scores indicating better health, and high scores 
more severe symptoms. 


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d. EQ-5D 
 
EQ-5D is a questionnaire designed to provide measures of health-related quality of life states, 
consisting in five domains (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). 
 
e. Montreal Cognitive Assessment (MoCA) 
 
MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive 
domains: attention and concentration, executive functions, memory, language, visuo- 
constructional skills, conceptual thinking, calculations, and orientation. Severity ranges are 
approximately: 26 to 30 normal; 18 to 26 mild cognitive impairment; 10-17 moderate cognitive 
impairment; < 10 severe cognitive impairment. 
 
f. Beck Depression Inventory (BDI) 
 
The BDI is a self-reporting inventory that measures characteristic attitudes and symptoms of 
depression, including physical symptoms. Twenty-one questions have four responses each (rated 
0 to 3) with a total cumulative score scale ranging from 1-10 considered normal) > 40 (extreme 
depression). 
 
g. Montgomery and Asberg Depression rating scale (MADRS) 
 
The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. 
Ten core symptoms and cognitive features are rated on a severity scale of 0 to 6. Higher scores 
indicate increasing depressive symptoms. 
 
h. Timed motor tests as ON state only (for subjects on dopamine therapy) 
 
Timed motor tests are simple, objective, quantitative measures for the assessment of Parkinson’s 
disease. They include, in an on-medication and an off-medication state, timed recorded physical 
movements. Since missing dopamine could impair a subject’s mobility including their ability to 
drive the next morning for study visits, the subjects should be encouraged to continue to take 
their dopamine as prescribed. In order to avoid missing PM dose of the dopamine the previous 
night, the sites can perform the TUG test on subjects as ON state only. 
 
 
 
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VIII. STATISTICAL CONSIDERATIONS 
A. 
Statistical Analysis 
 
In this subject-controlled, open label study the incidence of drug related SAEs in addition to 
changes from baseline to Month 3 for disease-relevant peripheral and CNS biomarkers as well as 
clinical measures will be calculated for each subject. 
 
A1. 
Analysis Populations 
 
Demographic characteristics and baseline efficacy data will be presented and summarized by 
treatment group for all subjects in the efficacy intent to treat (EITT) population. Demographic 
information will also be summarized by treatment group for the Safety population. No formal 
statistical comparisons will be made for either the EITT or Safety populations. 
 
B. 
Efficacy Analysis 
B1. 
Efficacy Variables 
 
The efficacy variables in this study are: 
1. Fasting blood-based glutathione cycle biomarkers 
2. Fasting CNS biomarkers 
3. Fasting urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests as ON state only (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Safety Analysis 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
Assessment of safety will include calculating the overall number of subjects (by absolute number 
and percentage) with a particular AE. Safety will also be evaluated through examining clinical 
laboratory data (including chemistry and hematology and coagulation information) and physical 
examination findings, including vital signs obtained throughout the course of the study. A 
medical monitor will provide study oversight. 


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D. 
Sample Size 
 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 idiopathic PD 
subjects). Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker-responsive idiopathic PD subjects to achieve a higher number 
of subjects in whom we could understand the biochemical effects of the investigative drug and 
its potential clinical impact as assessed by the same study protocol and outcome metrics. 
 
 
 
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IX. STUDY MEDICATION 
A. 
Description 
 
EPI-589 is presented as an immediate release film-coated tablet. Each tablet contains 250 mg of 
EPI-589 and the following compendial excipients: lactose, microcrystalline cellulose, 
polyvinylpyrrolidone, crospovidone and magnesium stearate. Each tablet is film-coated with 
Opadry® II yellow. The tablets are yellow-colored and oval-shaped with a total target weight of 
824 mg. The tablets are packaged at 28 tablets per bottle in high-density polyethylene (HDPE) 
pharmaceutical wide mouth containers, induction sealed, and closed with a child-resistant 
closure. Each container is labeled with appropriate product information meeting current 
regulatory requirements. 
 
B. 
Packaging 
B1. 
Labeling 
 
Each container is labeled with appropriate product information meeting current regulatory 
requirements, in compliance with 21 CFR 312.6 and Eudralex Vol. 4 EU Guidelines to Good 
Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 13 
 
B2. 
Dosage Form 
 
The EPI-589 drug product will be provided in a 250-mg tablet formulation. 
 
B3. 
Dispensing 
 
Tablets are packaged in white round HPDE wide mouth containers. Each container holds 28 
tablets without desiccant. Each container is sealed with an induction seal held in place with a 
child-resistant closure. The packaged tablets are stored at controlled room temperature 20° to 
25°C (68° to 77°F). (See United States Pharmacopeia [USP]). 
 
C. 
Treatment Compliance and Adherence 
 
Study medication will be counted to assess compliance during each scheduled clinic visit. 
Subjects who take ≥ 80 percent of the prescribed doses and no more than 100 percent will be 
considered compliant. Subjects who fall outside the boundaries of these thresholds will be 
counseled and re-instructed on proper dosing procedures. Medication compliance will be 
recorded on the CRF for each visit after verification with subject-completed diary cards and 
returned used drug supply. 
 
D. 
Drug Accountability 
 
Dosing information will be captured on a subject Dosing Diary Form. This form is part of the 
source documentation and will be utilized as a source for the completion of CRFs associated 
with dosing and for reconciliation of study drug administered and returned to the study site for 


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accounting and destruction. Adequate records of study drug receipt and disposition should be 
maintained by pharmacy records of receipts, investigational drug orders, dispensing records, and 
disposition forms. The Study Monitor will also assess drug accountability and will 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 either be returned to the Sponsor or designee 
or destroyed per study site guidelines for destruction of investigational product immediately after 
drug accountability is performed by the study monitor. 
 
 
 
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X. 
SAFETY MANAGEMENT 
A. 
Clinical Adverse Events 
 
Clinical AEs will be monitored throughout the study. All AEs, whether observed by the 
Investigator, reported by the subject, from clinically significant laboratory findings, or other 
means, will be recorded in the CRF. 
 
B. 
Adverse Event Reporting 
 
All SAEs will be reported to the IRB/ IEC in accordance with their policies and as detailed 
below. 
 
B1. 
Safety Guidance 
 
Based on the known clinical manifestations of Parkinson’s disease, we expect that many AEs 
could occur during the course of the trial that are well documented to occur as the results of the 
natural history of this disease. These include, but are not limited to worsening neuromuscular 
function, depression, decline in cognitive function, loss of vision and other ophthalmological 
symptoms, loss of coordination and loss of speech. 
 
As there are no data available regarding EPI-589 phototoxicity, investigators are to advise 
subjects to take measures to minimize exposure to ultraviolet (UV) light for the duration of the 
study and for one week after the last dose. 
 
BioElectron Technology Corporation 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, BioElectron Technology Corporation 
should be provided with a copy of any post-mortem findings, including histopathology. 
 
C. 
Definition of an Adverse Event 
C1. Adverse Event 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
The AE may be: 
1. A new illness 
2. Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 


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3. An effect of the study medication, including comparator 
4. A combination of 2 or more of these factors 
No causal relationship with the study medication or with the clinical study itself is implied by the 
use of the term “adverse event” or “AE”. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs. 
 
Adverse events fall into the categories “non-serious” and “serious”. 
 
C2. Definition of a Serious Adverse Event (SAE) 
 
An SAE is one that at any dose results in any of the following: 
1. Death; 
2. A life-threatening adverse drug experience; 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability/incapacity; or 
5. A congenital anomaly/birth defect. 
ICH guidance also recommends that important medical events that may or may not be 
immediately life-threatening or result in death or hospitalization should also be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the serious definition. 
 
The term ”life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE. It does not refer to an SAE which 
hypothetically might have caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether other AEs, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject, require intervention to prevent one of the other 
outcomes listed 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. 
 
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 
has received 
study drug, 
should discontinue dosing, complete all end-of-study procedures, and be 
followed to determine the outcome of the pregnancy; follow-up of the pregnancy, fetus, and 
child will continue for at least 8 weeks after delivery. While pregnancy itself is not considered an 
AE or SAE, all pregnancies should be reported using the same process as for SAEs. Any 


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pregnancy complications or an outcome other than a healthy, normal outcome will be recorded 
as an AE or SAE. 
 
Clarification on the difference in meaning between “severe” and “serious”: The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as “serious,” which is based on the outcome or 
action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
C3. Non-serious Adverse Event 
 
A non-serious AE is any AE not meeting the SAE criteria. 
 
C4. Definition of Relationship to Study Medication 
 
Association or relatedness to the study medication will be graded as either “probably”, 
“possibly”, or “unlikely”. Determination of relatedness includes: 
 
PROBABLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Abates upon discontinuation of the drug and reappears with re-introduction of the drug 
3. Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state 
POSSIBLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
UNLIKELY – The adverse event: 
1. Does not follow a reasonable temporal sequence from drug administration 
2. Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
C5. Definition of Severity 
 
All AEs will be graded if possible by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. The severity of AEs that cannot be graded by CTCAE v4.03 will be categorized 
as follows: 
 
Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
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Grade 2 – Moderate limitation in activity, some assistance may be needed; minimal noninvasive 
medical intervention/therapy indicated. 
 
Grade 3 – Severe limitation in activity, assistance usually required; medical intervention/therapy 
required; hospitalization or prolongation of hospitalization indicated; disabling. 
 
Grade 4 – Extreme limitation in activity, significant assistance required; urgent medical 
intervention/therapy required; life-threatening consequences. 
 
Grade 5 – Death 
 
C6. Definition of Unexpected Adverse Event 
 
Any AE, the specificity or severity of which is not consistent with those listed in the current 
investigator’s brochure is considered “unexpected.” 
 
C7. Notification of SAEs 
 
The Investigator is responsible for promptly notifying the IRB/IEC of all study on-site SAEs and 
other unanticipated problems related to research. 
 
External SAEs that are unexpected and related to the study intervention should be reported as 
they are received using the MedWatch or CIOMs form (as appropriate). 
 
SAEs (whether unexpected or expected AEs) must be documented on the designated SAE form. 
The SAE must be reported to the medical expert and appropriate BioElectron Technology 
Corporation BioElectron-assigned pharmacovigilance staff within 24 hours, according to 
regulatory, Sponsor, or ICH-E6 Good Clinical Practice, followed by the SAE form within two 
calendar days. The designated SAE form and the instructions are provided in the Investigator’s 
site file. 
 
The SAE contact information will be provided separately from the protocol. 
 
The Investigator and/or Medical Expert must also inform the Study Monitor and the Sponsor in 
all cases. Any SAEs must also be reported to the IRB/IEC. The Sponsor or designee will ensure 
that all legal reporting requirements are met. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and the 
study medication. 
 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up SAE forms. 


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The instructions to sites for the completion of SAE reports give detailed guidance on the 
reporting of SAEs and AEs initially reported as non-serious that become serious. When a non- 
serious event becomes serious, details must be forwarded immediately to the Medical expert and 
BioElectron Technology Corporation or BioElectron-assigned pharmacovigilance staff first for 
assessment and then submitted to the Sponsor on the designated SAE form within 24 hours. 
 
All relevant information about suspected unexpected serious adverse reactions (SUSARs) that 
are fatal or life-threatening are to be recorded and reported to the relevant competent authorities. 
 
In the US, all fatal or life-threatening suspected unexpected serious adverse events assessed as 
possibly or probably related to study drug by the Sponsor must be reported to the FDA as soon as 
possible (i.e., by telephone or facsimile transmission), but no later than 7 calendar days after first 
knowledge by the Sponsor that a report qualifies as a suspected unexpected fatal or life- 
threatening reaction. All unexpected serious adverse events, other than fatal or life-threatening, 
assessed as possibly or probably related to study drug by the Sponsor must be reported to the 
FDA within 15 calendar days from the day the Sponsor determines that the information qualifies 
as a SUSAR. 
 
In the UK, the Sponsor or trial investigator must act immediately or at least within 24 hours after 
becoming aware of a SUSAR by informing the MHRA’s Clinical Trial Unit by telephone. The 
MHRA must then be informed in writing within 3 days of the incident. All SUSARs originating 
in the UK or originating outside the UK involving the same medicinal product are to be reported. 
Fatal or life-threatening SUSARs are to be reported as soon as possible, but no later than after 7 
days. Any additional relevant information must be sent within 8 days of the report. Non-fatal or 
non-life-threatening SUSARs are to be reported as soon as possible but no later than 15 days 
after becoming aware of the reaction. 
 
C8. Follow-up Report 
 
If an SAE has not resolved at the time of the initial report, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB/ IEC . All SAEs should be followed until either resolved or stable. 
 
C9. Dose Modification Guidelines 
 
In the event that any patient develops elevated INR ≥ grade 2 in severity (> 1.5-2.5 x ULN) per CTCAE 
criteria version 4.0 thought to be related to treatment with EPI-589, administration of EPI-589 will be 
reduced by 1/2 to 50 percent of the starting dose. Should the INR toxicity not resolve to at least grade 1 in 
severity within two weeks of the initial dose reduction, administration of EPI-589 may either be further 
reduced or discontinued. 
 
Once a patient’s dose is reduced due to elevated INR thought to be related to study drug administration, 
their dose should not be re-escalated. 


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D. 
Medical Emergencies 
 
In medical emergencies, the Investigator should use medical judgment and remove the subject 
from the immediate hazard. The Medical Expert and the IRB/ IEC must be notified regarding the 
type of emergency and course of action taken and the procedures for SAE reporting must be 
followed. 
 
D1. Emergency Sponsor Contact 
 
In emergency situations, the Investigator should contact the Medical Monitor: 
 
D2. Emergency Treatment 
 
At present, the threshold and extent of clinical adverse effects are not known as only limited 
information is available in healthy volunteers. It is anticipated in the planned study that any 
effects will be minimal and laboratory measurements will detect study drug effects before they 
become clinically significant. 
 
 
 
 
 
 
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XI. STUDY ADMINISTRATION 
A. 
Treatment Assignment Methods 
 
This is an open-label study. 
 
B. 
Data Collection and Management 
 
Monitoring and auditing procedures, developed or endorsed by BioElectron Technology 
Corporation will be followed in order to comply with GCP guidelines. Direct access to on-site 
study documentation including all source data, documentation and medical records should be 
ensured. 
 
The study will be monitored by BioElectron Technology Corporation throughout the course of 
the study, the Study Monitor will make frequent contact with the Investigator. This will include 
telephone calls and on-site visits. During the on-site visits, the completed CRF will be compared 
to the source documentation for completeness, accuracy and adherence to the protocol. As part of 
the data audit, source documents must be made available to the Study Monitor for review. The 
Study Monitor will also perform drug accountability checks and will review the Investigator 
study file to assure completeness of documentation in all respects of clinical study conduct. 
 
Upon completion of the study, the Study Monitor will arrange for a final review of the study 
files, after which the files should be secured for the appropriate time period. The Investigator, or 
appointed delegate, will meet with the Study Monitor during the on-site visits and will cooperate 
in providing the documents for inspection and responding to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of BioElectron 
Technology Corporation or the regulatory agencies. 
 
US and other competent regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. Medical records and other 
study documents may be copied during audit or inspection provided that subject names are 
obliterated on the copies to ensure confidentiality. 
 
C. 
Data Quality Assurance 
 
As a final step in the data management process, a 100% audit will be performed on the key 
safety and critical efficacy parameters. In addition, a random subject sample (10%) will be 
selected in order to perform a partial audit of remaining data. The purpose of this audit is to 
detect systematic and random errors. Any errors found from this audit will be corrected and, if 
the error rate is greater than 1 error per 1,000 fields (0.001%), a systematic review of the 
database will be undertaken and corrections will be made to achieve an error rate of less than 
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AEs will be coded using MedDRA, version (14.3). Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary, March 2014. 
 
D. 
Retention of Study Records 
 
The following records must be retained by the Investigator for a minimum of 2 years after the 
Sponsor has notified the FDA or other competent authority that investigations have been 
discontinued, or after the FDA or other competent authority has approved the new drug 
application. In accordance with European regulatory requirements (Directive 2005/28/EC and 
Annex 17 and 2001/83/EC and Annex1), the Sponsor may request retention for a longer period 
of time. 
1. Signed informed consent documents for all subjects 
2. Subject identification code list, screening log (if applicable), and enrollment log 
3. Record of all communications between the Investigator and the IRB/IEC 
4. Composition of the IRB/IEC or other applicable statement 
5. Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
6. List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in the 
study and their signatures 
7. Copies of CRFs and of documentation of corrections for all subjects 
8. Drug accountability records 
9. Record of any body fluids or tissue samples retained 
10. All other source documents (subject records, hospital records, laboratory records, etc.) 
11. All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. 
 
Normally, these records will be held in the Investigator's archives. If the Investigator is unable to 
meet this obligation, 
or 
must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 
E. 
Confidentiality 
 
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the Sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be told that representatives of the Sponsor, IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection and privacy laws, including the Health Insurance 
Portability and Accountability Act (HIPAA) Guidelines, and the General Data Protection 
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The Investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
F. 
Documentation of Study Results 
 
A CRF will be provided for each enrolled subject. 
 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the CRF. Details of CRF completion and correction will be 
explained to the Investigator. If the Investigator authorizes other persons to make entries in the 
CRF, the names, positions, signatures, and initials of these persons must be supplied to the 
Sponsor. 
 
The Investigator, or designated representative, should complete the CRF pages as soon as 
possible after information is collected, preferably on the same day that a study subject is seen for 
an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
 
By signing the completed CRFs, the Investigator or Subinvestigator attests to the accuracy, 
completeness, legibility, and timeliness of the data collected on the CRF and casebooks. 
 
The Sponsor will retain the originals of all CRFs. The Investigator will retain a copy of all 
completed CRF pages. 
 
G. 
Regulatory and Ethical Considerations 
G1. Risk Assessment 
 
Based on the safety results of Study EPI-589-14-01 as summarized in the Clinical Study Report, 
it is not foreseen that subjects will endure any risks greater than minimal at the 500-mg BID dose 
selected for this study. 
 
G2. Potential Benefits of Trial Participation 
 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 
benefit in subjects with PD. Therefore, we cannot assure that subjects will benefit from treatment 
with EPI-589. Potential benefits may manifest in a variety of ways, such as in disease-related 
parameters, functioning, and quality of life. 
 
G3. Risk-Benefit Assessment 
 
There are no effective and/or approved disease modifying treatments available for PD, although 
a number of clinical interventions are being researched. Based on disease mechanism, EPI-589 
mechanism of action and pre-clinical studies, EPI-589 may hold benefit for patients with PD. 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 


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benefit in subjects with PD. In order to further minimize risks, subjects will be closely monitored 
with a variety of safety measures. 
 
H. 
Informed Consent 
 
Before being enrolled in the clinical study, subjects must provide written consent to participate 
after the nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them. The Investigator will not undertake any measures specifically 
required only for the clinical study until valid consent has been obtained. 
 
An informed consent document that includes both information about the study and the consent 
form will be prepared and given to the subject. This document will contain all the elements 
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements 
required by local regulations and must be in a language understandable to the subject. Where 
required by local law, the person who informs the subject must be a physician. It should be 
signed and dated by all the parties concerned including the subject, legal guardian (where 
applicable), witness (where applicable) and the person obtaining the consent. 
 
A copy of the signed consent document must be given to the subject. The original signed consent 
document will be retained by the Investigator. 
 
The Investigator must inform the subject’s primary physician about the subject’s participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
 
 
 
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XII. PUBLICATION 
A. Use of Study Results 
 
All information concerning the product, as well as any matter concerning the operation of 
BioElectron Technology Corporation(such as clinical indications for the drug, its formula, 
methods of manufacture, and other scientific data relating to it, that have been provided by 
BioElectron Technology Corporation and are unpublished), are confidential and must remain the 
sole property of BioElectron. The Investigator will agree to use the information only for the 
purposes of carrying out this study and for no other purpose unless prior written permission from 
BioElectron Technology Corporation is obtained. The Sponsor has full ownership of the CRFs 
completed as part of the study. 
 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by BioElectron. If necessary, the authorities will be 
notified of the Investigator's name, address, qualifications, and extent of involvement. 
 
This Study is part of a multicenter clinical research study. Accordingly, Sponsor will act as 
coordinator and referee with respect to publications of the data generated thereunder. Principal 
Investigator shall not publish or disclose any data, result or information with respect to any 
matters resulting from work performed under this Protocol while this Study is being conducted at 
other center/s. Only after the completion of this Study at all other centers, provision of the data to 
the FDA or EMA for review and comment, and publishing the combined data from all of the 
centers, may the Principal Investigator publish/present the individual results of the Study in 
accordance with this paragraph. 
 
Principal Investigator may publish provided, however, that no publication, abstract, 
announcement or disclosure (“Publication”) shall be made until the Principal Investigator 
submits to Sponsor any proposed Publication for Sponsor’s review. Sponsor shall have a period 
of sixty (60) days to review such Publication. If Sponsor determines during the review period 
that the Publication contains patentable subject matter, then the above sixty (60) days shall be 
extended to one hundred twenty (120) days in order to allow for the preparation of patent 
applications covering said patentable subject matter. Unless Sponsor approves in writing, no 
Publication may contain any Confidential Information (other than data and results generated 
under the Study). 
 
Without limiting the foregoing, Institution and Principal Investigator, and all other study 
investigators in other study institutions, shall give due regard to Sponsor’s legitimate interests, 
such as manuscript authorship, coordinating and maintaining the proprietary nature of 
submissions to health authorities, and coordinating with other ongoing studies in the same field, 
and agree to accept Sponsor’s reasonable comments and suggestions with respect to such 
Publications. 


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If the Investigator is to be an author of a publication manuscript prepared by BioElectron 
Technology Corporation, BioElectron will allow the Investigator or CRO 60 days for full review 
of the manuscript before publication. 
 
 
 
 
 
 
 
 
 
 
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XIII. LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AR 
accumulation ratio 
BDI 
Beck Depression Inventory 
BID 
twice daily 
BSO 
L-buthionine-(S,R)-sulfoximine 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatinine kinase 
CNS 
central nervous system 
CoQ10 
Coenzyme Q 10 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DaT 
dopamine transporters 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EITT 
efficacy intent-to-treat 
EPDA 
European Parkinson’s Disease Association 
EU 
European Union 
%F 
percent fluctuation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GCRC 
good clinical research practice 
GDPR 
General Data Protection Regulation 
GSH 
glutathione 
GSSG 
glutathione disulfide 
HDPE 
high density polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HMPAO 
hexamethylpropylene amine oxime 
ICF 
informed consent form 
ICH 
International Committee on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 


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kg 
kilogram 
Λz 
apparent terminal constant 
LFT 
liver function test 
MAD 
multiple ascending (oral) dose 
MADRS 
Montgomery and Asberg Depression rating scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale 
mg 
milligram 
mL 
milliliter 
MoCA 
Montreal Cognitive Assessment 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
MPV 
mean platelet volume 
mtDNA 
mitochondrial DNA 
N/A 
not applicable 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NF 
National Formulary 
nM 
nanomolar 
NMSS 
Non-motor Symptoms Scale 
NOAEL 
no observed adverse effect level 
NQ01 
NAD(P)H Quinone oxidoreductase 1 
OD 
once daily 
OTC 
over-the-counter 
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PO 
by mouth 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 
PVP 
polyvinylpyrrolidone 
QT 
interval between the start of the Q wave and the end of the T wave 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAD 
single ascending (oral) dose 
SAE 
serious adverse event 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
Tmax 
time to peak concentration 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
UV 
ultraviolet 


 
 
Protocol EPI589-15-002 
EPI-589 
Version: Amendment 5.0 
 
XIV. SIGNATURE OF SPONSOR 
 
A. Declaration of Sponsor 
This study protocol was subject to critical review and the information it contains is consistent 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP as described in 21 CFR parts 50, 54, 56, and 
312. 
 
The Investigator will be supplied with details of any significant or new findings on EPI-589, 
including AEs. 
 
 
 
Date: 2 q S v{I r 2,-cl-,Signature: 
 
BioElectron Technology Corporation 
350 North Bernardo Ave 
Mountain View, CA 94043 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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XV. REFERENCES 
 
Ashrafi G, Schlehe JS, LaVoie MJ, Schwartz TL. Mitophagy of damaged mitochondria occurs 
locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014; 1;206(5):655- 
70. 
 
Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces 
features of Parkinson's disease. Nat Neurosci. 2000; 3(12): 1301-1306. 
 
Dauer W and Przedborski S. Parkinson's disease: mechanisms and models, Neuron 2003; 39: 
889–909. 
 
de Lau LM and Breteler MM. Epidemology of Parkinson’s Disease. Lancet Neur.2006; 5: 525- 
35. 
 
EPDA-European Parkinson’s Disease Association. http://www.epda.eu.com/en/resources/life- 
with-parkinsons/part-1/prevalence-of-parkinsons-disease/ (consulted 04 December 2014). 
 
Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, et al. Biochemical and pathological 
characterization of Lrrk2. Ann Neurol. 2006: 59(2): 315-22. 
 
Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, 
environment and mitochondria. Parkinsonism Relat. Disord. 2003; 9 (Suppl 2): S59–S64. 
 
Holmay, MJ, Terpstra M, Coles LD, et al. N-acetylcysteine Boosts Brain and Blood Glutathione 
in Gaucher and Parkinson Diseases. Clin. Neuropharm. 2013; 36, 4: 103-106. 
 
Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, et al. Glutathione Depletion in PC12 Results in 
Selective Inhibition of Mitochondrial Complex I Activity. Implications for Parkinson’s disease. J 
Biol Chem. 2000; 25;275 (34): 26096-101. 
 
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product 
of meperidine-analog synthesis. Science. 1983; 219: 979–980. 
 
Lin MT and Beal FB. Mitochondrial dysfunction and oxidative stress in neurodegenerative 
diseases. Nature. 2006; 443: 787-795. 
 
Maarouf CL, Beach TG, Adler CH, Shill HA, Sabbagh MN, et al. Cerebrospinal fluid 
biomarkers of neuropathologically diagnosed Parkinson's disease subjects. Neurol Res. 2012; 
34:669–676. 
 
Mao P and Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and 
mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and 
therapeutics. Biochim. Biophys. Acta. 2011; 1812: 1359-1370. 


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Narendra, DP and Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and parkin in 
mitochondrial quality control. Antioxi. Redox Signal. 2011; 14: 1929-1938. 
 
The Parkinson’s Disease Foundation. http://www.pdf.org/en/parkinson_statistics (consulted 27 
April 2015). 
 
Pinto M, Pickrell AM, Moraes CT. Regional susceptibilities to mitochondrial dysfunctions in the 
CNS. Biol. Chem. 2012; 393: 275-281. 
 
Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, et al. Transition metals, ferritin, 
glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 1989; Feb;52(2): 515-20. 
 
Winklhofer KF and Haass C. Mytochondrial dysfunction in Parkinson’s disease. Biochimica et 
Biophysica Acta. 2010; 1802: 29-44. 
 
Zhu X, Babar A, Siedlak SL, Yang Q, Ito G, et al. LRRK2 in Parkinson's disease and dementia 
with Lewy bodies. Mol Neurodegener. 2006;1:17. 


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Summary of Changes 
Amendment 5.0 
EPI589-15-002 
 
A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial Subtype and 
Idiopathic Parkinson’s Disease Subjects 
 
Protocol Number 
EPI589-15-002 
Original Protocol Date 
27 April 2015 
Amendment 1.0 Date 
09 September 2015 
Amendment 2.0 Date 
04 January 2016 
Amendment 3.0 Date 
10 October 2016 
Amendment 4.0 Date 
17 February 2017 
Amendment 5.0 Date 
29 September2017 
Study Sponsor 
BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Sponsor’s Representative 
 
BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
 
The information contained in this document is confidential and will not be disclosed to others 
without written authorization from BioElectron Technology Corporation, except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be 
administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the 
study. 


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Amendment 5.0 provides the following change and rationale: 
 
 
Change 
Rationale 
1. Fasting conditions for biomarker 
samples 
To clarify that biomarker samples should be fasting samples. 
2. Added the term morning and evening 
dose to BID 
To provide further clarification that dosing is twice daily rather 
than every 12 hours. 
3.  Non-clinical studies language 
To provide updated information on nonclinical studies. 
4. Changed the language under 
pharmacokinetics (PK) section 
To clearly define the expected number of PK blood draws 
5. Changed the timed motor test as ON 
state only (for subjects on dopamine 
therapy) 
To clarify that sites can perform TUG test on subjects in ON 
state only 
6.  Dose Limiting Toxicity 
To provide clear definition for dose limiting toxicities (DLTs) 
7.  Administration of clinical assessment 
To clarify the primary administrator of the PD assessments for 
the study 
8. Washout period for subjects on high 
doses of Vitamin E or C 
To clarify the need for a 2 week wash out prior to enrollment 
for subjects on higher doses of vitamin C and E supplements 
9. CBC differential as absolute or 
percentages 
For better clarity about recording the values 
10. CO2 for serum chemistry 
CO2 is taken and assessed as biocarbonate in most clinical 
labs. Hence replaced the term Co2 as bicarbonate in the 
protocol. This is a venous sample. 
11. Day 1 first dose language 
To clarify that first dose may be taken same day as baseline 
visit after completing all assessments 
12. Changed the height measurement to 
screening visit only 
To clarify that height measurement need not be repeated after 
screening visit 
13. Included breast exam as part of 
screening physical exam 
To capture the findings from breast exam as part of the 
screening physical exam 
14. Removed language in adverse event 
reporting 
To clarify reporting for adverse events 
15. Changed the AE language under 
post-treatment follow up 
To clearly define the post treatment follow-up to be at least 10 
days after last dose and if there are any ongoing or new AEs 
noted at month 3, then the follow up will be up to 30 days after 
last dose 
 
 
 
 
DESCRIPTION OF CHANGES TO THE PROTOCOL 


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Changes to the protocol by section appear in the table below. Administrative and editorial 
clarifications, corrections or adjustments may not be individually identified. 
 
In this summary document, bold italic font indicates additions to existing text, and strikethrough 
font indicates deleted text. The actual amended protocol does not include bold or strikethrough 
font to indicate changes. 
 
Protocol Section 
Modification 
I. Synopsis 
Study Objectives 
Secondary Objectives 
To evaluate the effects of EPI-589 in subjects with PD on: 
1. Fasting Gglutathione cycle biomarkers as measured in blood, cerebral spinal 
fluid, and urine 
I. Synopsis 
Test product, mode of 
administration and dose 
Dose 
EPI-589 500-mg BID (morning and evening dose along with food) 
I. Synopsis 
Efficacy variables 
1. Fasting Bblood-based glutathione biomarkers 
2. Fasting CNS biomarkers 
3. Fasting Uurine-based biomarkers 
11. Timed motor tests in ON and OFF state only (for subjects on dopamine 
therapy) 
IV. Study Objectives 
B. Safety Variables 
Clinical 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
4. C-SSRS 
5. Laboratory 
6. Routine serum chemistries with liver function tests 
7. Routine hematology tests with coagulation tests 


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III. Introduction 
D1. Non Clinical Studies 
EPI 589 is an orally available compound that has been demonstrated in vitro and 
in vivo to cross the blood-brain-barrier. In 28-day and 91-day repeat-dose toxicity 
studies in rat and cynomolgus monkey, the no observed adverse effect level 
(NOAEL) was 300 mg/kg/day, corresponding to combined mean Cmax values of 
37,717 to 56,500 ng/mL (rat) and 14,300 to 16,417 ng/mL (monkey), and a 
combined mean area under the plasma concentration time curve from time zero to 
the last measurable concentration (AUClast) value of 149,495 to 297,000 
ng.h/mL (rat) and 47,300 to 67,656 ng.h/mL (monkey) (Studies 1660 038, 1660 
039, 1660 063, and 1660 064). 
A phase 1 clinical study demonstrated that healthy subjects administered 500 mg 
EPI 589 BID for 14 days showed a mean Cmax value of 1,890 ng/mL and a mean 
AUClast value of 5,240 ng.h/mL (Study EPI589-14-01). These plasma 
concentrations are well below the mean exposure values in monkey associated 
with the NOAEL in the toxicity studies, corresponding to safety margins of 
approximately 7 to 8 fold for the mean Cmax and 9 to 12 fold for the mean 
AUC. 
During the 28 day repeat dose toxicity studies, rat and monkey were exposed to 
up to 1,000 mg/kg/day EPI 589 PO (Studies 1660 039 and 1660 038). The 
NOAEL for both studies was 300 mg/kg/day. Rats exposed to 1,000 mg/kg/day 
exhibited adverse test article related effects on hematology parameters consistent 
with hemolysis and bone marrow regeneration, mild to moderately enlarged 
spleens, and increased organ weights with some organs showing corresponding 
microscopic pathology. The majority of these findings were resolved following 
the 28 day recovery period. Monkeys exposed to 1,000 mg/kg/day showed 
significant test article related morbundity that resulted in half the animals in the 
high dose group being euthanized on Days 3 and 4 and the remaining animals 
being euthanized on Day 9. These animals exhibited significant elevations in 
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values, 
and microscopic findings in the kidney, liver, skeletal muscle, heart, and 
lymphoid tissues. In several of the animals the primary cause of morbidity was 
determined to be test article related renal tubular degeneration/necrosis. 
During the 91 day repeat dose toxicity studies, rat and monkey were exposed to 
up to 300 mg/kg/day EPI 589 PO (Studies 1660 063 and 1660 064). The NOAEL 
for the rat study was 300 mg/kg/day and the no observed effect level (NOEL) for 
the monkey study was 300 mg/kg/day. Male rats exposed to 300 mg/kg/day and 
female rats exposed to ≥ 100 mg/kg/day exhibited mild test article related effects 
on hematology parameters consistent with hemolysis and bone marrow 
regeneration. These findings were not considered adverse. 
Development and reproductive toxicology studies were conducted in rat and 
rabbit at doses up to 1,000 mg/kg/day EPI 589 PO (Studies 1660 069, 1660 067, 
and 1660 068). The NOAEL for reproductive toxicity in rat was demonstrated to 
be 1,000 mg/kg/day (1660 069). The NOAEL for developmental toxicity in rat 
and rabbit during the embryofetal studies was deemed to be 300 mg/kg/day 
(Studies 1660 067 and 1660 068). 


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Rats exposed to 1,000 mg/kg/day exhibited decreased maternal body weights, 
decreased food consumption, and decreased fetal body weights. There was no 
teratogenic potential in rat at doses up to 1,000 mg/kg/day. Rabbits exposed to 
1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, decreased number of viable fetuses, decreased litter size, increased 
postimplantation loss, increased resorptions (early and late), and increased fetal 
skeletal malformations. The margin of exposure between healthy humans exposed 
to 500 mg BID EPI-589 (relevant clinical dose) for 14 days (Study EPI589-14-01) 
and rabbits exposed to 1,000 and 300 mg/kg/day EPI 589 is approximately 179 
to 236 fold and 47 to 50 fold, respectively. Based on these data, EPI 589 is not 
anticipated to increase the risk of adverse developmental or reproductive 
outcomes in humans when used in accordance with dosing information. 
EPI-589 was negative for mutagenic response in the in vitro Ames bacterial 
reverse mutation assay (Study AD58AS.502ICH.BTL); equivocal for the 
induction of structural and negative for the induction of numerical chromosomal 
aberrations in the in vitro chromosome aberration assay in Chinese hamster ovary 
(CHO) cells (Study AD58AS.331ICH.BTL); and negative in the in vivo 
micronucleus assay in rat (Study AD58AS.125012ICH.BTL). These data indicate 
a low clinical mutagenicity risk. 
Primary pharmacodynamics studies demonstrated that EPI 589 is a potent rescue 
agent in cellular models of diseases of energy metabolism and oxidative stress. In 
vitro cellular models utilizing primary human fibroblasts from patients with ALS, 
Parkinson’s disease and other diseases characterized by high levels of oxidative 
stress, or striatal cells derived from mouse models of Huntingdon’s disease were 
used to assess the potential of EPI 589 to mitigate the harmful effects of oxidative 
stress (Studies EPI BA 000216, EPI BA 000363, and EPI BA 000362). 
Pretreatment of patient cells with EPI 589 potently protected against oxidative 
stress mediated cell death in a concentration dependent manner. Furthermore, 
EPI 589 normalized 3 nitrosotyrosine (3NT) levels, a biomarker of oxidative 
stress, and increased glutathione levels in mouse striatal cells under oxidative 
stress conditions. 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, 
EPI 589 did not significantly affect off target molecular targets (Study EPI BA 
159). In safety pharmacology studies, EPI 589 did not significantly affect ion 
channel current in the hERG assay (Study 130719.FEK); did not affect ECG 
parameters during the 28 day and 3 month repeat dose toxicology studies in 
monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for animals 
administered 1,000 mg/kg/day and up to Day 91 data collected for animals 
administered up to 300 mg/kg/day) (Studies 1660 038 and 1660 064); and did not 
change respiratory function or adversely impact neurobehavioral function in rat at 
doses up to 1,000 mg/kg (Studies 1660 051, 1660 050, and 1660 063). 
In single dose exposure PK studies, EPI 589 was absorbed rapidly in rat, dog, and 
monkey, with mean Tmax values ranging from .08 to 1 hour and mean T1/2 
values ranging from 3.7 to 5.0 hours (Studies EPI BA 53, EPI BA 59, EPI BA 
72, and EPI BA 302). EPI 589 does not significantly induce cytochrome P450 
(CYP) enzymes and appears to be metabolized by reductases in the liver cytosol 


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and microsomal subcellular fractions and to a lesser extent by the family of CYP 
enzymes (Studies MC12M 0037 and MC14M 0018). 
EPI-589 exhibited weak direct inhibition of CYP2B6, CYP2C8, CYP2C9, and 
CYP3A4/5 (both midazolam and testosterone as probe substrates) with estimated 
IC50 (μM) values and R values based on free plasma concentrations (shown in 
parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 34 (1.21), and 53 (1.13), 
respectively (Study MC14M 0020)Based on these data, EPI 589 is not anticipated 
to increase the risk of adverse developmental or reproductive outcomes in humans 
when used in accordance with dosing information. 
EPI-589 is an orally available compound that has been demonstrated in vitro 
and in vivo to cross the blood-brain-barrier. In 28-day, 91-day, 6-month, and 9- 
month repeat-dose toxicity studies in rat and cynomolgus monkey, the no 
observed adverse effect level (NOAEL) was 300 mg/kg/day, corresponding to 
terminal combined mean Cmax values of 37,717 to 56,500 ng/mL (rat) and 
14,300 to 24,500 ng/mL (monkey), and terminal combined mean area under the 
plasma concentration-time curve (AUC) values of 149,495 to 297,000 ng.h/mL 
(rat) and 47,300 to 124,000 ng.h/mL (monkey) (Studies 1660-038, 1660-039, 
1660-063, 1660-064, 1660-079, and 1660-080). 
The dose-limiting drug-associated toxicity observed in the 28-day, 3-month, and 
9-month (monkey) animal studies was hemolysis in rat and significant acute 
toxicity leading to moribundity with indication of skeletal, renal, liver, and 
lymphoid tissue effects in monkey. All clinical program investigators have been 
required to monitor hematology parameters and clinical chemistry parameters 
for kidney, liver, and muscle function in all EPI-589 subjects. To date, no dose- 
limiting toxicities have been reported with EPI-589 in humans. 
A phase 1 clinical study demonstrated that healthy young and elderly subjects 
administered 500 mg EPI-589 BID for 14 days showed mean Cmax values of 
1,890 to 1,960 ng/mL and mean AUC values of 10,480 to 11,000 ng.h/mL 
(Study EPI589-14-01). These plasma concentrations are well below the 300 
mg/kg/day NOAEL exposure values in monkey, the most sensitive toxicity 
species, corresponding to repeat-dose exposure safety margins of approximately 
7- to 12- fold for the mean Cmax and 4- to 8-fold for the mean AUC. 
During the 9-month repeat-dose toxicity study in monkey, animals were 
administered 60, 100, 300, or 500 mg/kg/day EPI-589 PO (Study 1660-080). 
The NOAEL was 300 mg/kg/day. Monkeys that received 500 mg/kg/day showed 
significant test-article related moribundity after receiving only three or four 
doses resulting in three animals being euthanized on Days 4, 5, and 7 and the 
remaining animals being euthanized on Day 11 


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Animals exhibited significant elevations in AST and ALT values, and 
microscopic findings in multiple sites in the skeletal muscle, kidney, liver, and 
lymphoid tissues. The primary cause of morbidity in the three animals 
euthanized on Days 4, 5, and 7 was myofiber degeneration and degenerative 
changes in kidney (3/3 animals). The toxicity observed following administration 
of three to four doses of 500 mg/kg/day EPI-589 were similar and consistent 
with toxicity observed following administration of two doses of 1,000 mg/kg/day 
during the 28-day toxicity study (Study 1660-038), likely due to similar 
exposures between the two doses. The margin of exposure between healthy 
young and elderly humans exposed to 500 mg BID EPI-589 (relevant clinical 
dose) for 14 days (Study EPI589-14-01) and monkeys exposed to EPI-589 PO 
on Day 1 is approximately 26-fold for the mean Cmax and 21-fold for the mean 
AUClast at 500 mg/kg, and approximately 29-fold for the mean Cmax and 27-fold 
for the mean AUClast at 1,000 mg/kg. 
During the 6-month repeat-dose toxicity study in rat, animals were exposed to 
up to 300 mg/kg/day EPI-589 PO (Study 1660-079). The NOAEL was 300 
mg/kg/day. Rats exposed to 300 mg/kg/day exhibited mild test-article related 
effects on hematology parameters consistent with hemolysis and compensating 
reticulocytosis. These findings were not considered adverse. 
During the 91-day repeat-dose toxicity studies, rat and monkey were exposed to 
up to 300 mg/kg/day EPI-589 PO (Studies 1660-063 and 1660-064). The 
NOAEL for the rat study was 300 mg/kg/day and the no observed effect level 
(NOEL) for the monkey study was 300 mg/kg/day. Male rats exposed to 300 
mg/kg/day and female rats exposed to ≥ 100 mg/kg/day exhibited mild test- 
article related effects on hematology parameters consistent with hemolysis and 
bone marrow regeneration. These findings were not considered adverse. 
During the 28-day repeat-dose toxicity studies, rat and monkey were exposed to 
up to 1,000 mg/kg/day EPI-589 PO (Studies 1660-039 and 1660-038). The 
NOAEL for both studies was 300 mg/kg/day. Rats exposed to 1,000 mg/kg/day 
exhibited adverse test-article related effects on hematology parameters 
consistent with hemolysis and bone marrow regeneration, mild to moderately 
enlarged spleens, and increased organ weights with some organs showing 
corresponding microscopic pathology. The majority of these findings were 
resolved following the 28-day recovery period. Monkeys exposed to 1,000 
mg/kg/day showed significant test-article related moribundity after receiving 
only two doses resulting in half the animals in the high dose group being 
euthanized on Days 3 and 4 and the remaining animals being euthanized on 
Day 9. Animals exhibited significant elevations in aspartate aminotransferase 
(AST) and alanine aminotransferase (ALT) values, and microscopic findings in 
multiple sites in the skeletal muscle, kidney, liver, lymphoid tissues, and heart. 
The primary cause of morbidity in five animals euthanized on Days 3 and 4 was 
renal tubular degeneration and necrosis (2/5 animals) or was not able to be 
determined (3/5 animals). 


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Development and reproductive toxicology studies were conducted in rat and 
rabbit at doses up to 1,000 mg/kg/day EPI-589 PO (Studies 1660-069, 1660-067, 
and 1660-068). The NOAEL for reproductive toxicity in rat was demonstrated 
to be 1,000 mg/kg/day (Study 1660-069). The NOAEL for developmental 
toxicity in rat and rabbit during the embryofetal studies was deemed to be 
300 mg/kg/day (Studies 1660-067 and 1660-068). Rats exposed to 1,000 
mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, and decreased fetal body weights. There was no teratogenic 
potential in rat at doses up to 1,000 mg/kg/day. Rabbits exposed to 
1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, decreased number of viable fetuses, decreased litter size, 
increased postimplantation loss, increased resorptions (early and late), and 
increased fetal skeletal malformations. The margin of exposure between 
healthy young and elderly humans exposed to 500 mg BID EPI-589 (relevant 
clinical dose) for 14 days (Study EPI589-14-01) and rabbits exposed to 300 or 
1,000 mg/kg/day EPI-589 is approximately 22-fold and 84-fold, respectively. 
Based on these data, EPI-589 is not anticipated to increase the risk of adverse 
developmental or reproductive outcomes in humans when used in accordance 
with dosing information. 
EPI-589 was negative for mutagenic response in the in vitro Ames bacterial 
reverse mutation assay (Study AD58AS.502ICH.BTL); equivocal for the 
induction of structural and negative for the induction of numerical 
chromosomal aberrations in the in vitro chromosome aberration assay in 
Chinese hamster ovary (CHO) cells (Study AD58AS.331ICH.BTL); and 
negative in the in vivo micronucleus assay in rat (Study 
AD58AS.125012ICH.BTL). These data indicate a low clinical mutagenicity 
risk. 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, 
EPI-589 did not significantly affect off-target molecular targets (Study EPI- 
BA-186). In safety pharmacology studies, EPI-589 did not significantly affect 
ion channel current in the human ether-a-go-go-related gene (hERG) assay 
(Study 130719.FEK); did not adversely affect electrocardiogram (ECG) 
parameters during the 28-day, 3-month, or 39-week repeat-dose toxicology 
studies in monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for 
animals administered 500 or 1,000 mg/kg/day and up to Day 91 data collected 
for animals administered up to 300 mg/kg/day) (Studies 1660-038, 1660-064, 
and 1660-080); and did not change respiratory function or adversely impact 
neurobehavioral function in rat at doses up to 1,000 mg/kg (Studies 1660-051, 
1660-050, and 1660-063). 
EPI-589 is approximately 60% protein bound in human plasma (Study 
MC14M-0067). EPI-589 did not significantly induce cytochrome P450 (CYP) 
enzymes (Study MC12M-0037) and exhibited weak direct inhibition of CYP2B6, 
CYP2C8, CYP2C9, and CYP3A4/5 (both midazolam and testosterone as probe 


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substrates) with estimated IC50 (µM) values and R values based on free plasma 
concentrations (shown in parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 
34 (1.21), and 53 (1.13), respectively (Study MC14M-0020). EPI-589 is 
metabolized by reductases in the liver cytosol and microsomal subcellular 
fractions, and to a lesser extent by the family of CYP enzymes (Study MC14M- 
0018). EPI-589 is an inhibitor of the BCRP efflux transporter, possibly an 
inhibitor of the MATE1, OATP1B3, MATE2-K, OCT1, OATP1B1, OCT2 and 
OAT3 uptake transporters (in order of increasing inhibitory potential), and 
possibly a substrate of the MDR1 and BCRP efflux transporters (Edison-04- 
25Feb2014). 
An in vivo primary pharmacodynamic study demonstrated that EPI-589 
significantly reduced disease progression as measured by standard functional 
outcomes of rotarod test and forelimb deformity score as compared with vehicle 
controls in the gold standard in vivo wobbler mouse model of ALS. These EPI- 
589 effects were superior to riluzole. In addition, EPI-589 had synergistic 
effects with riluzole when co-administered. These results indicate that EPI-589, 
alone or in combination with riluzole, may have beneficial effects on the 
progression of neuromuscular dysfunction in ALS patients (Study R-PH-EPI- 
589-002). 
In vitro primary pharmacodynamics studies demonstrated EPI-589 is a potent 
rescue agent in cellular models of diseases of energy metabolism and oxidative 
stress. In vitro cellular models utilizing primary human fibroblasts from 
patients with ALS, Parkinson’s disease and other diseases characterized by 
high levels of oxidative stress, or striatal cells derived from mouse models of 
Huntingdon’s disease were used to assess the potential of EPI-589 to mitigate 
the harmful effects of oxidative stress (Studies EPI-BA-000216, EPI-BA- 
000363, and EPI-BA-000362). Pretreatment of patient cells with EPI-589 
potently protected against oxidative stress-mediated cell death in a 
concentration dependent manner. Furthermore, EPI-589 normalized 3- 
nitrosotyrosine (3NT) levels, a biomarker of oxidative stress, and increased 
glutathione levels in mouse striatal cells under oxidative stress conditions. 
The nonclinical laboratory studies conducted in accordance with the United 
States Food and Drug Administration (FDA) Good Laboratory Practice (GLP) 
Regulations 21 Code of Federal Regulations (CFR) Part 58 were conducted in 
conformance with the principles of OECD-GLP in the United States, a country 
that is part of the OECD Mutual Acceptance of Data process. 


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IV. Study Objectives 
B. Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with 
PD on: 
Fasting Gglutathione cycle biomarkers as measured in blood, cerebral spinal 
fluid, and urine 
V. Investigational Plan 
A4. Treatment Phase 
EPI-589 dosing will start on Day 1. Subjects will self-administer EPI-589 at a 
dose of 500-mg BID (morning and evening dose along with food) 
V. Investigational Plan 
A4. Post-Treatment 
Follow-up 
Post-Treatment Follow-up will be at least 10 days after last dose and if there are 
any ongoing or new AEs noted at month 3 then the follow up will be up to 30 
days after last dose: AE/SAE and concomitant medication assessments conducted 
by telephone. Additional assessments to be determined at Investigator discretion. 
VI. Study Procedures 
A. Screening Visit 
4. Physical examination* including vital signs 
5. Height** and Weight 
7. Laboratory assessments for hematology, coagulation, and serum chemistry*** 
* Breast exam is at screening physical exam only. 
**Height is measured at screening visit only. 
*** Screening values can be used if done within one month of baseline and 
if completed under fasted conditions 
VI. Study Procedures 
A1. Run-In Assessments 
1. Fasting Bblood-based glutathione cycle biomarkers 
2. Fasting CNS biomarkers (lumbar puncture) 
3. Fasting Uurine biomarkers 


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VI. Study Procedures 
Treatment Phase 
After the Run-in phase, the subject must return to the clinic within 30 days (± 3 
days) for baseline assessments. In-clinic study visits are scheduled at Month 1 and 
Month 3. The Month 2 study assessments can be conducted via telephone. End of 
treatment assessments will be conducted at the Month 3 study visit. 
Pharmacokinetic sampling takes place at Month 1 and Month 3. The baseline and 
all subsequent laboratory assessments should be obtained under fasting 
conditions. 
B1. Baseline Assessments 
The following will be assessed or performed at this visit. 
4. Fasting Bblood-based GSH cycle biomarkers 
5. Fasting Uurine-based biomarkers 
6. Laboratory assessments for hematology, coagulation and serum 
chemistry* 
*Screening results for these assessments may be used if obtained within 1 
month of Baseline and if they are completed under fasted conditions. The 
baseline laboratory assessments should be obtained under fasting 
conditions. 
VI. Study Procedures 
B2. Study Visit 
Assessments 
Month 1 Clinic Visit (Day 29 ± 3 days) 
The following will be assessed or performed at the Month 1 clinic visit: 
7. Laboratory assessments for hematology, coagulation, and serum 
chemistry* 
8. Fasting Bblood-based GSH cycle biomarkers 
9. Fasting Uurine-based biomarkers 
10. Pharmacokinetics**: a full plasma drug concentration profile will be 
obtained from the first 10 subjects to complete 1 month of therapy at each 
site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours after dosing. 12 hour 
time point may be obtained at 0 hour. 
*The laboratory assessments should be obtained under fasting conditions. 


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VI. Study Procedures 
B2. Study Visit 
Assessments 
Month 3 Clinic Visit (Day 85 ± 3 days) 
The following will be assessed or performed at the Month 3 clinic visit: 
7. Laboratory assessments for hematology, coagulation, and serum 
chemistry* 
8. Fasting Bblood-based GSH cycle biomarkers 
9. Fasting Uurine-based biomarkers 
10. Fasting CNS biomarkers 
13. Pharmacokinetics**: a full plasma drug concentration profile will be 
obtained from the first 10 subjects to complete 1 month of therapy at each 
site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours after dosing.12 hour 
time point may be obtained at 0 hour. 
*The laboratory assessments should be obtained under fasting conditions. 
VI. Study Procedures 
B3. Pharmacokinetics 
Plasma concentration samples will be collected from 20 subjects (10 idiopathic 
and 10 with genetically defined subtypes) the first 10 subjects to complete 1 
month of therapy at each site, at the following time points: 
• Month 1 (Day 29 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours 
post-dose 
• Month 3 (Day 85 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours 
post-dose 
** 12 hour PK can be obtained at time 0 
The pharmacokinetics samples collection will be monitored as subjects are 
enrolling and Sponsor will alert each principal investigator once the required 
samples for each subtype are obtained. 
VI. Study Procedures 
H. Prohibited Medications 
The following are prohibited while the subject is on study treatment: 
1. Use of antioxidants, specifically vitamins E and C beyond the 
recommended daily allowance. However if the subjects are on high doses 
of Vitamin E and C and are eligible to participate , they are allowed a 2 
weeks washout period prior to enrollment. 
2. Participation 3 months prior to and for the duration of the study in a trial 
of a device, drug or other therapy for PD 


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VII. Study Endpoints and 
Evaluations 
B. Secondary Endpoints 
(Efficacy) 
1. Fasting Bblood-based glutathione biomarkers 
2. Fasting CNS biomarkers 
3. Fasting Uurine-based biomarkers 
11. Timed motor tests in ON and OFF state only (for subjects on dopamine 
therapy) 
VII. Study Endpoints and 
Evaluations 
D1. Physical Examination, height and weight 
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. 
Vital sign measurements (pulse rate, blood pressure and respiration rate) will be 
obtained in the sitting position (after the subject has been sitting for five minutes). 
The findings from breast exam will be captured as part of the screening 
physical exam. The findings from breast exams conducted within 6 months of 
the screening visit and those collected as part of medical history, may be used 
for the screening physical exam. 
Medical history and demographics including age, gender, race, height and weight 
will be collected at Screening. 
D2. Height and Weight 
Weight (kg) will be measured in ordinary indoor clothing (i.e., street clothes, 
scrubs, etc.) with shoes off. Height will be recorded in centimeters (cm) and need 
not be repeated after screening visit. 
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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VII. Study Endpoints and 
Evaluations 
D2. Laboratory 
Evaluations 
a. Hematology 
a. Leukocytes: white blood cell count (WBC) and differential (basophils, 
eosinophils, lymphocytes, monocytes, and neutrophils). The differential 
can be recorded as an absolute value or percentages. 
b. Serum Chemistry 
c. Electrolytes: sodium, potassium, chloride and carbon dioxide (CO2 ) 
bicarbonate 
VII. Study Endpoints and 
Evaluations 
D3. Dose Limiting 
Toxicity (DLT) 
There were no DLTs noted in the phase 1 study; the dose-limiting (NOAEL) in 
nonclinical studies, as described in the protocol were increased LFTs (ALT, 
AST), rhabdomyolysis (elevated CPK), renal dysfunction (likely secondary to 
rhabdo), and marrow toxicity (most notably hemolysis). Therefore for this 
study, any increased LFT, BUN/Cr or CPK (or CK) should be considered 
related to study drug and should be designated as a DLT. If there is a DLT, a 
dose reduction will be attempted. Contact the medical monitor for further 
instructions. 
VII. Study Endpoints and 
Evaluations 
F. Efficacy Evaluations 
F1. Fasting Glutathione Cycle Biomarkers 
VII. Study Endpoints and 
Evaluations 
F. Efficacy Evaluations 
F2. Study Clinical Assessments 
The investigator or sub-investigator should be the primary administrator of 
these assessments, though they may delegate this study procedure to another 
qualified staff member on their team. It is recommended that the same 
administrator conduct this assessment on the same patient(s) throughout the 
study to ensure consistency when at all possible. 


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VII. Study Endpoints and 
Evaluations 
F2. Administration of 
Study Clinical 
Assessments 
h. Timed Motor Tests in ON and OFF state only (for subjects on dopamine 
therapy) 
Timed motor tests are simple, objective, quantitative measures for the assessment 
of Parkinson’s disease. They include, in an on-medication and an off-medication 
state, timed recorded physical movements. Since missing dopamine could 
impair a subject’s mobility including their ability to drive the next morning for 
study visits, the subjects should be encouraged to continue to take their 
dopamine as prescribed. In order to avoid missing PM dose of the dopamine the 
previous night, the sites can perform the TUG test on subjects as ON state only. 
VIII. Statistical 
Considerations 
C. Efficacy Analysis 
1. Fasting Bblood-based glutathione biomarkers 
2. Fasting CNS biomarkers 
3. Fasting Uurine-based biomarkers 
11. Timed motor tests in ON and OFF state only (for subjects on dopamine 
therapy) 
X. Safety Management 
B. Adverse Event Reporting 
All SAEs will be reported to the IRB/IEC in accordance with their the IRB 
policies and as detailed below. AEs that are not serious will be summarized in 
narrative or other format and submitted to the IRB at the time of continuing 
review. 
C8. Follow-up Report 
If an SAE has not resolved at the time of the initial report, a follow-up report 
including all relevant new or reassessed information (e.g., concomitant 
medication, medical history) should be submitted to the IRB/ IEC . All SAEs 
should be followed until either resolved or stable. 
 
End of Document 
#### 


 
௭ 
 
 
 
 
EPI589-15-002 
A Phase 2A Safety 
and Biomarker Study of 
EPI-589 in Mitochondrial 
Subtype and Idiopathic 
Parkinson's Disease Subjects 
 
 
 
Original Protocol: 
Protocol Amendment 1.0: 
Protocol Amendment 2.0: 
Protocol Amendment 3.0: 
Protocol Amendment 4.0: 
27 April 2015 
09 September 2015 
04 January 2016 
10 October 2016 
17 February 2017 
 
BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
The information contained in this document is confidential and will not be disclosed to others without 
written authorization from BioElectron except to the ex,tent necessary to obtain informed consent from 
those persons to whom tile drug may be administered or for discussions with local regulatory authorities, 
Ethics Committee/lnvestigational Review Boards, or people participating in the conduct of tile study. 


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Table of Contents 
I. PROTOCOL SYNOPSIS .................................................................................................. 6 
I. EDULE OF ASSESSMENTS AND DOSING SCHEDULE ........................................ 11 
A. hedule of Dosing .......................................................................................................... 12 
I. 13 
A. round Information and Rationale ............................................................................. 13 
B. nale for the Study of EPI-589 in Parkinson’s Disease ............................................. 14 
C. and Description of Investigational Product .............................................................. 14 
D. ngs from Non-Clinical and Clinical Studies ............................................................. 15 
D1. Non-Clinical Studies .................................................................................................. 15 
D2. Clinical Studies ........................................................................................................... 17 
E. Pharmacokinetics ........................................................................................................ 17 
F. 
18 
G. ction of Drugs and Dosages ......................................................................................... 18 
H. ce Statement ................................................................................................................ 18 
I. 
erature and Data ......................................................................................................... 18 
I. ES ...................................................................................................................................... 19 
A. y Objective ................................................................................................................... 19 
B. bjectives ....................................................................................................................... 19 
I. ONAL PLAN .................................................................................................................... 20 
A. hema of Study Design ................................................................................................. 20 
A1. Screening Phase ......................................................................................................... 20 
A2. 30-Day Run-in Phase ................................................................................................. 20 
A3. Baseline ...................................................................................................................... 20 
A4. Treatment Phase ........................................................................................................ 20 
A5. End of Treatment........................................................................................................ 21 
A6. Post-Treatment Follow-up ......................................................................................... 21 
B. and Blinding ................................................................................................................ 21 
C. Enrollment and Number of Sites ............................................................................... 21 
C1. Duration of Subject Treatment ................................................................................... 21 
C2. Total Number of Study Sites/Total Number of Subjects Projected ............................ 21 
D.  


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D1. Inclusion Criteria ....................................................................................................... 22 
D2. Exclusion Criteria ...................................................................................................... 22 
I. 24 
A. it .................................................................................................................................... 24 
A1. Run-in Assessments ..................................................................................................... 24 
B. 24 
B1. Baseline Assessments .................................................................................................. 25 
B2. Study Visit Assessments .............................................................................................. 25 
B3. Pharmacokinetics ....................................................................................................... 26 
B4. Early Termination Study Visit .................................................................................... 26 
C. nt Visit .......................................................................................................................... 27 
D. ent Follow-up ............................................................................................................... 27 
E.  
F. 
tion ................................................................................................................................ 27 
G. dications ....................................................................................................................... 27 
H. wals ............................................................................................................................... 27 
I. 
29 
A.  
B. cy) ................................................................................................................................. 29 
C. fety) .............................................................................................................................. 29 
D. uation ........................................................................................................................... 29 
D1. Physical Examination................................................................................................. 29 
D2. Height and Weight ..................................................................................................... 30 
D3. Laboratory Evaluations ............................................................................................. 30 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) .................................................... 31 
E. cedures, Bioanalytical Methods and Sample Shipment .......................................... 31 
F. 
 
F1. Glutathione Cycle Biomarkers ................................................................................... 31 
F2. Parkinson’s Disease Rating (MDS-UPDRS) ............................................................. 31 
F3. Non-motor Symptoms (NMSS) ................................................................................... 32 
F4. Parkinson’s Disease Questionnaire (PDQ-39) ......................................................... 32 
F5. EQ-5D ........................................................................................................................ 32 


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F6. Montreal Cognitive Assessment (MoCA) ................................................................... 32 
F7. Beck Depression Inventory (BDI) .............................................................................. 32 
F8. Montgomery and Asberg Depression rating scale (MADRS) .................................... 32 
F9. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) ........... 33 
I. 
34 
A.  
A1. Analysis Populations ................................................................................................... 34 
B.  
B1. Efficacy Variables ...................................................................................................... 34 
C.  
D.  
I. 36 
A.  
B.  
B1. Labeling ..................................................................................................................... 36 
B2. Dosage Form .............................................................................................................. 36 
B3. Dispensing.................................................................................................................. 36 
C. Adherence .................................................................................................................... 36 
D.  
I.  
A.  
B.  
B1. Safety Guidance ......................................................................................................... 38 
C. ent ................................................................................................................................. 38 
C1. Adverse Event ............................................................................................................. 38 
C2. Definition of a Serious Adverse Event (SAE) ............................................................. 39 
C3. Non-serious Adverse Event ........................................................................................ 40 
C4. Definition of Relationship to Study Medication .......................................................... 40 
C5. Definition of Severity ................................................................................................. 40 
C6. Definition of Unexpected Adverse Event .................................................................... 41 
C7. Notification of SAEs ................................................................................................... 41 
C8. Follow-up Report ....................................................................................................... 42 


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C9. Dose Modification Guidelines ................................................................................... 42 
D.  
D1. Emergency Sponsor Contact ...................................................................................... 43 
D2. Emergency Treatment ................................................................................................ 43 
I. 44 
A. 44 
B.  
C.  
D.  
E.  
F. 
46 
G.  
G1. Risk Assessment .......................................................................................................... 46 
G2. Potential Benefits of Trial Participation .................................................................... 46 
G3. Risk-Benefit Assessment ............................................................................................. 46 
H.  
I. 
48 
A.  
II. 
50 
I. 
52 
A.  
II. 53 
 
 
 
 
 
Space intentionally left blank 


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I. 
PROTOCOL SYNOPSIS 
 
Title of study 
A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial 
Subtype and Idiopathic Parkinson’s Disease Subjects 
Protocol number 
EPI589-15-002 
IND number 
126,795 
EudraCT number 
2015-001786-10 
Original Protocol 
27 April 2015 
Protocol Amendment 1.0 
09 September 2015 
Protocol Amendment 2.0 
04 January 2016 
Protocol Amendment 3.0 
10 October 2016 
Protocol Amendment 4.0 
17 February 2017 
Investigative Drug 
EPI-589 
Study Sponsor 
BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Investigators and 
Investigative Sites 
• 
USA 
• 
USA 
• 
UK 
• 
USA 
• 
Germany 
Study population 
Approximately 40 subjects with Parkinson’s disease (PD) including 20 
subjects with genetically-defined subtypes 


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Rationale for Study 
Mitochondrial pathophysiology 
It is now well appreciated that defects in mitochondrial function contribute 
to the pathophysiology of PD both in subjects with defined genetic defects 
as well as those with idiopathic forms of the disease. 
High morbidity 
Despite the available therapies for symptomatic relief, PD remains a highly 
morbid disease. There are no approved treatments for PD capable of 
modifying disease progression. 
Pre-clinical efficacy data 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 < 
100nM) and efficacy (>80% rescue from oxidative stress-induced cell 
death) in cells derived from patients diagnosed with idiopathic and familial 
PD subtypes including PINK1, parkin and LRRK2. 
Study objectives 
Primary Objective 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of 
drug-related serious adverse events in subjects with PD. 
Secondary Objectives 
To evaluate the effects of EPI-589 in subjects with PD on: 
1. Glutathione cycle biomarkers as measured in blood, cerebral spinal 
fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society- 
sponsored revision of the Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale 
(NMSS), PDQ-39 and EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment 
(MoCA) and 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the 
Montgomery and Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 


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Study design 
Open-label study with 30-day run-in phase. 
Planned number of 
subjects 
Approximately 40 subjects (20 with genetically-defined subtypes of PD 
and 20 idiopathic PD subjects). (Adaptive design component allows 
enrollment of up to 20 additional subjects with idiopathic PD to try to 
achieve a total of 20 subjects that have a biomarker response to EPI-589.) 
Study duration 
3 months (85 days ± 3 days) of study treatment preceded by a 1-month 
baseline parameter run-in period. 
Test product, mode of 
administration, and dose 
Test product 
EPI-589 in a tablet formulation at a strength of 250 mg 
Mode of Administration 
Oral with meal 
Dose 
EPI-589 500-mg BID 
Reference therapy, dose, 
and mode of 
administration 
None 
Safety monitoring 
Clinical 
1. Physical exam and vital signs 
2. Evaluation of adverse events 
3. 12-lead Electrocardiogram 
4. Columbia Suicide Severity Rating Scale (C-SSRS) 
Laboratory 
1. Routine serum chemistries 
2. Routine hematology tests and coagulation tests 
Inclusion criteria (all 
subjects) 
1. Hoehn and Yahr stage ≤ 3.0 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners must agree to use 
medically accepted methods of contraception (e.g., hormonal 
methods, including oral, subcutaneous, and intrauterine; barrier 
methods, including 
condom, 
condom, or diaphragm with 
spermicidal gel) during the course of the study and for 3 months after 
the last dose of study treatment. 
4. Willingness and ability to comply with study procedures 


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5. If on medications for PD drugs, then medication regimen must be 
stable for 60 days prior to enrollment 
6. Abstention from use of other investigative or non-approved drugs for 
the duration of the trial 
For Idiopathic Subjects 
7. A diagnosis of idiopathic PD confirmed by the presence of 
bradykinesia plus one or both of the following symptoms: rigidity or 
resting tremor; and with an abnormal DaTscan consistent with a 
dopaminergic deficit 
8. Age 40 to 75 years 
9. Within 5 years of diagnosis of Parkinson’s disease 
For Genetic Subtype Subjects 
10. A confirmed diagnosis of PD plus a genetic diagnosis consistent with 
PD, specifically PINK1, parkin, LRRK2 or other mitochondrial 
genetic subtype 
11. Age 21 to 75 years 
Exclusion criteria 
1. Allergy to EPI-589 or other components of the EPI-589 tablet 
formulation 
2. Use of antioxidant supplements, specifically vitamins E and C 
beyond the recommended daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that 
will confound the assessment of effect of study drug on disease 
progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper 
limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial 
of a device, drug or other therapy for PD 


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Treatment 
Following study enrollment, baseline assessments will be performed. 
Subjects will participate in a 30-day run-in phase to establish 
biomarker and clinical baseline measurements. EPI-589 will then be 
administered for up to 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. Post-treatment follow-up 
will be at least 10 days and up to 30 days after last dose. 
Efficacy variables 
1. Blood-based glutathione biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. Non-motor Symptoms Scale (NMSS) 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. Beck Depression Inventory (BDI) 
10. Montgomery & Asberg Depression rating scale (MADRS) 
11. Timed motor tests in ON and OFF state (for subjects on dopamine 
therapy) 
12. Pharmacokinetics 
Safety variables 
Clinical 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
4. C-SSRS 
5. Laboratory 
6. Routine serum chemistries with liver function tests 
7. Routine hematology tests with coagulation tests 
Statistical Considerations 
Data Analysis 
This is a within-subject, controlled open-label study seeking to determine 
the safety and tolerability of EPI-589 in patients with PD as well as to 
determine if EPI-589 can alter the biochemical signature of PD as assessed 
by peripheral blood biomarkers, CNS biomarkers, brain imaging 
biomarkers, and urine biomarker analysis. In addition, data on a number of 
disease-relevant clinical measures will be collected. 


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II. 
SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE 
 
 
 
Tests 
-2 to -1 Months 
DayO 
Month 1 
Month 2 
Month3 
End of Treatment 
Visit 
Post-Treatment
Follow-up 
Screening 
Run-in 
(upto 30 
days from 
screenin2) 
Baseline (27-33 
days from run-in
Day29 
(± 3 days) 
Day 57d 
(±3 days) 
Day85 
(±3 days) 
Up to 30Days 
afte1·Last Dose•
Informed consent 
Day 1 
First 
Dose 
Inclusion/Exclusion criteria 
Past Medical history 
Pre:wous genetic testing 
review 
Physical exam & Vital signs 
Height & weight 
• 
12-lead ECG 
• 
Hematology (including 
coagulation panel) 
• 
f 
f 
Semm Chemistiy 
• 
f 
f 
Pregnancy test" 
C-SSRS 
Monti·eal Cognitive 
Assessment 
DaTscan (for idiopathic 
subjects) 
Revised Hamilton Rating 
Scale for Depression 
Subject enrolls in study 
X 
Fasting blood-based 
glutathione cycle biomarkers 
Lumbar puncture (CNS 
biomarkers) 
Urine-based biomarkers 
MDS-UPDRS 
Timed motor tests (for 
subjects on dopaniine therapy) 
NMSS, PDQ-39, EQ-5D 
BDI,MADRS 
Dmg plasma concenti·ation° 
c 
c 
AE/SAE assessment 
• 
• 
• 
d 
d 
• 
Concomitant medications 
assessment 
d 
d 
• 
Post-Treatment Assessments• 
• 
a. 
Screening values can be used if done w-ithin one month of baseline and if completed under fasted conditions 
- Female subjects of childbea1mg potential must have a negative pregnancy test. 
C. 
Full plasma concenti·ation profile will be obtained at Time= 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours aft.er dosing from the first IO subjects to complete 
I month of therapy at each site.12 hour PK can be obtained at time 0. 
d. 
Month 2 assessments can be done by telephone. Any new AEs and associated concomitant medications repo1ted at Month 3 must be followed for 30 
days; this follow up may be conducted by telephone. 
e. 
AE/SAE and concomitant medication assessments conducted by telephone at least 10 days aft.er last dose. Additional assessments detenuined at 
Investigator discretion. SAEs are ti-acked from the time ICF is signed and all other AEs are ti·acked from the time first dose is administered; 


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f. 
TI1e baseline and all subsequent laboratory assessments should be obtained under fasting conditions. 
 
 
A. 
Schedule of Dosing 
 
 
 
-2 to -1 Months 
Day0 
Month 1 
Month2 
Month3 
Post-Treatment 
Dosing Schedule 
Screening 
Run-in 
(±30 days) Baseline
Day29 
(±3 days) 
Day 57d 
(±3 days) 
Day85 
(±3 days) 
Up to30 Days 
after Last Dose• 
 
EPI-589 500-mg BID 
Dispense Study Drug 
Dmg Reconciliation with diaries 


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III. INTRODUCTION 
A. 
Background Information and Rationale 
 
Parkinson’s disease (PD) is a highly morbid neurodegenerative movement disorder that has a 
number of neuromuscular, cognitive and neuropsychiatric manifestations as well as non- 
neurological symptoms. PD is the second most common neurodegenerative disorder with an 
estimated prevalence of 6.3 million people worldwide (EPDA). 
 
PD has long been considered a non-genetic (idiopathic) disease; however, about 5% of patients 
have an identifiable mutation. Disease onset typically occurs after age 50, however, in a subset of 
patients, disease onset can occur at a younger age. The primary motor symptoms result from 
death of dopamine-producing cells in the pars compacta region of the substantia nigra. However, 
the mechanisms underlying this cell death and disease pathology remain poorly understood. 
There is no approved treatment for PD capable of modifying disease progression. Current 
therapies partially address disease motor symptoms through levodopa or dopamine agonists or 
other agents, and other disease symptoms (e.g. neuropsychiatric symptoms), but disability tends 
to increase over time despite these treatments. 
 
The association of PD with mitochondrial pathology and high levels of oxidative stress are well 
established. Increased levels of oxidative stress have been consistently measured in post-mortem 
specimens from PD patients (Maarouf 2012, Reale 2012). The occurrence of PD-like symptoms 
in heroin addicts exposed to MPTP in the 1980s established a first link between PD and 
mitochondrial injury (Langston 1983, Dauer and Przedborski 2003). MPTP inhibits complex 1 of 
the mitochondrial respiratory chain and induces degeneration of dopaminergic cells through 
oxidative stress-mediated injury. The link between mitochondrial injury and PD was further 
strengthened by the induction of PD symptoms following exposure to another neurotoxic 
complex 1 inhibitor, rotenone (Betarbet et al 2000, Greenamyre et al. 2003), which like MPTP 
has come to be used in pre-clinical testing for its phenotypic similarities to PD. 
 
Furthermore, the identification of genetic mutations such as PINK1, parkin, LRRK2 and others 
in mitochondrial genes in familial PD patients provided the strongest link between the 
mitochondria and PD (Winklhofer and Haass 2010). Normally these genes influence oxidative 
balance and provide neural protection of the dopaminergic neurons that are affected by PD. 
PINK1 and parkin are involved in protecting against oxidative stress (OS) and overabundant 
reactive oxygen species (ROS), and are implicated in cell morphology and dynamics, as well as 
in the preferential degradation of dysfunctional mitochondria or “mitophagy” (Ashrafi et al. 
2014). Mutant LRRK2 leads to the accumulation of misfolding intracellular protein 
accumulations, cell stress and apoptosis (Giasson et al. 2006, Zhu et al. 2006). 
 
The importance of oxidative stress in PD pathology is further substantiated by the measurement 
of decreased levels of reduced glutathione in the brains of patients with PD (Holmay et al. 2013). 
Glutathione levels are low at very early stages of PD and correlate with disease severity 
(Riederer et al. 1989), and experimental induction of glutathione depletion leads to mitochondrial 
complex I dysfunction (Jha et al, 2000;). Reduced glutathione is an essential intermediary 


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metabolite that serves as the primary native cellular antioxidant. In a state of high oxidative 
stress, elevated levels of ROS outstrip the supply of glutathione (GSH) resulting in depletion of 
GSH and ROS-mediated cell death. 
 
Given the important role of oxidative stress and mitochondrial pathology in PD, a redox-active 
therapy that could target key pathways in cellular OS response pathways may hold promise for 
the treatment of PD. 
 
B. 
Rationale for the Study of EPI-589 in Parkinson’s Disease 
 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 <100nM ) and efficacy 
(>80% rescue from oxidative stress-induced cell death) in cells derived from patients diagnosed 
with idiopathic and familial PD genetic subtypes including PINK1, parkin and LRRK2. 
In these cell-based assays, primary fibroblasts from patients (and control) were pre-incubated 
with and without test compound, then treated with L-buthionine-(S,R)-sulfoximine (BSO), a 
GSH synthesis inhibitor, to initiate depletion of cellular GSH. GSH depletion has been shown to 
lead to OS and disruption of calcium homeostasis resulting in loss of the mitochondrial 
membrane potential and cell death. Under these conditions, the control cells are resistant to the 
stress and the fibroblast cells from patients with disease indications die within 36 to 48 hours. 
Pretreatment of cells with EPI-589 prior to initiation of GSH depletion potently protected against 
oxidative stress-mediated cell death, with EC50 response concentrations of 16 to 52 nM. (Table 
1). 
Table 1: 
Cell Line Rescue with EPI-589 in Parkinson’s Disease Genetic Subtypes 
 
EPI-589 
EC50 (nM range) 
PINK1 
26-36 
LRRK2 
16-18 
parkin 
42-52 
 
C. 
Name and Description of Investigational Product 
The IUPAC name of EPI-589 is: 
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide. 
 
A common chemical name of EPI-589 is (R)-troloxamide quinone. EPI-589 is derived from 
resolved (R)-Trolox®, a derivative of vitamin E in the form of a pale yellow to yellow solid. The 
EPI-589 drug product will be provided in a 250-mg tablet formulation. 


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The Investigator will ensure that all study drugs are stored and dispensed in accordance with the 
Food and Drug Administration (FDA) and local regulations concerning the storage and 
administration of investigational drugs. 
 
D. 
Findings from Non-Clinical and Clinical Studies 
D1. Non-Clinical Studies 
 
EPI-589 is an orally available compound that has been demonstrated in vitro and in vivo to cross 
the blood-brain-barrier. In 28-day and 91-day repeat-dose toxicity studies in rat and cynomolgus 
monkey, the no observed adverse effect level (NOAEL) was 300 mg/kg/day, corresponding to 
combined mean Cmax values of 37,717 to 56,500 ng/mL (rat) and 14,300 to 16,417 ng/mL 
(monkey), and a combined mean area under the plasma concentration-time curve from time zero 
to the last measurable concentration (AUClast) value of 149,495 to 297,000 ng.h/mL (rat) and 
47,300 to 67,656 ng.h/mL (monkey) (Studies 1660-038, 1660-039, 1660-063, and 1660-064). 
 
A phase 1 clinical study demonstrated that healthy subjects administered 500 mg EPI-589 BID 
for 14 days showed a mean Cmax value of 1,890 ng/mL and a mean AUClast value of 5,240 
ng.h/mL (Study EPI589-14-01). These plasma concentrations are well below the mean exposure 
values in monkey associated with the NOAEL in the toxicity studies, corresponding to safety 
margins of approximately 7- to 8-fold for the mean Cmax and 9- to 12-fold for the mean AUC. 
 
During the 28-day repeat-dose toxicity studies, rat and monkey were exposed to up to 1,000 
mg/kg/day EPI-589 PO (Studies 1660-039 and 1660-038). The NOAEL for both studies was 300 
mg/kg/day. Rats exposed to 1,000 mg/kg/day exhibited adverse test-article related effects on 
hematology parameters consistent with hemolysis and bone marrow regeneration, mild to 
moderately enlarged spleens, and increased organ weights with some organs showing 
corresponding microscopic pathology. The majority of these findings were resolved following 
the 28-day recovery period. Monkeys exposed to 1,000 mg/kg/day showed significant test-article 
related morbundity that resulted in half the animals in the high dose group being euthanized on 
Days 3 and 4 and the remaining animals being euthanized on Day 9. These animals exhibited 
significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
values, and microscopic findings in the kidney, liver, skeletal muscle, heart, and lymphoid 
tissues. In several of the animals the primary cause of morbidity was determined to be test-article 
related renal tubular degeneration/necrosis. 
 
During the 91-day repeat-dose toxicity studies, rat and monkey were exposed to up to 300 
mg/kg/day EPI-589 PO (Studies 1660-063 and 1660-064). The NOAEL for the rat study was 300 
mg/kg/day and the no observed effect level (NOEL) for the monkey study was 300 mg/kg/day. 
Male rats exposed to 300 mg/kg/day and 
rats exposed to ≥ 100 mg/kg/day exhibited mild 
test-article related effects on hematology parameters consistent with hemolysis and bone marrow 
regeneration. These findings were not considered adverse. 
 
Development and reproductive toxicology studies were conducted in rat and rabbit at doses up to 
1,000 mg/kg/day EPI-589 PO (Studies 1660-069, 1660-067, and 1660-068). The NOAEL for 
reproductive toxicity in rat was demonstrated to be 1,000 mg/kg/day (1660-069). The NOAEL 


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for developmental toxicity in rat and rabbit during the embryofetal studies was deemed to be 300 
mg/kg/day (Studies 1660-067 and 1660-068). Rats exposed to 1,000 mg/kg/day exhibited 
decreased maternal body weights, decreased food consumption, and decreased fetal body 
weights. There was no teratogenic potential in rat at doses up to 1,000 mg/kg/day. Rabbits 
exposed to 1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, decreased number of viable fetuses, decreased litter size, increased 
postimplantation loss, increased resorptions (early and late), and increased fetal skeletal 
malformations. The margin of exposure between healthy humans exposed to 500 mg BID EPI- 
589 (relevant clinical dose) for 14 days (Study EPI589-14-01) and rabbits exposed to 1,000 and 
300 mg/kg/day EPI-589 is approximately 179- to 236-fold and 47- to 50-fold, respectively. 
Based on these data, EPI-589 is not anticipated to increase the risk of adverse developmental or 
reproductive outcomes in humans when used in accordance with dosing information. 
 
EPI-589 was negative for mutagenic response in the in vitro Ames bacterial reverse mutation 
assay (Study AD58AS.502ICH.BTL); equivocal for the induction of structural and negative for 
the induction of numerical chromosomal aberrations in the in vitro chromosome aberration assay 
in Chinese hamster ovary (CHO) cells (Study AD58AS.331ICH.BTL); and negative in the in 
vivo micronucleus assay in rat (Study AD58AS.125012ICH.BTL). These data indicate a low 
clinical mutagenicity risk. 
 
Primary pharmacodynamics studies demonstrated that EPI-589 is a potent rescue agent in 
cellular models of diseases of energy metabolism and oxidative stress. In vitro cellular models 
utilizing primary human fibroblasts from patients with ALS, Parkinson’s disease and other 
diseases characterized by high levels of oxidative stress, or striatal cells derived from mouse 
models of Huntingdon’s disease were used to assess the potential of EPI-589 to mitigate the 
harmful effects of oxidative stress (Studies EPI-BA-000216, EPI-BA-000363, and EPI-BA- 
000362). Pretreatment of patient cells with EPI-589 potently protected against oxidative stress- 
mediated cell death in a concentration dependent manner. Furthermore, EPI-589 normalized 3- 
nitrosotyrosine (3NT) levels, a biomarker of oxidative stress, and increased glutathione levels in 
mouse striatal cells under oxidative stress conditions. 
 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, EPI-589 did not 
significantly affect off-target molecular targets (Study EPI-BA-159). In safety pharmacology 
studies, EPI-589 did not significantly affect ion channel current in the hERG assay (Study 
130719.FEK); did not affect ECG parameters during the 28-day and 3-month repeat-dose 
toxicology studies in monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for 
animals administered 1,000 mg/kg/day and up to Day 91 data collected for animals administered 
up to 300 mg/kg/day) (Studies 1660-038 and 1660-064); and did not change respiratory function 
or adversely impact neurobehavioral function in rat at doses up to 1,000 mg/kg (Studies 1660- 
051, 1660-050, and 1660-063). 
 
In single dose exposure PK studies, EPI-589 was absorbed rapidly in rat, dog, and monkey, with 
mean Tmax values ranging from .08 to 1 hour and mean T1/2 values ranging from 3.7 to 5.0 hours 
(Studies EPI-BA-53, EPI-BA-59, EPI-BA-72, and EPI-BA-302). EPI-589 does not significantly 
induce cytochrome P450 (CYP) enzymes and appears to be metabolized by reductases in the 


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liver cytosol and microsomal subcellular fractions and to a lesser extent by the family of CYP 
enzymes (Studies MC12M-0037 and MC14M-0018). 
 
EPI-589 exhibited weak direct inhibition of CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (both 
midazolam and testosterone as probe substrates) with estimated IC50 (µM) values and R values 
based on free plasma concentrations (shown in parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 34 
(1.21), and 53 (1.13), respectively (Study MC14M-0020)Based on these data, EPI-589 is not 
anticipated to increase the risk of adverse developmental or reproductive outcomes in humans 
when used in accordance with dosing information. 
 
D2. Clinical Studies 
 
Phase I Study EPI589-13-022 evaluated the pharmacokinetics, safety and tolerability of single 
ascending oral doses (SADs) of EPI-589 in healthy subjects and a preliminary evaluation of 
safety and tolerability data was performed. Sixteen AEs were reported in the 36 subjects who 
received administration of EPI-589. Ten subjects (27.8%) who received EPI-589 (and 2 subjects, 
20% on placebo) reported AEs that were assessed as related. All were mild and resolved during 
the study, with the exception of a common cold (1 subject) and cold sore (1 subject). None of the 
vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant change 
compared to baseline. From all preliminary data available from this SAD study it may be 
concluded that there is no objection to proceed with treatment with 50 mg, 100 mg, 250 mg or 
500 mg of EPI-589. 
 
Phase I Study EPI589-14-01 evaluated the pharmacokinetics, safety and tolerability of multiple 
ascending oral doses (MAD) of EPI-589 in healthy subjects, and an evaluation of safety and 
tolerability data was performed. No severe or serious adverse events were observed. Twenty-six 
subjects (65.0%) on EPI-589, and 8 subjects (80%) on placebo reported AEs. Twenty-four of 34 
AEs were considered by the Investigator to be related to EPI-589. Nineteen subjects (47.5%) on 
EPI-589, and 6 subjects (60%) on placebo reported AEs that were assessed as related. All 
adverse events were mild, except for 1 AE which was moderate (unrelated brain contusion). All 
AEs were resolved during the study, with the exception of one, which was a common cold. None 
of the vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant 
change compared to baseline. From all preliminary data available from the MAD study it may be 
concluded that there is no objection to proceed with treatment with 250-mg, or 500-mg doses of 
EPI-589. 
 
E. 
Human Pharmacokinetics 
 
EPI-589 was fast absorbed following oral administration in SAD Study EPI589-13-022. The 
median Cmax was attained approximately within 1 hour under fasted conditions after dosing. The 
median Tmax values were attained in 0.50 to 1.00 hours over the dose range of 50 to 1000 mg 
under fasted conditions and 3.01 hours at the 500 mg dose level under fed conditions. Mean half- 
life ranged from 5.55 to 10.7 hours over the dose range of 50 to 1000 mg under fasted conditions 
and 4.91 hours at the 500 mg dose level under fed conditions. Half-life was independent of the 
dose levels over the dose range of 50 to 1000 mg under fasted conditions. The rate of EPI-589 
absorption, as measured by Cmax, was decreased by 24.07% under fed conditions at the 500 mg 


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dose level. The extent of absorption as measured by AUCs (AUC0-t or AUC0-inf) was not affected 
under fed conditions in the 500 mg dose groups. 
 
In MAD study EPI589-14-01, EPI-589 was rapidly absorbed following oral administration and 
the median Cmax was attained within 1 hour (0.50 to 0.76 hours) under fasted conditions after 
single or multiple dosing among these five cohorts. The mean half-life of EPI-589 ranged from 
5.64 to 8.47 hours among these five cohorts. In general, the mean values of the time to peak 
concentration (Tmax), half-life (t½), apparent terminal constant (λz), accumulation ratio (AR), 
percent fluctuation (%F) and accumulation index (AI) of EPI-589 were similar among the five 
cohorts of various ages and smoking status. No significant effects of age or smoking on EPI-589 
pharmacokinetics were observed in this study. Dose proportionality existed in the exposures 
(AUC0-tau, Cmax, Cmin and Cavg) over the dose range of 250 to 500-mg BID EPI-589 under fasted 
conditions. 
 
F. 
Clinical Study 
 
EPI589-15-002: A Phase 2A Safety and Biomarker Study of EPI-589 in in Mitochondrial 
Subtype and Idiopathic Parkinson’s Disease Subjects. 
 
G. 
Selection of Drugs and Dosages 
 
The study drug in this trial is EPI-589: common chemical name (R)-troloxamide quinone. 
 
Each tablet contains 250 mg of EPI-589. The study dose is 500-mg BID, to be maintained in the 
absence of treatment-emergent toxicity. EPI-589 tablets must be taken with meals. 
 
H. 
Compliance Statement 
 
This study will be conducted in full accordance with all applicable research policies and 
procedures, the EU Clinical Trials Directive, all applicable EU and US federal and local laws 
and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312 and 314, and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonization (ICH). Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
will report AEs in accordance with local institutional policies and procedures and all EU and US 
federal requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the study. 
 
I. 
Relevant Literature and Data 
 
Literature references have been provided in Section XV. Additional information can be found in 
the Investigator’s Brochure. 


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IV. STUDY OBJECTIVES 
A. 
Primary Objective 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
B. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with PD on: 
1. Glutathione cycle biomarkers as measured in blood, cerebral spinal fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society-sponsored revision 
of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale (NMSS), PDQ-39 and 
EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment (MoCA) 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the Montgomery & 
Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 
 
 
 
 
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V. 
INVESTIGATIONAL PLAN 
A. 
General Schema of Study Design 
 
Following study enrollment, baseline assessments will be performed. Subjects will participate in 
a 30-day run-in phase to establish biomarker and clinical baseline measurements. EPI-589 will 
then be administered for up to 3 months (85 days ± 3 days) unless discontinued for safety or 
tolerability issues. 
 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. Given that the investigational drug 
targets an enzyme key to glutathione synthesis and that glutathione depletion has been found to 
be associated with PD, we are seeking to determine the safety and potential biochemical benefit 
of EPI-589 in PD subjects as assessed by glutathione cycle biomarkers. If we determine that 
there are a subset of idiopathic PD patients—whether due to disease stage or baseline biomarker 
profile—who are more likely to be EPI-589 responsive, we will seek to enroll additional 
numbers of these subjects in the adaptive phase so that we can increase the number of likely 
biomarker responsive subjects. EPI-589 will be administered for up to 3 months (85 days ± 3 
days) unless discontinued for safety or tolerability issues. 
 
A1. 
Screening Phase 
 
Suitable candidates for the trial will receive a short overview of the study by the Investigator’s 
staff and, if interested, will undergo Screening. The Investigator will inform each prospective 
subject of the nature and details of the study, explain the potential risks and must obtain written 
informed consent from the subject or their legally authorized representative prior to performing 
any study related procedures. 
 
A2. 
30-Day Run-in Phase 
 
Once eligibility is confirmed, the subject will be enrolled in the study and the run-in scans, CNS, 
blood-based biomarker, urine-based biomarker and clinical measurements will be collected. 
 
A3. 
Baseline 
 
Baseline assessments, scans, blood-based biomarker, urine biomarker, and clinical measurements 
will be collected. 
 
A4. 
Treatment Phase 
 
EPI-589 dosing will start on Day 1. Subjects will self-administer EPI-589 at a dose of 500-mg 
BID. 
 
Blood-based biomarker, urine biomarker, and clinical measurements will be collected at Day 29 
(± 3 days) and Day 85 (± 3 days). 


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A5. 
End of Treatment 
 
End of treatment data will be collected at the last study visit Day 85 (± 3 days). 
 
AEs reported as ongoing at Day 85 (± 3 days) and/or any concomitant medications associated 
with such events 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. 
 
A6. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose: AE/SAE and 
concomitant medication assessments conducted by telephone. Additional assessments to be 
determined at Investigator discretion. 
 
 
B. 
Randomization and Blinding 
 
This is an open-label study. 
 
C. 
Study Duration, Enrollment and Number of Sites 
C1. Duration of Subject Treatment 
 
Subjects will participate in a 30-day run-in phase to establish biomarker and clinical baseline 
measurements. EPI-589 will then be administered for 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. A post-treatment follow-up will be conducted at 
least 10 days and up to 30 days after last dose. 
 
C2. Total Number of Study Sites/Total Number of Subjects Projected 
 
This study will be conducted at five study sites: 
• 
, UK 
• 
, USA. 
• 
Germany 
• 
USA 
• 
USA 
Approximately 40 subjects with PD are projected: 
• 20 with genetically-defined subtypes 
• 20 PD idiopathic PD 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects to achieve a higher number of subjects in 
whom we could understand the biochemical effects of the investigative drug and its potential 
clinical impact as assessed by the same study protocol and outcome metrics. 


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D. 
Study Population 
D1. Inclusion Criteria 
 
1. Hoehn and Yahr stage ≤ 3.0 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners must agree to use medically accepted 
methods of contraception (e.g., hormonal methods, including oral, subcutaneous, and 
intrauterine; barrier methods, including 
condom, 
condom, or diaphragm with 
spermicidal gel) during the course of the study and for 3 months after the last dose of 
study treatment. 
4. Willingness and ability to comply with study procedures 
5. If on medications for PD drugs, then medication regimen must be stable for 60 days prior 
to enrollment 
6. Abstention from use of other investigative or non-approved drugs for the duration of the 
trial 
For Idiopathic Subjects 
7. A diagnosis of idiopathic PD confirmed by the presence of bradykinesia plus one or both 
of the following symptoms: rigidity or resting tremor; and with an abnormal DaTscan 
consistent with a dopaminergic deficit 
8. Age 40 to 75 years 
9. Within 5 years of diagnosis of Parkinson’s disease 
 
For Genetic Subtype Subjects 
10. A confirmed diagnosis of PD plus a genetic diagnosis consistent with PD, specifically 
PINK1, parkin, LRKK2 or other mitochondrial genetic subtype 
11. Age 21 to 75 years 
 
D2. Exclusion Criteria 
 
1. Allergy to EPI-589 or other components of the EPI-589 tablet formulation 
2. Use of antioxidant supplements, specifically vitamins E and C beyond the recommended 
daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that will confound the 
assessment of effect of study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper limit of normal 


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13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial of a device, drug or 
other therapy for PD 
 
 
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VI. STUDY PROCEDURES 
A. 
Screening Visit 
 
Screening evaluations will be performed within two months of first dose. The Investigator will 
inform each prospective subject of the nature of the study, explain the potential risks, and must 
obtain written informed consent from the subject prior to performing any study-related 
procedures and prior to the administration of study drug. Screening evaluations consist of the 
following: 
1. Assessment of eligibility 
2. Medical history, chart review 
3. Receipt and review of previous testing including genetic tests 
4. Physical examination including vital signs 
5. Height and weight 
6. 12-lead ECG 
7. Laboratory assessments for hematology, coagulation, and serum chemistry (See Sections 
VII.D3.a and VII.D3.b) 
8. Urine pregnancy test (women of childbearing potential must have a negative urine 
pregnancy test; see Section VII.D3.c) 
9. MDS-UPDRS 
10. MoCA 
11. DaTscan (for idiopathic subjects only) 
12. Revised Hamilton Rating Scale for Depression 
13. AE/SAE assessments 
14. Concomitant medications assessment (last 60 days prior to enrollment) 
 
A1. 
Run-in Assessments 
 
If the subject is eligible for the study following all screening procedures and is still willing to 
participate in the study, the subject must return to the clinic within one month for Run-in 
assessments. These will be performed 30 days (± 3 days) prior to baseline after eligibility is 
confirmed and subject is enrolled in the study. Run-in evaluations consist of the following: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers (lumbar puncture) 
3. Urine biomarkers 
4. Timed motor tests (for subjects on dopamine therapy) 
5. AE/SAE assessments 
6. Concomitant medications review 
 
B. 
Treatment Phase 
 
After the Run-in phase, the subject must return to the clinic within 30 days (± 3 days) for 
baseline assessments. In-clinic study visits are scheduled at Month 1 and Month 3. The Month 2 
study assessments can be conducted via telephone. End of treatment assessments will be 


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conducted at the Month 3 study visit. Pharmacokinetic sampling takes place at Month 1 and 
Month 3. 
 
B1. 
Baseline Assessments 
 
The following will be assessed or performed at this visit. 
1. Physical examination including vital signs 
2. Height and weight* 
3. 12-Lead ECG* 
4. Blood-based GSH cycle biomarkers 
5. Urine-based biomarkers 
6. Laboratory assessments for hematology, coagulation and serum chemistry* 
7. Urine pregnancy test ( 
of child bearing potential) 
8. C-SSRS (Columbia Suicide Severity Rating Scale) 
9. MDS-UPDRS 
10. NMSS, PDQ-39, EQ-5D 
11. BDI, MADRS 
12. Timed motor tests (for subjects on dopamine therapy) 
13. AE/SAE assessments 
14. Concomitant medications review 
* Screening results for these assessments may be used if obtained within 1 month of Baseline 
and if they are completed under fasted conditions. 
 
B2. 
Study Visit Assessments 
 
• Month 1 Clinic Visit (Day 29 ± 3 days): 
 
The following will be assessed or performed at the Month 1 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test ( 
of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. MDS-UPDRS 
10. Pharmacokinetics**: a full plasma drug concentration profile will be obtained from the 
first 10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 
6, 8, and 12 hours after dosing. 
11. AE/SAE assessments 
12. Concomitant medications review 


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• Month 2 Visit (Day 57 ± 3 days) 
 
Month 2 assessments can be conducted by telephone and must include review of: 
1. AE/SAE assessments 
2. Concomitant medication 
 
• Month 3 Clinic Visit (Day 85 ± 3 days) 
 
The following will be assessed or performed at the Month 3 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test ( 
of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. CNS biomarkers 
10. MDS-UPDRS 
11. Pharmacokinetics**: a full plasma drug concentration profile will be obtained from the 
first 10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 
6, 8, and 12 hours after dosing. 
12. AE/SAE assessments 
13. Concomitant medications review 
14. MoCA 
15. NMSS, PDQ-39, EQ-5D 
16. BDI, MADRS 
17. Timed motor tests (for subjects on dopamine therapy) 
 
B3. 
Pharmacokinetics** 
 
Plasma concentration samples will be collected from the first 10 subjects to complete 1 month of 
therapy at each site, at the following time points: 
• Month 1 (Day 29 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
• Month 3 (Day 85 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
** 12 hour PK can be obtained at time 0 
 
B4. 
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. 


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C. 
End of Treatment Visit 
 
End of treatment visit takes place at Month 3 (Day 85 ± 3 days) and includes the assessments 
listed in Section VB2 Study Visit Assessments. 
 
Subjects who have an ongoing AE at the time of study completion will be followed for up to 30 
days, until the event resolves, or until the Sponsor and the Investigator agree that further follow- 
up is not medically necessary. 
 
D. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose, with 
AE/SAE and concomitant medication assessments conducted by telephone. Additional 
assessments to be determined at Investigator discretion. 
 
E. 
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 case report form (CRF) using the supplemental visit CRF pages. 
 
F. 
Concomitant Medication 
 
Any medication taken by a subject ≤ 60 days prior to enrollment and during the course of the 
study and the reason for use of the medication will be recorded on the 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 [OTC] medications) without consulting the Investigator. 
 
G. 
Prohibited Medications 
 
The following are prohibited while the subject is on study treatment: 
1. Use of antioxidants, specifically vitamins E and C beyond the recommended daily 
allowance 
2. Participation 3 months prior to and for the duration of the study in a trial of a device, drug 
or other therapy for PD 
 
H. 
Subject Withdrawals 
 
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 


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2. If a subject experiences an adverse event that is deemed related to treatment with EPI-589 
and in the Investigator’s or the Sponsor’s medical judgment continuation of treatment 
would be detrimental to the subject. 
3. At the specific request of a regulatory agency for termination of treatment of an 
individual subject or all subjects under the protocol 
4. Subject participation in another clinical study using an investigational agent or 
investigational medical device 
5. Use of prohibited medications such as vitamins E and C beyond the recommended daily 
allowance. 
6. Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use medically accepted methods of contraception 
7. If a subject becomes pregnant. 
8. Significant noncompliance with the protocol in the opinion of the Investigator or the 
Sponsor 
In all cases, the reason for withdrawal must be recorded in the 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 
X.B. 
 
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. 
 
Every effort will be made to follow subjects who have an ongoing AE at the time of withdrawal 
until the event resolves, or until the Sponsor and the Investigator agree that further follow-up is 
not medically necessary. 
 
 
 
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VII. STUDY ENDPOINTS AND EVALUATIONS 
A. 
Primary Endpoint 
 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of drug-related serious 
adverse events in subjects with PD. 
 
B. 
Secondary Endpoints (Efficacy) 
 
1. Blood-based biomarkers 
2. CNS-based biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Secondary Endpoints (Safety) 
 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Routine serum chemistries with liver function tests 
4. C-SSRS 
5. Routine hematology tests with coagulation tests 
6. Electrocardiogram 
 
D. 
Screening and Baseline Evaluation 
D1. Physical Examination 
 
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. 
 
Vital sign measurements (pulse rate, blood pressure and respiration rate) will be obtained in the 
sitting position (after the subject has been sitting for five minutes). 
 
Medical history and demographics including age, gender, race, height and weight will be 
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D2. Height and Weight 
 
Weight (kg) will be measured in ordinary indoor clothing (i.e., street clothes, scrubs, etc.) with 
shoes off. Height will be recorded in centimeters (cm). 
 
If clinically significant findings, as determined by the Investigator, are recorded for a particular 
symptom, sign or abnormal measurement, that measurement will be repeated at medically 
appropriate intervals until the value returns to an acceptable range, a specific diagnosis is 
established, or the condition is otherwise explained. 
 
D3. Laboratory Evaluations 
 
Subjects will have less than 100 mL of blood drawn over the course of the study. 
The following variables will be collected at various times (as detailed in Section I). 
a. 
Hematology 
 
a. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, , mean corpuscular 
volume (MCV) 
b. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) 
c. Platelets: platelet count 
d. Coagulation: prothrombin time (PT) with INR, and partial thromboplastin time (PTT) 
 
b. 
Serum chemistry 
 
a. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total and 
direct), gamma-glutamyl transferase (GGT), and lactic dehydrogenase (LDH) 
b. Renal: blood urea nitrogen (BUN), and creatinine 
c. Electrolytes: sodium, potassium, chloride and carbon dioxide (CO2 ) 
d. General: creatine phosphokinase (CPK), total protein, albumin, calcium, magnesium, 
glucose, phosphate 
e. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL), cholesterol, and triglycerides 
 
c. 
Urine pregnancy test 
1. Human chorionic gonadotropin (HCG) beta subunit will be measured on all 
subjects of childbearing potential. 
 
Laboratory tests that result in significantly abnormal values should be repeated for verification. 
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abnormal result, or to monitor the course of an AE, should be obtained when clinically indicated. 
In particular, if a clinically significant abnormal result is observed that is not resolved by the 
final study visit, repeat tests should be performed to document resolution or stability of the 
abnormality. 
 
Diagnoses associated with any NIH Common Terminology Criteria for Adverse Events (CTC 
v4.03) Grade 3 or 4 laboratory abnormalities will be recorded as adverse events (AEs) on the 
CRF. The recorded event should indicate the underlying abnormality or diagnosis (e.g., renal 
insufficiency) if known, as opposed to the observed deviation in laboratory results (e.g., elevated 
creatinine). Any additional relevant laboratory results obtained by the Investigator during the 
study will be supplied to the Sponsor. 
 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a semi-structured tool for assessing suicidal ideation (Questions 1-5) and 
behavior (Questions 6-10) through a series of questions. 
 
E. 
Sample Collection Procedures, Bioanalytical Methods and Sample Shipment 
 
Subject samples will be identified by unique sample codes. 
 
Blood, urine, and cerebral spinal fluid samples will be collected for determination of levels of 
GSH cycle markers. Additional information about the collection, handling, storage, and 
shipment of the GSH cycle marker samples will be provided separately prior to start of the study. 
 
F. 
Efficacy Evaluations 
F1. 
Glutathione Cycle Biomarkers 
 
Blood, urine, and CNS levels of oxidized and reduced GSH as well as GSH metabolites will be 
used to evaluate EPI-589 target engagement and ability to correct a key biochemical aspect of 
disease pathology. 
 
F2. 
Parkinson’s Disease Rating (MDS-UPDRS) 
 
The MDS-UPDRS is a tool for monitoring the impact of PD, the degree of disability caused, and 
complications from treatment. Part I evaluates nonmotor experiences of daily living; Part II 
evaluates motor experiences of daily living; Part III is a motor examination and includes the 
Hoehn and Yahr scale; Part IV examines motor complications (e.g., motor fluctuations and 
dyskinesias). 
 
Several questions from Part I and all questions from Part II are designed to be amenable to a 
patient/caregiver questionnaire format; the remaining interview (Part I and Part III) and 
examination (Part IV) are designed with the expectation they can be completed within 30 
minutes. Each item is measured on a five-point scale. 


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F3. 
Non-motor Symptoms (NMSS) 
 
Non-motor symptoms are evaluated using the NMSS which is divided into 30 questions in 9 
different domains including such symptoms as dribbling saliva, constipation, depression, sleep 
disorders, apathy, hallucinations and dementia. Symptoms are quantified based on their severity 
(using a scale of 0 to 3) and frequency (using a scale of 0 to 4). The final cumulative scores are 
derived from adding up the product of the frequency score times severity score for each of the 30 
questions. 
 
F4. 
Parkinson’s Disease Questionnaire (PDQ-39) 
 
PDQ-39 is a self-administered questionnaire for patients with PD that has 39 questions relating 
to eight key areas of health and daily activities, including both motor and non-motor symptoms. 
It is scored on a scale of 0 to 100, with lower scores indicating better health, and high scores 
more severe symptoms. 
 
F5. 
EQ-5D 
 
EQ-5D is a questionnaire designed to provide measures of health-related quality of life states, 
consisting in five domains (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). 
 
F6. 
Montreal Cognitive Assessment (MoCA) 
 
MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive 
domains: attention and concentration, executive functions, memory, language, visuo- 
constructional skills, conceptual thinking, calculations, and orientation. Severity ranges are 
approximately: 26 to 30 normal; 18 to 26 mild cognitive impairment; 10-17 moderate cognitive 
impairment; < 10 severe cognitive impairment. 
 
F7. 
Beck Depression Inventory (BDI) 
 
The BDI is a self-reporting inventory that measures characteristic attitudes and symptoms of 
depression, including physical symptoms. Twenty-one questions have four responses each (rated 
0 to 3) with a total cumulative score scale ranging from 1-10 considered normal) > 40 (extreme 
depression). 
 
F8. 
Montgomery and Asberg Depression rating scale (MADRS) 
 
The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. 
Ten core symptoms and cognitive features are rated on a severity scale of 0 to 6. Higher scores 
indicate increasing depressive symptoms. 


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F9. 
Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
 
Timed motor tests are simple, objective, quantitative measures for the assessment of Parkinson’s 
disease. They include, in an on-medication and an off-medication state, timed recorded physical 
movements. 
 
 
 
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VIII. STATISTICAL CONSIDERATIONS 
A. 
Statistical Analysis 
 
In this subject-controlled, open label study the incidence of drug related SAEs in addition to 
changes from baseline to Month 3 for disease-relevant peripheral and CNS biomarkers as well as 
clinical measures will be calculated for each subject. 
 
A1. 
Analysis Populations 
 
Demographic characteristics and baseline efficacy data will be presented and summarized by 
treatment group for all subjects in the efficacy intent to treat (EITT) population. Demographic 
information will also be summarized by treatment group for the Safety population. No formal 
statistical comparisons will be made for either the EITT or Safety populations. 
 
B. 
Efficacy Analysis 
B1. 
Efficacy Variables 
 
The efficacy variables in this study are: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Safety Analysis 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
Assessment of safety will include calculating the overall number of subjects (by absolute number 
and percentage) with a particular AE. Safety will also be evaluated through examining clinical 
laboratory data (including chemistry and hematology and coagulation information) and physical 
examination findings, including vital signs obtained throughout the course of the study. A 
medical monitor will provide study oversight. 


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D. 
Sample Size 
 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 idiopathic PD 
subjects). Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker-responsive idiopathic PD subjects to achieve a higher number 
of subjects in whom we could understand the biochemical effects of the investigative drug and 
its potential clinical impact as assessed by the same study protocol and outcome metrics. 
 
 
 
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IX. STUDY MEDICATION 
A. 
Description 
 
EPI-589 is presented as an immediate release film-coated tablet. Each tablet contains 250 mg of 
EPI-589 and the following compendial excipients: lactose, microcrystalline cellulose, 
polyvinylpyrrolidone, crospovidone and magnesium stearate. Each tablet is film-coated with 
Opadry® II yellow. The tablets are yellow-colored and oval-shaped with a total target weight of 
824 mg. The tablets are packaged at 28 tablets per bottle in high-density polyethylene (HDPE) 
pharmaceutical wide mouth containers, induction sealed, and closed with a child-resistant 
closure. Each container is labeled with appropriate product information meeting current 
regulatory requirements. 
 
B. 
Packaging 
B1. 
Labeling 
 
Each container is labeled with appropriate product information meeting current regulatory 
requirements, in compliance with 21 CFR 312.6 and Eudralex Vol. 4 EU Guidelines to Good 
Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 13 
 
B2. 
Dosage Form 
 
The EPI-589 drug product will be provided in a 250-mg tablet formulation. 
 
B3. 
Dispensing 
 
Tablets are packaged in white round HPDE wide mouth containers. Each container holds 28 
tablets without desiccant. Each container is sealed with an induction seal held in place with a 
child-resistant closure. The packaged tablets are stored at controlled room temperature 20° to 
25°C (68° to 77°F). (See United States Pharmacopeia [USP]). 
 
C. 
Treatment Compliance and Adherence 
 
Study medication will be counted to assess compliance during each scheduled clinic visit. 
Subjects who take ≥ 80 percent of the prescribed doses and no more than 100 percent will be 
considered compliant. Subjects who fall outside the boundaries of these thresholds will be 
counseled and re-instructed on proper dosing procedures. Medication compliance will be 
recorded on the CRF for each visit after verification with subject-completed diary cards and 
returned used drug supply. 
 
D. 
Drug Accountability 
 
Dosing information will be captured on a subject Dosing Diary Form. This form is part of the 
source documentation and will be utilized as a source for the completion of CRFs associated 
with dosing and for reconciliation of study drug administered and returned to the study site for 


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accounting and destruction. Adequate records of study drug receipt and disposition should be 
maintained by pharmacy records of receipts, investigational drug orders, dispensing records, and 
disposition forms. The Study Monitor will also assess drug accountability and will 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 either be returned to the Sponsor or designee 
or destroyed per study site guidelines for destruction of investigational product immediately after 
drug accountability is performed by the study monitor. 
 
 
 
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X. 
SAFETY MANAGEMENT 
A. 
Clinical Adverse Events 
 
Clinical AEs will be monitored throughout the study. All AEs, whether observed by the 
Investigator, reported by the subject, from clinically significant laboratory findings, or other 
means, will be recorded in the CRF. 
 
B. 
Adverse Event Reporting 
 
All SAEs will be reported to the IRB in accordance with the IRB policies and as detailed below. 
AEs that are not serious will be summarized in narrative or other format and submitted to the 
IRB at the time of continuing review. 
 
B1. 
Safety Guidance 
 
Based on the known clinical manifestations of Parkinson’s disease, we expect that many AEs 
could occur during the course of the trial that are well documented to occur as the results of the 
natural history of this disease. These include, but are not limited to worsening neuromuscular 
function, depression, decline in cognitive function, loss of vision and other ophthalmological 
symptoms, loss of coordination and loss of speech. 
 
As there are no data available regarding EPI-589 phototoxicity, investigators are to advise 
subjects to take measures to minimize exposure to ultraviolet (UV) light for the duration of the 
study and for one week after the last dose. 
 
BioElectron Technology Corporation 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, BioElectron Technology Corporation 
should be provided with a copy of any post-mortem findings, including histopathology. 
 
C. 
Definition of an Adverse Event 
C1. Adverse Event 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
The AE may be: 
1. A new illness 


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2. Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 
3. An effect of the study medication, including comparator 
4. A combination of 2 or more of these factors 
No causal relationship with the study medication or with the clinical study itself is implied by the 
use of the term “adverse event” or “AE”. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs. 
 
Adverse events fall into the categories “non-serious” and “serious”. 
 
C2. Definition of a Serious Adverse Event (SAE) 
 
An SAE is one that at any dose results in any of the following: 
1. Death; 
2. A life-threatening adverse drug experience; 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability/incapacity; or 
5. A congenital anomaly/birth defect. 
ICH guidance also recommends that important medical events that may or may not be 
immediately life-threatening or result in death or hospitalization should also be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the serious definition. 
 
The term ”life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE. It does not refer to an SAE which 
hypothetically might have caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether other AEs, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject, require intervention to prevent one of the other 
outcomes listed 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. 
 
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 
has received 
study drug, 
should discontinue dosing, complete all end-of-study procedures, and be 
followed to determine the outcome of the pregnancy; follow-up of the pregnancy, fetus, and 
child will continue for at least 8 weeks after delivery. While pregnancy itself is not considered an 


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AE or SAE, all pregnancies should be reported using the same process as for SAEs. Any 
pregnancy complications or an outcome other than a healthy, normal outcome will be recorded 
as an AE or SAE. 
 
Clarification on the difference in meaning between “severe” and “serious”: The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as “serious,” which is based on the outcome or 
action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
C3. Non-serious Adverse Event 
 
A non-serious AE is any AE not meeting the SAE criteria. 
 
C4. Definition of Relationship to Study Medication 
 
Association or relatedness to the study medication will be graded as either “probably”, 
“possibly”, or “unlikely”. Determination of relatedness includes: 
 
PROBABLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Abates upon discontinuation of the drug and reappears with re-introduction of the drug 
3. Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state 
POSSIBLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
UNLIKELY – The adverse event: 
1. Does not follow a reasonable temporal sequence from drug administration 
2. Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
C5. Definition of Severity 
 
All AEs will be graded if possible by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. The severity of AEs that cannot be graded by CTCAE v4.03 will be categorized 
as follows: 
 
Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy indicated. 


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Grade 2 – Moderate limitation in activity, some assistance may be needed; minimal noninvasive 
medical intervention/therapy indicated. 
 
Grade 3 – Severe limitation in activity, assistance usually required; medical intervention/therapy 
required; hospitalization or prolongation of hospitalization indicated; disabling. 
 
Grade 4 – Extreme limitation in activity, significant assistance required; urgent medical 
intervention/therapy required; life-threatening consequences. 
 
Grade 5 – Death 
 
C6. Definition of Unexpected Adverse Event 
 
Any AE, the specificity or severity of which is not consistent with those listed in the current 
investigator’s brochure is considered “unexpected.” 
 
C7. Notification of SAEs 
 
The Investigator is responsible for promptly notifying the IRB/IEC of all study on-site SAEs and 
other unanticipated problems related to research. 
 
External SAEs that are unexpected and related to the study intervention should be reported as 
they are received using the MedWatch or CIOMs form (as appropriate). 
 
SAEs (whether unexpected or expected AEs) must be documented on the designated SAE form. 
The SAE must be reported to the medical expert and appropriate BioElectron Technology 
Corporation BioElectron-assigned pharmacovigilance staff within 24 hours, according to 
regulatory, Sponsor, or ICH-E6 Good Clinical Practice, followed by the SAE form within two 
calendar days. The designated SAE form and the instructions are provided in the Investigator’s 
site file. 
 
The SAE contact information will be provided separately from the protocol. 
 
The Investigator and/or Medical Expert must also inform the Study Monitor and the Sponsor in 
all cases. Any SAEs must also be reported to the IRB/IEC. The Sponsor or designee will ensure 
that all legal reporting requirements are met. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and the 
study medication. 
 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up SAE forms. 


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The instructions to sites for the completion of SAE reports give detailed guidance on the 
reporting of SAEs and AEs initially reported as non-serious that become serious. When a non- 
serious event becomes serious, details must be forwarded immediately to the Medical expert and 
BioElectron Technology Corporation or BioElectron-assigned pharmacovigilance staff first for 
assessment and then submitted to the Sponsor on the designated SAE form within 24 hours. 
 
All relevant information about suspected unexpected serious adverse reactions (SUSARs) that 
are fatal or life-threatening are to be recorded and reported to the relevant competent authorities. 
 
In the US, all fatal or life-threatening suspected unexpected serious adverse events assessed as 
possibly or probably related to study drug by the Sponsor must be reported to the FDA as soon as 
possible (i.e., by telephone or facsimile transmission), but no later than 7 calendar days after first 
knowledge by the Sponsor that a report qualifies as a suspected unexpected fatal or life- 
threatening reaction. All unexpected serious adverse events, other than fatal or life-threatening, 
assessed as possibly or probably related to study drug by the Sponsor must be reported to the 
FDA within 15 calendar days from the day the Sponsor determines that the information qualifies 
as a SUSAR. 
 
In the UK, the Sponsor or trial investigator must act immediately or at least within 24 hours after 
becoming aware of a SUSAR by informing the MHRA’s Clinical Trial Unit by telephone. The 
MHRA must then be informed in writing within 3 days of the incident. All SUSARs originating 
in the UK or originating outside the UK involving the same medicinal product are to be reported. 
Fatal or life-threatening SUSARs are to be reported as soon as possible, but no later than after 7 
days. Any additional relevant information must be sent within 8 days of the report. Non-fatal or 
non-life-threatening SUSARs are to be reported as soon as possible but no later than 15 days 
after becoming aware of the reaction. 
 
C8. Follow-up Report 
 
If an SAE has not resolved at the time of the initial report, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. All SAEs should be followed until either resolved or stable. 
 
C9. Dose Modification Guidelines 
 
In the event that any patient develops elevated INR ≥ grade 2 in severity (> 1.5-2.5 x ULN) per CTCAE 
criteria version 4.0 thought to be related to treatment with EPI-743, administration of EPI-589 will be 
reduced by 1/2 to 50 percent of the starting dose. Should the INR toxicity not resolve to at least grade 1 in 
severity within two weeks of the initial dose reduction, administration of EPI-589 may either be further 
reduced or discontinued. 
 
Once a patient’s dose is reduced due to elevated INR thought to be related to study drug administration, 
their dose should not be re-escalated. 


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D. 
Medical Emergencies 
 
In medical emergencies, the Investigator should use medical judgment and remove the subject 
from the immediate hazard. The Medical Expert and the IRB/ IEC must be notified regarding the 
type of emergency and course of action taken and the procedures for SAE reporting must be 
followed. 
 
D1. Emergency Sponsor Contact 
 
In emergency situations, the Investigator should contact the Medical Monitor: 
 
 
D2. Emergency Treatment 
 
At present, the threshold and extent of clinical adverse effects are not known as only limited 
information is available in healthy volunteers. It is anticipated in the planned study that any 
effects will be minimal and laboratory measurements will detect study drug effects before they 
become clinically significant. 
 
 
 
 
 
 
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XI. STUDY ADMINISTRATION 
A. 
Treatment Assignment Methods 
 
This is an open-label study. 
 
B. 
Data Collection and Management 
 
Monitoring and auditing procedures, developed or endorsed by BioElectron Technology 
Corporation will be followed in order to comply with GCP guidelines. Direct access to on-site 
study documentation including all source data, documentation and medical records should be 
ensured. 
 
The study will be monitored by BioElectron Technology Corporation throughout the course of 
the study, the Study Monitor will make frequent contact with the Investigator. This will include 
telephone calls and on-site visits. During the on-site visits, the completed CRF will be compared 
to the source documentation for completeness, accuracy and adherence to the protocol. As part of 
the data audit, source documents must be made available to the Study Monitor for review. The 
Study Monitor will also perform drug accountability checks and will review the Investigator 
study file to assure completeness of documentation in all respects of clinical study conduct. 
 
Upon completion of the study, the Study Monitor will arrange for a final review of the study 
files, after which the files should be secured for the appropriate time period. The Investigator, or 
appointed delegate, will meet with the Study Monitor during the on-site visits and will cooperate 
in providing the documents for inspection and responding to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of BioElectron 
Technology Corporation or the regulatory agencies. 
 
US and other competent regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. Medical records and other 
study documents may be copied during audit or inspection provided that subject names are 
obliterated on the copies to ensure confidentiality. 
 
C. 
Data Quality Assurance 
 
As a final step in the data management process, a 100% audit will be performed on the key 
safety and critical efficacy parameters. In addition, a random subject sample (10%) will be 
selected in order to perform a partial audit of remaining data. The purpose of this audit is to 
detect systematic and random errors. Any errors found from this audit will be corrected and, if 
the error rate is greater than 1 error per 1,000 fields (0.001%), a systematic review of the 
database will be undertaken and corrections will be made to achieve an error rate of less than 
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AEs will be coded using MedDRA, version (14.3). Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary, March 2014. 
 
D. 
Retention of Study Records 
 
The following records must be retained by the Investigator for a minimum of 2 years after the 
Sponsor has notified the FDA or other competent authority that investigations have been 
discontinued, or after the FDA or other competent authority has approved the new drug 
application. In accordance with European regulatory requirements (Directive 2005/28/EC and 
Annex 17 and 2001/83/EC and Annex1), the Sponsor may request retention for a longer period 
of time. 
1. Signed informed consent documents for all subjects 
2. Subject identification code list, screening log (if applicable), and enrollment log 
3. Record of all communications between the Investigator and the IRB/IEC 
4. Composition of the IRB/IEC or other applicable statement 
5. Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
6. List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in the 
study and their signatures 
7. Copies of CRFs and of documentation of corrections for all subjects 
8. Drug accountability records 
9. Record of any body fluids or tissue samples retained 
10. All other source documents (subject records, hospital records, laboratory records, etc.) 
11. All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. 
 
Normally, these records will be held in the Investigator's archives. If the Investigator is unable to 
meet this obligation, 
or 
must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 
E. 
Confidentiality 
 
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the Sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be told that representatives of the Sponsor, IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection and privacy laws, including the Health Insurance 
Portability and Accountability Act (HIPAA) Guidelines, and the General Data Protection 
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The Investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
F. 
Documentation of Study Results 
 
A CRF will be provided for each enrolled subject. 
 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the CRF. Details of CRF completion and correction will be 
explained to the Investigator. If the Investigator authorizes other persons to make entries in the 
CRF, the names, positions, signatures, and initials of these persons must be supplied to the 
Sponsor. 
 
The Investigator, or designated representative, should complete the CRF pages as soon as 
possible after information is collected, preferably on the same day that a study subject is seen for 
an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
 
By signing the completed CRFs, the Investigator or Subinvestigator attests to the accuracy, 
completeness, legibility, and timeliness of the data collected on the CRF and casebooks. 
 
The Sponsor will retain the originals of all CRFs. The Investigator will retain a copy of all 
completed CRF pages. 
 
G. 
Regulatory and Ethical Considerations 
G1. Risk Assessment 
 
Based on the safety results of Study EPI-589-14-01 as summarized in the Clinical Study Report, 
it is not foreseen that subjects will endure any risks greater than minimal at the 500-mg BID dose 
selected for this study. 
 
G2. Potential Benefits of Trial Participation 
 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 
benefit in subjects with PD. Therefore, we cannot assure that subjects will benefit from treatment 
with EPI-589. Potential benefits may manifest in a variety of ways, such as in disease-related 
parameters, functioning, and quality of life. 
 
G3. Risk-Benefit Assessment 
 
There are no effective and/or approved disease modifying treatments available for PD, although 
a number of clinical interventions are being researched. Based on disease mechanism, EPI-589 
mechanism of action and pre-clinical studies, EPI-589 may hold benefit for patients with PD. 
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benefit in subjects with PD. In order to further minimize risks, subjects will be closely monitored 
with a variety of safety measures. 
 
H. 
Informed Consent 
 
Before being enrolled in the clinical study, subjects must provide written consent to participate 
after the nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them. The Investigator will not undertake any measures specifically 
required only for the clinical study until valid consent has been obtained. 
 
An informed consent document that includes both information about the study and the consent 
form will be prepared and given to the subject. This document will contain all the elements 
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements 
required by local regulations and must be in a language understandable to the subject. Where 
required by local law, the person who informs the subject must be a physician. It should be 
signed and dated by all the parties concerned including the subject, legal guardian (where 
applicable), witness (where applicable) and the person obtaining the consent. 
 
A copy of the signed consent document must be given to the subject. The original signed consent 
document will be retained by the Investigator. 
 
The Investigator must inform the subject’s primary physician about the subject’s participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
 
 
 
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XII. PUBLICATION 
A. Use of Study Results 
 
All information concerning the product, as well as any matter concerning the operation of 
BioElectron Technology Corporation(such as clinical indications for the drug, its formula, 
methods of manufacture, and other scientific data relating to it, that have been provided by 
BioElectron Technology Corporation and are unpublished), are confidential and must remain the 
sole property of BioElectron. The Investigator will agree to use the information only for the 
purposes of carrying out this study and for no other purpose unless prior written permission from 
BioElectron Technology Corporation is obtained. The Sponsor has full ownership of the CRFs 
completed as part of the study. 
 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by BioElectron. If necessary, the authorities will be 
notified of the Investigator's name, address, qualifications, and extent of involvement. 
 
This Study is part of a multicenter clinical research study. Accordingly, Sponsor will act as 
coordinator and referee with respect to publications of the data generated thereunder. Principal 
Investigator shall not publish or disclose any data, result or information with respect to any 
matters resulting from work performed under this Protocol while this Study is being conducted at 
other center/s. Only after the completion of this Study at all other centers, provision of the data to 
the FDA or EMA for review and comment, and publishing the combined data from all of the 
centers, may the Principal Investigator publish/present the individual results of the Study in 
accordance with this paragraph. 
 
Principal Investigator may publish provided, however, that no publication, abstract, 
announcement or disclosure (“Publication”) shall be made until the Principal Investigator 
submits to Sponsor any proposed Publication for Sponsor’s review. Sponsor shall have a period 
of sixty (60) days to review such Publication. If Sponsor determines during the review period 
that the Publication contains patentable subject matter, then the above sixty (60) days shall be 
extended to one hundred twenty (120) days in order to allow for the preparation of patent 
applications covering said patentable subject matter. Unless Sponsor approves in writing, no 
Publication may contain any Confidential Information (other than data and results generated 
under the Study). 
 
Without limiting the foregoing, Institution and Principal Investigator, and all other study 
investigators in other study institutions, shall give due regard to Sponsor’s legitimate interests, 
such as manuscript authorship, coordinating and maintaining the proprietary nature of 
submissions to health authorities, and coordinating with other ongoing studies in the same field, 
and agree to accept Sponsor’s reasonable comments and suggestions with respect to such 
Publications. 


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If the Investigator is to be an author of a publication manuscript prepared by BioElectron 
Technology Corporation, BioElectron will allow the Investigator or CRO 60 days for full review 
of the manuscript before publication. 


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XIII. LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AR 
accumulation ratio 
BDI 
Beck Depression Inventory 
BID 
twice daily 
BSO 
L-buthionine-(S,R)-sulfoximine 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatinine kinase 
CNS 
central nervous system 
CoQ10 
Coenzyme Q 10 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DaT 
dopamine transporters 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EITT 
efficacy intent-to-treat 
EPDA 
European Parkinson’s Disease Association 
EU 
European Union 
%F 
percent fluctuation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GCRC 
good clinical research practice 
GDPR 
General Data Protection Regulation 
GSH 
glutathione 
GSSG 
glutathione disulfide 
HDPE 
high density polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HMPAO 
hexamethylpropylene amine oxime 
ICF 
informed consent form 
ICH 
International Committee on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 


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kg 
kilogram 
Λz 
apparent terminal constant 
LFT 
liver function test 
MAD 
multiple ascending (oral) dose 
MADRS 
Montgomery and Asberg Depression rating scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale 
mg 
milligram 
mL 
milliliter 
MoCA 
Montreal Cognitive Assessment 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
MPV 
mean platelet volume 
mtDNA 
mitochondrial DNA 
N/A 
not applicable 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NF 
National Formulary 
nM 
nanomolar 
NMSS 
Non-motor Symptoms Scale 
NOAEL 
no observed adverse effect level 
NQ01 
NAD(P)H Quinone oxidoreductase 1 
OD 
once daily 
OTC 
over-the-counter 
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PO 
by mouth 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 
PVP 
polyvinylpyrrolidone 
QT 
interval between the start of the Q wave and the end of the T wave 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAD 
single ascending (oral) dose 
SAE 
serious adverse event 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
Tmax 
time to peak concentration 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
UV 
ultraviolet 


 
I
 
 
 
 
 
Protocol EPI589-15-002 
EPI-589 
Version: Amendment 4.0 
 
 
 
XIV. SIGNATURE OF SPONSOR 
 
A. Declaration of Sponsor 
 
This study protocol was subject to critical review and the information it contains is consistent 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP as described in 21 CFR parts 50, 54, 56, and 
312. 
 
The Investigator will be supplied with details of any significant or new findings on EPI-589, 
including AEs. 
 
 
Date: 11 R,l;i 2ol 7 
Signature: 
 
BioElectron Technology Corporation 
350 North Bernardo Ave 
Mountain View, CA 94043 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
17Feb2017 
BioElectron Technology Corporation 
Page 52 of54 
r


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Protocol EPI589-15-002 
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Page 53 of 54 
 
 
 
XV. REFERENCES 
 
Ashrafi G, Schlehe JS, LaVoie MJ, Schwartz TL. Mitophagy of damaged mitochondria occurs 
locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014; 1;206(5):655- 
70. 
 
Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces 
features of Parkinson's disease. Nat Neurosci. 2000; 3(12): 1301-1306. 
 
Dauer W and Przedborski S. Parkinson's disease: mechanisms and models, Neuron 2003; 39: 
889–909. 
 
de Lau LM and Breteler MM. Epidemology of Parkinson’s Disease. Lancet Neur.2006; 5: 525- 
35. 
 
EPDA-European Parkinson’s Disease Association. http://www.epda.eu.com/en/resources/life- 
with-parkinsons/part-1/prevalence-of-parkinsons-disease/ (consulted 04 December 2014). 
 
Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, et al. Biochemical and pathological 
characterization of Lrrk2. Ann Neurol. 2006: 59(2): 315-22. 
 
Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, 
environment and mitochondria. Parkinsonism Relat. Disord. 2003; 9 (Suppl 2): S59–S64. 
 
Holmay, MJ, Terpstra M, Coles LD, et al. N-acetylcysteine Boosts Brain and Blood Glutathione 
in Gaucher and Parkinson Diseases. Clin. Neuropharm. 2013; 36, 4: 103-106. 
 
Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, et al. Glutathione Depletion in PC12 Results in 
Selective Inhibition of Mitochondrial Complex I Activity. Implications for Parkinson’s disease. J 
Biol Chem. 2000; 25;275 (34): 26096-101. 
 
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product 
of meperidine-analog synthesis. Science. 1983; 219: 979–980. 
 
Lin MT and Beal FB. Mitochondrial dysfunction and oxidative stress in neurodegenerative 
diseases. Nature. 2006; 443: 787-795. 
 
Maarouf CL, Beach TG, Adler CH, Shill HA, Sabbagh MN, et al. Cerebrospinal fluid 
biomarkers of neuropathologically diagnosed Parkinson's disease subjects. Neurol Res. 2012; 
34:669–676. 
 
Mao P and Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and 
mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and 
therapeutics. Biochim. Biophys. Acta. 2011; 1812: 1359-1370. 


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Narendra, DP and Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and parkin in 
mitochondrial quality control. Antioxi. Redox Signal. 2011; 14: 1929-1938. 
 
The Parkinson’s Disease Foundation. http://www.pdf.org/en/parkinson_statistics (consulted 27 
April 2015). 
 
Pinto M, Pickrell AM, Moraes CT. Regional susceptibilities to mitochondrial dysfunctions in the 
CNS. Biol. Chem. 2012; 393: 275-281. 
 
Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, et al. Transition metals, ferritin, 
glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 1989; Feb;52(2): 515-20. 
 
Winklhofer KF and Haass C. Mytochondrial dysfunction in Parkinson’s disease. Biochimica et 
Biophysica Acta. 2010; 1802: 29-44. 
 
Zhu X, Babar A, Siedlak SL, Yang Q, Ito G, et al. LRRK2 in Parkinson's disease and dementia 
with Lewy bodies. Mol Neurodegener. 2006;1:17. 


BioElectron Technology Corporation 
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Version: Amendment 4.0 
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Page 1 of 2 
 
 
 
 
 
Summary of Changes 
Amendment 4.0 
EPI589-15-002 
 
A Phase 2A Safety and Biomarker Study of EPI-589 
in Mitochondrial Subtype and Idiopathic Parkinson’s 
Disease Subjects 
 
Protocol Number 
EPI589-15-002 
Original Protocol Date 
27 April 2015 
Amendment 1.0 Date 
09 September 2015 
Amendment 2.0 Date 
04 January 2016 
Amendment 3.0 Date 
10 October 2016 
Amendment 4.0 Date 
17 February 2017 
Study Sponsor 
BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Sponsor’s Representative 
 
BioElectron Technology Corporation 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
The information contained in this document is confidential and will not be disclosed to others without written authorization from 
BioElectron Technology Corporation, except to the extent necessary to obtain informed consent from those persons to whom the drug may 
be administered or for discussions with local regulatory authorities, Ethics Committee/Investigational Review Boards, or people 
participating in the conduct of the study. 


BioElectron Technology Corporation 
Protocol EPI589-15-002 
EPI-589 
Version: Amendment 4.0 
Confidential 
Page 2 of 2 
 
 
 
 
KEY CHANGES TO THE PROTOCOL 
 
Amendment 4.0 provides the following change and rationale: 
 
 
Change 
Rationale 
• Change in Company Name from Edison 
Pharmaceuticals to BioElectron 
Technology Corporation 
• Edison Pharmaceuticals, Inc. has changed its 
name to reflect our broader mission and business 
applications. 
 
 
 
 
End of Document 
#### 


 
 
 
 
 
 
EPI589-15-002 
A Phase 2A Safety 
and Biomarker Study of 
EPI-589 in Mitochondrial 
Subtype and Idiopathic 
Parkinson’s Disease Subjects 
 
Original Protocol: 
27 April 2015 
Protocol Amendment 1.0: 
09 September 2015 
Protocol Amendment 2.0: 
04 January 2016 
Protocol Amendment 3.0: 
10 October 2016 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
The information contained in this document is confidential and will not be disclosed to others without 
written authorization from Edison, except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the study. 


Edison Pharmaceuticals, Inc 
Protocol EPI589-15-002 
EPI-589 
Version: Amendment 3.0 
Confidential 
10Oct2016 
Edison Pharmaceuticals Inc. 
Page 2 of 53 
 
 
 
Table of Contents 
I. PROTOCOL SYNOPSIS .................................................................................................. 6 
II. SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE ................................ 11 
A. Schedule of Dosing ...................................................................................................... 12 
III. INTRODUCTION ........................................................................................................... 13 
A. Background Information and Rationale................................................................... 13 
B. Rationale for the Study of EPI-589 in Parkinson’s Disease .................................... 14 
C. Name and Description of Investigational Product ................................................... 14 
D. Findings from Non-Clinical and Clinical Studies .................................................... 15 
D1. Non-Clinical Studies .................................................................................................. 15 
D2. Clinical Studies ........................................................................................................... 17 
E. Human Pharmacokinetics ............................................................................................ 17 
F. 
Clinical Study .............................................................................................................. 18 
G. Selection of Drugs and Dosages ................................................................................. 18 
H. Compliance Statement ................................................................................................ 18 
I. 
Relevant Literature and Data .................................................................................... 18 
IV. STUDY OBJECTIVES ................................................................................................... 19 
A. Primary Objective ...................................................................................................... 19 
B. Secondary Objectives .................................................................................................. 19 
V. INVESTIGATIONAL PLAN ......................................................................................... 20 
A. General Schema of Study Design .............................................................................. 20 
A1. Screening Phase ......................................................................................................... 20 
A2. 30-Day Run-in Phase ................................................................................................. 20 
A3. Baseline ...................................................................................................................... 20 
A4. Treatment Phase ........................................................................................................ 20 
A5. End of Treatment........................................................................................................ 21 
A6. Post-Treatment Follow-up ......................................................................................... 21 
B. Randomization and Blinding ..................................................................................... 21 
C. Study Duration, Enrollment and Number of Sites .................................................. 21 
C1. Duration of Subject Treatment ................................................................................... 21 
C2. Total Number of Study Sites/Total Number of Subjects Projected ............................ 21 
D. Study Population ......................................................................................................... 22 


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D1. Inclusion Criteria ....................................................................................................... 22 
D2. Exclusion Criteria ...................................................................................................... 22 
VI. STUDY PROCEDURES ................................................................................................. 24 
A. Screening Visit ............................................................................................................ 24 
A1. Run-in Assessments ..................................................................................................... 24 
B. Treatment Phase ......................................................................................................... 24 
B1. Baseline Assessments .................................................................................................. 25 
B2. Study Visit Assessments .............................................................................................. 25 
B3. Pharmacokinetics ....................................................................................................... 26 
B4. Early Termination Study Visit .................................................................................... 26 
C. End of Treatment Visit ............................................................................................... 27 
D. Post-Treatment Follow-up ......................................................................................... 27 
E. Unscheduled Visits ...................................................................................................... 27 
F. 
Concomitant Medication ............................................................................................ 27 
G. Prohibited Medications .............................................................................................. 27 
H. Subject Withdrawals .................................................................................................. 27 
VII. STUDY ENDPOINTS AND EVALUATIONS ............................................................. 29 
A. Primary Endpoint ....................................................................................................... 29 
B. Secondary Endpoints (Efficacy) ............................................................................... 29 
C. Secondary Endpoints (Safety) ................................................................................... 29 
D. Screening and Baseline Evaluation ........................................................................... 29 
D1. Physical Examination................................................................................................. 29 
D2. Height and Weight ..................................................................................................... 30 
D3. Laboratory Evaluations ............................................................................................. 30 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) .................................................... 31 
E. Sample Collection Procedures, Bioanalytical Methods and Sample Shipment .... 31 
F. 
Efficacy Evaluations ................................................................................................... 31 
F1. Glutathione Cycle Biomarkers ................................................................................... 31 
F2. Parkinson’s Disease Rating (MDS-UPDRS) ............................................................. 31 
F3. Non-motor Symptoms (NMSS) ................................................................................... 32 
F4. Parkinson’s Disease Questionnaire (PDQ-39) ......................................................... 32 
F5. EQ-5D ........................................................................................................................ 32 


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F6. Montreal Cognitive Assessment (MoCA) ................................................................... 32 
F7. Beck Depression Inventory (BDI) .............................................................................. 32 
F8. Montgomery and Asberg Depression rating scale (MADRS) .................................... 32 
F9. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) ........... 33 
VIII. 
STATISTICAL CONSIDERATIONS ................................................................... 34 
A. Statistical Analysis ...................................................................................................... 34 
A1. Analysis Populations ................................................................................................... 34 
B. Efficacy Analysis ......................................................................................................... 34 
B1. Efficacy Variables ...................................................................................................... 34 
C. Safety Analysis ............................................................................................................ 34 
D. Sample Size .................................................................................................................. 35 
IX. STUDY MEDICATION ................................................................................................... 36 
A. Description ................................................................................................................... 36 
B. Packaging .................................................................................................................... 36 
B1. Labeling ..................................................................................................................... 36 
B2. Dosage Form .............................................................................................................. 36 
B3. Dispensing.................................................................................................................. 36 
C. Treatment Compliance and Adherence .................................................................... 36 
D. Drug Accountability ..................................................................................................... 36 
X. SAFETY MANAGEMENT ............................................................................................ 38 
A. Clinical Adverse Events ............................................................................................. 38 
B. Adverse Event Reporting ........................................................................................... 38 
B1. Safety Guidance ......................................................................................................... 38 
C. Definition of an Adverse Event .................................................................................. 38 
C1. Adverse Event ............................................................................................................. 38 
C2. Definition of a Serious Adverse Event (SAE) ............................................................. 39 
C3. Non-serious Adverse Event ........................................................................................ 40 
C4. Definition of Relationship to Study Medication .......................................................... 40 
C5. Definition of Severity ................................................................................................. 40 
C6. Definition of Unexpected Adverse Event .................................................................... 41 
C7. Notification of SAEs ................................................................................................... 41 
C8. Follow-up Report ....................................................................................................... 42 


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C9. Dose Modification Guidelines ................................................................................... 42 
D. Medical Emergencies .................................................................................................. 43 
D1. Emergency Sponsor Contact ...................................................................................... 43 
D2. Emergency Treatment ................................................................................................ 43 
XI. STUDY ADMINISTRATION ........................................................................................ 44 
A. Treatment Assignment Methods ............................................................................... 44 
B. Data Collection and Management .............................................................................. 44 
C. Data Quality Assurance ............................................................................................. 44 
D. Retention of Study Records ....................................................................................... 45 
E. Confidentiality ............................................................................................................. 45 
F. 
Documentation of Study Results ............................................................................... 46 
G. Regulatory and Ethical Considerations .................................................................... 46 
G1. Risk Assessment .......................................................................................................... 46 
G2. Potential Benefits of Trial Participation .................................................................... 46 
G3. Risk-Benefit Assessment ............................................................................................. 46 
H. Informed Consent ....................................................................................................... 47 
XII. PUBLICATION .............................................................................................................. 48 
A. Use of Study Results ................................................................................................... 48 
XIII. 
LIST OF ABBREVIATIONS ................................................................................. 49 
XIV. 
SIGNATURE OF SPONSOR ................................................................................. 51 
A. Declaration of Sponsor ................................................................................................ 51 
XV. REFERENCES ................................................................................................................ 52 
 
 
 
 
 
Space intentionally left blank 


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I. 
PROTOCOL SYNOPSIS 
 
Title of study 
A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial 
Subtype and Idiopathic Parkinson’s Disease Subjects 
Protocol number 
EPI589-15-002 
IND number 
126,795 
EudraCT number 
2015-001786-10 
Original Protocol 
27 April 2015 
Protocol Amendment 1.0 
09 September 2015 
Protocol Amendment 2.0 
04 January 2016 
Protocol Amendment 3.0 
03 October 2016 
Investigative Drug 
EPI-589 
Study Sponsor 
Edison Pharmaceuticals Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Investigators and 
Investigative Sites 
• 
Germany 
• 
UK 
• 
USA 
• 
USA 
• 
USA 
Study population 
Approximately 40 subjects with Parkinson’s disease (PD) including 20 
subjects with genetically-defined subtypes 


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Rationale for Study 
Mitochondrial pathophysiology 
It is now well appreciated that defects in mitochondrial function contribute 
to the pathophysiology of PD both in subjects with defined genetic defects 
as well as those with idiopathic forms of the disease. 
High morbidity 
Despite the available therapies for symptomatic relief, PD remains a highly 
morbid disease. There are no approved treatments for PD capable of 
modifying disease progression. 
Pre-clinical efficacy data 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 < 
100nM) and efficacy (>80% rescue from oxidative stress-induced cell 
death) in cells derived from patients diagnosed with idiopathic and familial 
PD subtypes including PINK1, parkin and LRRK2. 
Study objectives 
Primary Objective 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of 
drug-related serious adverse events in subjects with PD. 
Secondary Objectives 
To evaluate the effects of EPI-589 in subjects with PD on: 
1. Glutathione cycle biomarkers as measured in blood, cerebral spinal 
fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society- 
sponsored revision of the Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale 
(NMSS), PDQ-39 and EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment 
(MoCA) and 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the 
Montgomery and Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 


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Study design 
Open-label study with 30-day run-in phase. 
Planned number of 
subjects 
Approximately 40 subjects (20 with genetically-defined subtypes of PD 
and 20 idiopathic PD subjects). (Adaptive design component allows 
enrollment of up to 20 additional subjects with idiopathic PD to try to 
achieve a total of 20 subjects that have a biomarker response to EPI-589.) 
Study duration 
3 months (85 days ± 3 days) of study treatment preceded by a 1-month 
baseline parameter run-in period. 
Test product, mode of 
administration, and dose 
Test product 
EPI-589 in a tablet formulation at a strength of 250 mg 
Mode of Administration 
Oral with meal 
Dose 
EPI-589 500-mg BID 
Reference therapy, dose, 
and mode of 
administration 
None 
Safety monitoring 
Clinical 
1. Physical exam and vital signs 
2. Evaluation of adverse events 
3. 12-lead Electrocardiogram 
4. Columbia Suicide Severity Rating Scale (C-SSRS) 
Laboratory 
1. Routine serum chemistries 
2. Routine hematology tests and coagulation tests 
Inclusion criteria (all 
subjects) 
1. Hoehn and Yahr stage ≤ 3.0 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners must agree to use 
medically accepted methods of contraception (e.g., hormonal 
methods, including oral, subcutaneous, and intrauterine; barrier 
methods, including 
condom, 
condom, or diaphragm with 
spermicidal gel) during the course of the study and for 3 months after 
the last dose of study treatment. 
4. Willingness and ability to comply with study procedures 


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5. If on medications and supplements for PD, then regimen must be 
stable for 60 days prior to enrollment 
6. Abstention from use of other investigative or non-approved drugs for 
the duration of the trial 
For Idiopathic Subjects 
7. A diagnosis of idiopathic PD confirmed by the presence of 
bradykinesia plus one or both of the following symptoms: rigidity or 
resting tremor; and with an abnormal DaTscan consistent with a 
dopaminergic deficit 
8. Age 40 to 75 years 
9. Within 5 years of diagnosis of Parkinson’s disease 
For Genetic Subtype Subjects 
10. A confirmed diagnosis of PD plus a genetic diagnosis consistent with 
PD, specifically PINK1, parkin, LRRK2 or other mitochondrial 
genetic subtype 
11. Age 21 to 75 years 
Exclusion criteria 
1. Allergy to EPI-589 or other components of the EPI-589 tablet 
formulation 
2. Vitamins E and C beyond the recommended daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that 
will confound the assessment of effect of study drug on disease 
progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper 
limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial 
of a device, drug or other therapy for PD 


Edison Pharmaceuticals, Inc 
Protocol EPI589-15-002 
EPI-589 
Version: Amendment 3.0 
10Oct2016 
 
 
 
 
Treatment 
Following study enrollment, baseline assessments will be performed. 
Subjects will participate in a 30-day run-in phase to establish biomarker 
and clinical baseline measurements. EPI-589 will then be administered for 
up to 3 months (85 days ± 3 days) unless discontinued for safety or 
tolerability issues. Post-treatment follow-up will be at least 10 days and up 
to 30 days after last dose. 
Efficacy variables 
1. Blood-based glutathione biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. Non-motor Symptoms Scale (NMSS) 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. Beck Depression Inventory (BDI) 
10. Montgomery & Asberg Depression rating scale (MADRS) 
11. Timed motor tests in ON and OFF state (for subjects on dopamine 
therapy) 
12. Pharmacokinetics 
Safety variables 
Clinical 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
4. C-SSRS 
5. Laboratory 
6. Routine serum chemistries with liver function tests 
7. Routine hematology tests with coagulation tests 
Statistical Considerations 
Data Analysis 
This is a within-subject, controlled open-label study seeking to determine 
the safety and tolerability of EPI-589 in patients with PD as well as to 
determine if EPI-589 can alter the biochemical signature of PD as assessed 
by peripheral blood biomarkers, CNS biomarkers, brain imaging 
biomarkers, and urine biomarker analysis. In addition, data on a number of 
disease-relevant clinical measures will be collected. 
 
 
 
 
 
 
Confidential 
Edison Pharmaceuticals Inc. 
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Page 11 of53 
 
 
 
II. 
SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE 
 
 
 
Tests 
-2 to -1 Months 
DayO 
Month 1 
Month 2 
Month3  
End of Treatment 
Visit 
Post-Treatment 
Follow-up 
Screening 
Run-in 
(upto 30 
days from 
screenin2) 
Baseline (27-33 
days from run-in) 
Day29 
(± 3 days) 
Day 57d 
(± 3 days) 
Day85 
(±3 days) 
Up to 30Days 
afte1·Last Dose•
Informed consent 
Day 1 
First 
Dose 
Inclusion/Exclusion criteria 
Past Medical history 
Pre:wous genetic testing 
review 
Physical exam & Vital signs 
Height & weight 
• 
12-lead ECG 
• 
Hematology (including 
coagulation panel) 
• 
f 
f 
Semm Chemistiy 
• 
f 
f 
Pregnancy test" 
C-SSRS 
Monti·eal Cognitive 
Assessment 
DaTscan (for idiopathic 
subjects) 
Revised Hamilton Rating 
Scale for Depression 
Subject enrolls in study 
X 
Fasting blood-based 
glutathione cycle biomarkers 
Lumbar puncture (CNS 
biomarkers) 
Urine-based biomarkers 
MDS-UPDRS 
Timed motor tests (for 
subjects on dopamine therapy) 
NMSS, PDQ-39, EQ-5D 
BDI,MADRS 
Dmg plasma concenti·ation° 
c 
c 
AE/SAE assessment 
• 
• 
• 
• 
d,• 
d,e 
• 
Concomitant medications 
assessment 
d 
d 
• 
Post-Treatment Assessments• 
• 
a. 
Screening values can be used if done w-ithin one month of baseline and if completed under fasted conditions 
- Female subjects of childbea1mg potential must have a negative pregnancy test. 
C. 
Full plasma concenti·ation profile w-ill be obtained at Time= 0, and 0.5, I, 2, 4, 6, 8, and 12 hours after dosing from the first 10 subjects to complete 
I month of therapy at each site. 12 hotu·PK can be obtained at time 0. 
d. 
Month 2 assessments can be done by telephone. Any new AEs and associated concomitant medications reported at Month 3 must be followed for 30 
days; this follow up may be conducted by telephone. 
e. 
AE/SAE and concomitant medication assessments conducted by telephone at least 10 days after last dose. Additional assessments detenuined at 
Investigator discretion. SAEs are ti·acked from the time ICF is signed and all other AEs are ti-acked from the time first dose is administered; 


EPI-589 
Version: Amendment 3.0 
Edison Pharmaceuticals, Inc 
Protocol EPI589-l 5-002 
10Oct2016 
 
 
 
 
 
f. 
TI1e baseline and all subsequent laboratory assessments should be obtained under fasting conditions. 
 
 
A. 
Schedule of Dosing 
 
 
 
-2 to -1 Months 
Day0 
Month 1 
Month2 
Month3 
Post-Treatment 
Dosing Schedule 
Screening 
Run-in 
(±30 days) Baseline
Day29 
(±3 days) 
Day 57d 
(±3 days) 
Day85 
(±3 days) 
Up to30 Days 
after Last Dose• 
 
EPI-589 500-mg BID 
Dispense Study Drug 
Dmg Reconciliation with diaries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
Edison Phannaceuticals Inc. 
Page 12 of53 


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III. INTRODUCTION 
A. 
Background Information and Rationale 
 
Parkinson’s disease (PD) is a highly morbid neurodegenerative movement disorder that has a 
number of neuromuscular, cognitive and neuropsychiatric manifestations as well as non- 
neurological symptoms. PD is the second most common neurodegenerative disorder with an 
estimated prevalence of 6.3 million people worldwide (EPDA). 
 
PD has long been considered a non-genetic (idiopathic) disease; however, about 5% of patients 
have an identifiable mutation. Disease onset typically occurs after age 50, however, in a subset of 
patients, disease onset can occur at a younger age. The primary motor symptoms result from 
death of dopamine-producing cells in the pars compacta region of the substantia nigra. However, 
the mechanisms underlying this cell death and disease pathology remain poorly understood. 
There is no approved treatment for PD capable of modifying disease progression. Current 
therapies partially address disease motor symptoms through levodopa or dopamine agonists or 
other agents, and other disease symptoms (e.g. neuropsychiatric symptoms), but disability tends 
to increase over time despite these treatments. 
 
The association of PD with mitochondrial pathology and high levels of oxidative stress are well 
established. Increased levels of oxidative stress have been consistently measured in post-mortem 
specimens from PD patients (Maarouf 2012, Reale 2012). The occurrence of PD-like symptoms 
in heroin addicts exposed to MPTP in the 1980s established a first link between PD and 
mitochondrial injury (Langston 1983, Dauer and Przedborski 2003). MPTP inhibits complex 1 of 
the mitochondrial respiratory chain and induces degeneration of dopaminergic cells through 
oxidative stress-mediated injury. The link between mitochondrial injury and PD was further 
strengthened by the induction of PD symptoms following exposure to another neurotoxic 
complex 1 inhibitor, rotenone (Betarbet et al 2000, Greenamyre et al. 2003), which like MPTP 
has come to be used in pre-clinical testing for its phenotypic similarities to PD. 
 
Furthermore, the identification of genetic mutations such as PINK1, parkin, LRRK2 and others 
in mitochondrial genes in familial PD patients provided the strongest link between the 
mitochondria and PD (Winklhofer and Haass 2010). Normally these genes influence oxidative 
balance and provide neural protection of the dopaminergic neurons that are affected by PD. 
PINK1 and parkin are involved in protecting against oxidative stress (OS) and overabundant 
reactive oxygen species (ROS), and are implicated in cell morphology and dynamics, as well as 
in the preferential degradation of dysfunctional mitochondria or “mitophagy” (Ashrafi et al. 
2014). Mutant LRRK2 leads to the accumulation of misfolding intracellular protein 
accumulations, cell stress and apoptosis (Giasson et al. 2006, Zhu et al. 2006). 
 
The importance of oxidative stress in PD pathology is further substantiated by the measurement 
of decreased levels of reduced glutathione in the brains of patients with PD (Holmay et al. 2013). 
Glutathione levels are low at very early stages of PD and correlate with disease severity 
(Riederer et al. 1989), and experimental induction of glutathione depletion leads to mitochondrial 
complex I dysfunction (Jha et al, 2000;). Reduced glutathione is an essential intermediary 


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metabolite that serves as the primary native cellular antioxidant. In a state of high oxidative 
stress, elevated levels of ROS outstrip the supply of glutathione (GSH) resulting in depletion of 
GSH and ROS-mediated cell death. 
 
Given the important role of oxidative stress and mitochondrial pathology in PD, a redox-active 
therapy that could target key pathways in cellular OS response pathways may hold promise for 
the treatment of PD. 
 
B. 
Rationale for the Study of EPI-589 in Parkinson’s Disease 
 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 <100nM ) and efficacy 
(>80% rescue from oxidative stress-induced cell death) in cells derived from patients diagnosed 
with idiopathic and familial PD genetic subtypes including PINK1, parkin and LRRK2. 
In these cell-based assays, primary fibroblasts from patients (and control) were pre-incubated 
with and without test compound, then treated with L-buthionine-(S,R)-sulfoximine (BSO), a 
GSH synthesis inhibitor, to initiate depletion of cellular GSH. GSH depletion has been shown to 
lead to OS and disruption of calcium homeostasis resulting in loss of the mitochondrial 
membrane potential and cell death. Under these conditions, the control cells are resistant to the 
stress and the fibroblast cells from patients with disease indications die within 36 to 48 hours. 
Pretreatment of cells with EPI-589 prior to initiation of GSH depletion potently protected against 
oxidative stress-mediated cell death, with EC50 response concentrations of 16 to 52 nM. (Table 
1). 
Table 1: 
Cell Line Rescue with EPI-589 in Parkinson’s Disease Genetic Subtypes 
 
EPI-589 
EC50 (nM range) 
PINK1 
26-36 
LRRK2 
16-18 
parkin 
42-52 
 
C. 
Name and Description of Investigational Product 
The IUPAC name of EPI-589 is: 
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide. 
 
A common chemical name of EPI-589 is (R)-troloxamide quinone. EPI-589 is derived from 
resolved (R)-Trolox®, a derivative of vitamin E in the form of a pale yellow to yellow solid. The 
EPI-589 drug product will be provided in a 250-mg tablet formulation. 


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The Investigator will ensure that all study drugs are stored and dispensed in accordance with the 
Food and Drug Administration (FDA) and local regulations concerning the storage and 
administration of investigational drugs. 
 
D. 
Findings from Non-Clinical and Clinical Studies 
D1. Non-Clinical Studies 
 
EPI-589 is an orally available compound that has been demonstrated in vitro and in vivo to cross 
the blood-brain-barrier. In 28-day and 91-day repeat-dose toxicity studies in rat and cynomolgus 
monkey, the no observed adverse effect level (NOAEL) was 300 mg/kg/day, corresponding to 
combined mean Cmax values of 37,717 to 56,500 ng/mL (rat) and 14,300 to 16,417 ng/mL 
(monkey), and a combined mean area under the plasma concentration-time curve from time zero 
to the last measurable concentration (AUClast) value of 149,495 to 297,000 ng.h/mL (rat) and 
47,300 to 67,656 ng.h/mL (monkey) (Studies 1660-038, 1660-039, 1660-063, and 1660-064). 
 
A phase 1 clinical study demonstrated that healthy subjects administered 500 mg EPI-589 BID 
for 14 days showed a mean Cmax value of 1,890 ng/mL and a mean AUClast value of 5,240 
ng.h/mL (Study EPI589-14-01). These plasma concentrations are well below the mean exposure 
values in monkey associated with the NOAEL in the toxicity studies, corresponding to safety 
margins of approximately 7- to 8-fold for the mean Cmax and 9- to 12-fold for the mean AUC. 
 
During the 28-day repeat-dose toxicity studies, rat and monkey were exposed to up to 1,000 
mg/kg/day EPI-589 PO (Studies 1660-039 and 1660-038). The NOAEL for both studies was 300 
mg/kg/day. Rats exposed to 1,000 mg/kg/day exhibited adverse test-article related effects on 
hematology parameters consistent with hemolysis and bone marrow regeneration, mild to 
moderately enlarged spleens, and increased organ weights with some organs showing 
corresponding microscopic pathology. The majority of these findings were resolved following 
the 28-day recovery period. Monkeys exposed to 1,000 mg/kg/day showed significant test-article 
related morbundity that resulted in half the animals in the high dose group being euthanized on 
Days 3 and 4 and the remaining animals being euthanized on Day 9. These animals exhibited 
significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
values, and microscopic findings in the kidney, liver, skeletal muscle, heart, and lymphoid 
tissues. In several of the animals the primary cause of morbidity was determined to be test-article 
related renal tubular degeneration/necrosis. 
 
During the 91-day repeat-dose toxicity studies, rat and monkey were exposed to up to 300 
mg/kg/day EPI-589 PO (Studies 1660-063 and 1660-064). The NOAEL for the rat study was 300 
mg/kg/day and the no observed effect level (NOEL) for the monkey study was 300 mg/kg/day. 
rats exposed to 300 mg/kg/day and 
rats exposed to ≥ 100 mg/kg/day exhibited mild 
test-article related effects on hematology parameters consistent with hemolysis and bone marrow 
regeneration. These findings were not considered adverse. 
 
Development and reproductive toxicology studies were conducted in rat and rabbit at doses up to 
1,000 mg/kg/day EPI-589 PO (Studies 1660-069, 1660-067, and 1660-068). The NOAEL for 
reproductive toxicity in rat was demonstrated to be 1,000 mg/kg/day (1660-069). The NOAEL 


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for developmental toxicity in rat and rabbit during the embryofetal studies was deemed to be 300 
mg/kg/day (Studies 1660-067 and 1660-068). Rats exposed to 1,000 mg/kg/day exhibited 
decreased maternal body weights, decreased food consumption, and decreased fetal body 
weights. There was no teratogenic potential in rat at doses up to 1,000 mg/kg/day. Rabbits 
exposed to 1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, decreased number of viable fetuses, decreased litter size, increased 
postimplantation loss, increased resorptions (early and late), and increased fetal skeletal 
malformations. The margin of exposure between healthy humans exposed to 500 mg BID EPI- 
589 (relevant clinical dose) for 14 days (Study EPI589-14-01) and rabbits exposed to 1,000 and 
300 mg/kg/day EPI-589 is approximately 179- to 236-fold and 47- to 50-fold, respectively. 
Based on these data, EPI-589 is not anticipated to increase the risk of adverse developmental or 
reproductive outcomes in humans when used in accordance with dosing information. 
 
EPI-589 was negative for mutagenic response in the in vitro Ames bacterial reverse mutation 
assay (Study AD58AS.502ICH.BTL); equivocal for the induction of structural and negative for 
the induction of numerical chromosomal aberrations in the in vitro chromosome aberration assay 
in Chinese hamster ovary (CHO) cells (Study AD58AS.331ICH.BTL); and negative in the in 
vivo micronucleus assay in rat (Study AD58AS.125012ICH.BTL). These data indicate a low 
clinical mutagenicity risk. 
 
Primary pharmacodynamics studies demonstrated that EPI-589 is a potent rescue agent in 
cellular models of diseases of energy metabolism and oxidative stress. In vitro cellular models 
utilizing primary human fibroblasts from patients with ALS, Parkinson’s disease and other 
diseases characterized by high levels of oxidative stress, or striatal cells derived from mouse 
models of Huntingdon’s disease were used to assess the potential of EPI-589 to mitigate the 
harmful effects of oxidative stress (Studies EPI-BA-000216, EPI-BA-000363, and EPI-BA- 
000362). Pretreatment of patient cells with EPI-589 potently protected against oxidative stress- 
mediated cell death in a concentration dependent manner. Furthermore, EPI-589 normalized 3- 
nitrosotyrosine (3NT) levels, a biomarker of oxidative stress, and increased glutathione levels in 
mouse striatal cells under oxidative stress conditions. 
 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, EPI-589 did not 
significantly affect off-target molecular targets (Study EPI-BA-159). In safety pharmacology 
studies, EPI-589 did not significantly affect ion channel current in the hERG assay (Study 
130719.FEK); did not affect ECG parameters during the 28-day and 3-month repeat-dose 
toxicology studies in monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for 
animals administered 1,000 mg/kg/day and up to Day 91 data collected for animals administered 
up to 300 mg/kg/day) (Studies 1660-038 and 1660-064); and did not change respiratory function 
or adversely impact neurobehavioral function in rat at doses up to 1,000 mg/kg (Studies 1660- 
051, 1660-050, and 1660-063). 
 
In single dose exposure PK studies, EPI-589 was absorbed rapidly in rat, dog, and monkey, with 
mean Tmax values ranging from .08 to 1 hour and mean T1/2 values ranging from 3.7 to 5.0 hours 
(Studies EPI-BA-53, EPI-BA-59, EPI-BA-72, and EPI-BA-302). EPI-589 does not significantly 
induce cytochrome P450 (CYP) enzymes and appears to be metabolized by reductases in the 


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liver cytosol and microsomal subcellular fractions and to a lesser extent by the family of CYP 
enzymes (Studies MC12M-0037 and MC14M-0018). 
 
EPI-589 exhibited weak direct inhibition of CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (both 
midazolam and testosterone as probe substrates) with estimated IC50 (µM) values and R values 
based on free plasma concentrations (shown in parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 34 
(1.21), and 53 (1.13), respectively (Study MC14M-0020)Based on these data, EPI-589 is not 
anticipated to increase the risk of adverse developmental or reproductive outcomes in humans 
when used in accordance with dosing information. 
 
D2. Clinical Studies 
 
Phase I Study EPI589-13-022 evaluated the pharmacokinetics, safety and tolerability of single 
ascending oral doses (SADs) of EPI-589 in healthy subjects and a preliminary evaluation of 
safety and tolerability data was performed. Sixteen AEs were reported in the 36 subjects who 
received administration of EPI-589. Ten subjects (27.8%) who received EPI-589 (and 2 subjects, 
20% on placebo) reported AEs that were assessed as related. All were mild and resolved during 
the study, with the exception of a common cold (1 subject) and cold sore (1 subject). None of the 
vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant change 
compared to baseline. From all preliminary data available from this SAD study it may be 
concluded that there is no objection to proceed with treatment with 50 mg, 100 mg, 250 mg or 
500 mg of EPI-589. 
 
Phase I Study EPI589-14-01 evaluated the pharmacokinetics, safety and tolerability of multiple 
ascending oral doses (MAD) of EPI-589 in healthy subjects, and an evaluation of safety and 
tolerability data was performed. No severe or serious adverse events were observed. Twenty-six 
subjects (65.0%) on EPI-589, and 8 subjects (80%) on placebo reported AEs. Twenty-four of 34 
AEs were considered by the Investigator to be related to EPI-589. Nineteen subjects (47.5%) on 
EPI-589, and 6 subjects (60%) on placebo reported AEs that were assessed as related. All 
adverse events were mild, except for 1 AE which was moderate (unrelated brain contusion). All 
AEs were resolved during the study, with the exception of one, which was a common cold. None 
of the vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant 
change compared to baseline. From all preliminary data available from the MAD study it may be 
concluded that there is no objection to proceed with treatment with 250-mg, or 500-mg doses of 
EPI-589. 
 
E. 
Human Pharmacokinetics 
 
EPI-589 was fast absorbed following oral administration in SAD Study EPI589-13-022. The 
median Cmax was attained approximately within 1 hour under fasted conditions after dosing. The 
median Tmax values were attained in 0.50 to 1.00 hours over the dose range of 50 to 1000 mg 
under fasted conditions and 3.01 hours at the 500 mg dose level under fed conditions. Mean half- 
life ranged from 5.55 to 10.7 hours over the dose range of 50 to 1000 mg under fasted conditions 
and 4.91 hours at the 500 mg dose level under fed conditions. Half-life was independent of the 
dose levels over the dose range of 50 to 1000 mg under fasted conditions. The rate of EPI-589 
absorption, as measured by Cmax, was decreased by 24.07% under fed conditions at the 500 mg 


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dose level. The extent of absorption as measured by AUCs (AUC0-t or AUC0-inf) was not affected 
under fed conditions in the 500 mg dose groups. 
 
In MAD study EPI589-14-01, EPI-589 was rapidly absorbed following oral administration and 
the median Cmax was attained within 1 hour (0.50 to 0.76 hours) under fasted conditions after 
single or multiple dosing among these five cohorts. The mean half-life of EPI-589 ranged from 
5.64 to 8.47 hours among these five cohorts. In general, the mean values of the time to peak 
concentration (Tmax), half-life (t½), apparent terminal constant (λz), accumulation ratio (AR), 
percent fluctuation (%F) and accumulation index (AI) of EPI-589 were similar among the five 
cohorts of various ages and smoking status. No significant effects of age or smoking on EPI-589 
pharmacokinetics were observed in this study. Dose proportionality existed in the exposures 
(AUC0-tau, Cmax, Cmin and Cavg) over the dose range of 250 to 500-mg BID EPI-589 under fasted 
conditions. 
 
F. 
Clinical Study 
 
EPI589-15-002: A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial Subtype 
and Idiopathic Parkinson’s Disease Subjects. 
 
G. 
Selection of Drugs and Dosages 
 
The study drug in this trial is EPI-589: common chemical name (R)-troloxamide quinone. 
 
Each tablet contains 250 mg of EPI-589. The study dose is 500-mg BID, to be maintained in the 
absence of treatment-emergent toxicity. EPI-589 tablets must be taken with meals. 
 
H. 
Compliance Statement 
 
This study will be conducted in full accordance with all applicable research policies and 
procedures, the EU Clinical Trials Directive, all applicable EU and US federal and local laws 
and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312 and 314, and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonization (ICH). Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
will report AEs in accordance with local institutional policies and procedures and all EU and US 
federal requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the study. 
 
I. 
Relevant Literature and Data 
 
Literature references have been provided in Section XV. Additional information can be found in 
the Investigator’s Brochure. 


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IV. STUDY OBJECTIVES 
A. 
Primary Objective 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
B. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with PD on: 
1. Glutathione cycle biomarkers as measured in blood, cerebral spinal fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society-sponsored revision 
of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale (NMSS), PDQ-39 and 
EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment (MoCA) 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the Montgomery & 
Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 
 
 
 
 
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V. 
INVESTIGATIONAL PLAN 
A. 
General Schema of Study Design 
 
Following study enrollment, baseline assessments will be performed. Subjects will participate in 
a 30-day run-in phase to establish biomarker and clinical baseline measurements. EPI-589 will 
then be administered for up to 3 months (85 days ± 3 days) unless discontinued for safety or 
tolerability issues. 
 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. Given that the investigational drug 
targets an enzyme key to glutathione synthesis and that glutathione depletion has been found to 
be associated with PD, we are seeking to determine the safety and potential biochemical benefit 
of EPI-589 in PD subjects as assessed by glutathione cycle biomarkers. If we determine that 
there are a subset of idiopathic PD patients—whether due to disease stage or baseline biomarker 
profile—who are more likely to be EPI-589 responsive, we will seek to enroll additional 
numbers of these subjects in the adaptive phase so that we can increase the number of likely 
biomarker responsive subjects. EPI-589 will be administered for up to 3 months (85 days ± 3 
days) unless discontinued for safety or tolerability issues. 
 
A1. 
Screening Phase 
 
Suitable candidates for the trial will receive a short overview of the study by the Investigator’s 
staff and, if interested, will undergo Screening. The Investigator will inform each prospective 
subject of the nature and details of the study, explain the potential risks and must obtain written 
informed consent from the subject or their legally authorized representative prior to performing 
any study related procedures. 
 
A2. 
30-Day Run-in Phase 
 
Once eligibility is confirmed, the subject will be enrolled in the study and the run-in scans, CNS, 
blood-based biomarker, urine-based biomarker and clinical measurements will be collected. 
 
A3. 
Baseline 
 
Baseline assessments, scans, blood-based biomarker, urine biomarker, and clinical measurements 
will be collected. 
 
A4. 
Treatment Phase 
 
EPI-589 dosing will start on Day 1. Subjects will self-administer EPI-589 at a dose of 500-mg 
BID. 
 
Blood-based biomarker, urine biomarker, and clinical measurements will be collected at Day 29 
(± 3 days) and Day 85 (± 3 days). 


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A5. 
End of Treatment 
 
End of treatment data will be collected at the last study visit Day 85 (± 3 days). 
 
AEs reported as ongoing at Day 85 (± 3 days) and/or any concomitant medications associated 
with such events 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. 
 
A6. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose: AE/SAE and 
concomitant medication assessments conducted by telephone. Additional assessments to be 
determined at Investigator discretion. 
 
 
B. 
Randomization and Blinding 
 
This is an open-label study. 
 
C. 
Study Duration, Enrollment and Number of Sites 
C1. Duration of Subject Treatment 
 
Subjects will participate in a 30-day run-in phase to establish biomarker and clinical baseline 
measurements. EPI-589 will then be administered for 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. A post-treatment follow-up will be conducted at 
least 10 days and up to 30 days after last dose. 
 
C2. Total Number of Study Sites / Total Number of Subjects Projected 
 
This study will be conducted at five study sites: 
• 
Germany 
• 
, UK 
• 
USA 
• 
USA 
• 
USA 
 
Approximately 40 subjects with PD are projected: 
• 20 with genetically-defined subtypes 
• 20 PD idiopathic PD 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects to achieve a higher number of subjects in 
whom we could understand the biochemical effects of the investigative drug and its potential 
clinical impact as assessed by the same study protocol and outcome metrics. 


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D. 
Study Population 
D1. Inclusion Criteria (all subjects) 
 
1. Hoehn and Yahr stage ≤ 3.0 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners must agree to use medically accepted 
methods of contraception (e.g., hormonal methods, including oral, subcutaneous, and 
intrauterine; barrier methods, including 
condom, 
condom, or diaphragm with 
spermicidal gel) during the course of the study and for 3 months after the last dose of 
study treatment. 
4. Willingness and ability to comply with study procedures 
5. If on medications and supplements for PD, then regimen must be stable for 60 days prior 
to enrollment 
6. Abstention from use of other investigative or non-approved drugs for the duration of the 
trial 
For Idiopathic Subjects 
7. A diagnosis of idiopathic PD confirmed by the presence of bradykinesia plus one or both 
of the following symptoms: rigidity or resting tremor; and with an abnormal DaTscan 
consistent with a dopaminergic deficit 
8. Age 40 to 75 years 
9. Within 5 years of diagnosis of Parkinson’s disease 
 
For Genetic Subtype Subjects 
10. A confirmed diagnosis of PD plus a genetic diagnosis consistent with PD, specifically 
PINK1, parkin, LRKK2 or other mitochondrial genetic subtype 
11. Age 21 to 75 years 
 
D2. Exclusion Criteria 
 
1. Allergy to EPI-589 or other components of the EPI-589 tablet formulation 
2. Vitamins E and C beyond the recommended daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that will confound the 
assessment of effect of study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 


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14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial of a device, drug or 
other therapy for PD 
 
 
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VI. STUDY PROCEDURES 
A. 
Screening Visit 
 
Screening evaluations will be performed within two months of first dose. The Investigator will 
inform each prospective subject of the nature of the study, explain the potential risks, and must 
obtain written informed consent from the subject prior to performing any study-related 
procedures and prior to the administration of study drug. Screening evaluations consist of the 
following: 
1. Assessment of eligibility 
2. Medical history, chart review 
3. Receipt and review of previous testing including genetic tests 
4. Physical examination including vital signs 
5. Height and weight 
6. 12-lead ECG 
7. Laboratory assessments for hematology, coagulation, and serum chemistry (See Sections 
VII.D3.a and VII.D3.b) 
8. Urine pregnancy test (women of childbearing potential must have a negative urine 
pregnancy test; see Section VII.D3.c) 
9. MDS-UPDRS 
10. MoCA 
11. DaTscan (for idiopathic subjects only) 
12. Revised Hamilton Rating Scale for Depression 
13. AE/SAE assessments 
14. Concomitant medications assessment (last 60 days prior to enrollment) 
 
A1. 
Run-in Assessments 
 
If the subject is eligible for the study following all screening procedures and is still willing to 
participate in the study, the subject must return to the clinic within one month for Run-in 
assessments. These will be performed 30 days (± 3 days) prior to baseline after eligibility is 
confirmed and subject is enrolled in the study. Run-in evaluations consist of the following: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers (lumbar puncture) 
3. Urine biomarkers 
4. Timed motor tests (for subjects on dopamine therapy) 
5. AE/SAE assessments 
6. Concomitant medications review 
 
B. 
Treatment Phase 
 
After the Run-in phase, the subject must return to the clinic within 30 days (± 3 days) for 
baseline assessments. In-clinic study visits are scheduled at Month 1 and Month 3. The Month 2 
study assessments can be conducted via telephone. End of treatment assessments will be 


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conducted at the Month 3 study visit. Pharmacokinetic sampling takes place at Month 1 and 
Month 3. 
 
B1. 
Baseline Assessments 
 
The following will be assessed or performed at this visit. 
1. Physical examination including vital signs 
2. Height and weight* 
3. 12-Lead ECG* 
4. Blood-based GSH cycle biomarkers 
5. Urine-based biomarkers 
6. Laboratory assessments for hematology, coagulation and serum chemistry* 
7. Urine pregnancy test ( 
of child bearing potential) 
8. C-SSRS (Columbia Suicide Severity Rating Scale) 
9. MDS-UPDRS 
10. NMSS, PDQ-39, EQ-5D 
11. BDI, MADRS 
12. Timed motor tests (for subjects on dopamine therapy) 
13. AE/SAE assessments 
14. Concomitant medications review 
* Screening results for these assessments may be used if obtained within 1 month of Baseline 
and if they are completed under fasted conditions. 
 
B2. 
Study Visit Assessments 
 
• Month 1 Clinic Visit (Day 29 ± 3 days): 
 
The following will be assessed or performed at the Month 1 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. MDS-UPDRS 
10. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
11. AE/SAE assessments 
12. Concomitant medications review 


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• Month 2 Visit (Day 57 ± 3 days) 
 
Month 2 assessments can be conducted by telephone and must include review of: 
1. AE/SAE assessments 
2. Concomitant medication 
 
• Month 3 Clinic Visit (Day 85 ± 3 days) 
 
The following will be assessed or performed at the Month 3 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. CNS biomarkers 
10. MDS-UPDRS 
11. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
12. AE/SAE assessments 
13. Concomitant medications review 
14. MoCA 
15. NMSS, PDQ-39, EQ-5D 
16. BDI, MADRS 
17. Timed motor tests (for subjects on dopamine therapy) 
 
B3. 
Pharmacokinetics 
 
Plasma concentration samples will be collected from the first 10 subjects to complete 1 month of 
therapy at each site, at the following time points: 
• Month 1 (Day 29 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
• Month 3 (Day 85 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
 
B4. 
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. 


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C. 
End of Treatment Visit 
 
End of treatment visit takes place at Month 3 (Day 85 ± 3 days) and includes the assessments 
listed in Section VIB2 Study Visit Assessments. 
 
Subjects who have an ongoing AE at the time of study completion will be followed for up to 30 
days, until the event resolves, or until the Sponsor and the Investigator agree that further follow- 
up is not medically necessary. 
 
D. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose, with 
AE/SAE and concomitant medication assessments conducted by telephone. Additional 
assessments to be determined at Investigator discretion. 
 
E. 
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 case report form (CRF) using the supplemental visit CRF pages. 
 
F. 
Concomitant Medication 
 
Any medication taken by a subject ≤ 60 days prior to enrollment and during the course of the 
study and the reason for use of the medication will be recorded on the 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 [OTC] medications) without consulting the Investigator. 
 
G. 
Prohibited Medications 
 
The following are prohibited while the subject is on study treatment: 
1. Vitamins E and C beyond the recommended daily allowance 
2. Participation 3 months prior to and for the duration of the study in a trial of a device, drug 
or other therapy for PD 
 
H. 
Subject Withdrawals 
 
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 


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2. If a subject experiences an adverse event that is deemed related to treatment with EPI-589 
and in the Investigator’s or the Sponsor’s medical judgment continuation of treatment 
would be detrimental to the subject. 
3. At the specific request of a regulatory agency for termination of treatment of an 
individual subject or all subjects under the protocol 
4. Subject participation in another clinical study using an investigational agent or 
investigational medical device 
5. Use of prohibited medications such as vitamins E and C beyond the recommended daily 
allowance. 
6. Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use medically accepted methods of contraception 
7. If a subject becomes pregnant. 
8. Significant noncompliance with the protocol in the opinion of the Investigator or the 
Sponsor 
In all cases, the reason for withdrawal must be recorded in the 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 
X.B. 
 
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. 
 
Every effort will be made to follow subjects who have an ongoing AE at the time of withdrawal 
until the event resolves, or until the Sponsor and the Investigator agree that further follow-up is 
not medically necessary. 
 
 
 
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VII. STUDY ENDPOINTS AND EVALUATIONS 
A. 
Primary Endpoint 
 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of drug-related serious 
adverse events in subjects with PD. 
 
B. 
Secondary Endpoints (Efficacy) 
 
1. Blood-based biomarkers 
2. CNS-based biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Secondary Endpoints (Safety) 
 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Routine serum chemistries with liver function tests 
4. C-SSRS 
5. Routine hematology tests with coagulation tests 
6. Electrocardiogram 
 
D. 
Screening and Baseline Evaluation 
D1. Physical Examination 
 
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. 
 
Vital sign measurements (pulse rate, blood pressure and respiration rate) will be obtained in the 
sitting position (after the subject has been sitting for five minutes). 
 
Medical history and demographics including age, gender, race, height and weight will be 
collected at Screening. 


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D2. Height and Weight 
 
Weight (kg) will be measured in ordinary indoor clothing (i.e., street clothes, scrubs, etc.) with 
shoes off. Height will be recorded in centimeters (cm). 
 
If clinically significant findings, as determined by the Investigator, are recorded for a particular 
symptom, sign or abnormal measurement, that measurement will be repeated at medically 
appropriate intervals until the value returns to an acceptable range, a specific diagnosis is 
established, or the condition is otherwise explained. 
 
D3. Laboratory Evaluations 
 
Subjects will have less than 100 mL of blood drawn over the course of the study. 
The following variables will be collected at various times (as detailed in Section I). 
a. 
Hematology 
 
a. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
volume (MCV) 
b. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) 
c. Platelets: platelet count 
d. Coagulation: prothrombin time (PT) with INR, and partial thromboplastin time (PTT) 
 
b. 
Serum chemistry 
 
a. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total and 
direct), gamma-glutamyl transferase (GGT), and lactic dehydrogenase (LDH) 
b. Renal: blood urea nitrogen (BUN), and creatinine 
c. Electrolytes: sodium, potassium, chloride and carbon dioxide (CO2 ) 
d. General: creatine phosphokinase (CPK), total protein, albumin, calcium, magnesium, 
glucose, phosphate 
e. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL), cholesterol, and triglycerides 
 
c. 
Urine pregnancy test 
1. Human chorionic gonadotropin (HCG) beta subunit will be measured on all female 
subjects of childbearing potential. 
 
Laboratory tests that result in significantly abnormal values should be repeated for verification. 
Additional tests and other evaluations required to establish the significance or etiology of an 


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abnormal result, or to monitor the course of an AE, should be obtained when clinically indicated. 
In particular, if a clinically significant abnormal result is observed that is not resolved by the 
final study visit, repeat tests should be performed to document resolution or stability of the 
abnormality. 
 
Diagnoses associated with any NIH Common Terminology Criteria for Adverse Events (CTC 
v4.03) Grade 3 or 4 laboratory abnormalities will be recorded as adverse events (AEs) on the 
CRF. Repeated and verified ≥ Grade 3 laboratory tests will be reported as an AE to the IRB per 
institutional requirements. The recorded event should indicate the underlying abnormality or 
diagnosis (e.g., renal insufficiency) if known, as opposed to the observed deviation in laboratory 
results (e.g., elevated creatinine). Any additional relevant laboratory results obtained by the 
Investigator during the study will be supplied to the Sponsor. 
 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a semi-structured tool for assessing suicidal ideation (Questions 1-5) and 
behavior (Questions 6-10) through a series of questions. 
 
E. 
Sample Collection Procedures, Bioanalytical Methods and Sample Shipment 
 
Subject samples will be identified by unique sample codes. 
 
Blood, urine, and cerebral spinal fluid samples will be collected for determination of levels of 
GSH cycle markers. Additional information about the collection, handling, storage, and 
shipment of the GSH cycle marker samples will be provided separately prior to start of the study. 
 
F. 
Efficacy Evaluations 
F1. 
Glutathione Cycle Biomarkers 
 
Blood, urine, and CNS levels of oxidized and reduced GSH as well as GSH metabolites will be 
used to evaluate EPI-589 target engagement and ability to correct a key biochemical aspect of 
disease pathology. 
 
F2. 
Parkinson’s Disease Rating (MDS-UPDRS) 
 
The MDS-UPDRS is a tool for monitoring the impact of PD, the degree of disability caused, and 
complications from treatment. Part I evaluates nonmotor experiences of daily living; Part II 
evaluates motor experiences of daily living; Part III is a motor examination and includes the 
Hoehn and Yahr scale; Part IV examines motor complications (e.g., motor fluctuations and 
dyskinesias). 
 
Several questions from Part I and all questions from Part II are designed to be amenable to a 
patient/caregiver questionnaire format; the remaining interview (Part I and Part III) and 
examination (Part IV) are designed with the expectation they can be completed within 30 
minutes. Each item is measured on a five-point scale. 


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F3. 
Non-motor Symptoms (NMSS) 
 
Non-motor symptoms are evaluated using the NMSS which is divided into 30 questions in 9 
different domains including such symptoms as dribbling saliva, constipation, depression, sleep 
disorders, apathy, hallucinations and dementia. Symptoms are quantified based on their severity 
(using a scale of 0 to 3) and frequency (using a scale of 0 to 4). The final cumulative scores are 
derived from adding up the product of the frequency score times severity score for each of the 30 
questions. 
 
F4. 
Parkinson’s Disease Questionnaire (PDQ-39) 
 
PDQ-39 is a self-administered questionnaire for patients with PD that has 39 questions relating 
to eight key areas of health and daily activities, including both motor and non-motor symptoms. 
It is scored on a scale of 0 to 100, with lower scores indicating better health, and high scores 
more severe symptoms. 
 
F5. 
EQ-5D 
 
EQ-5D is a questionnaire designed to provide measures of health-related quality of life states, 
consisting in five domains (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). 
 
F6. 
Montreal Cognitive Assessment (MoCA) 
 
MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive 
domains: attention and concentration, executive functions, memory, language, visuo- 
constructional skills, conceptual thinking, calculations, and orientation. Severity ranges are 
approximately: 26 to 30 normal; 18 to 26 mild cognitive impairment; 10-17 moderate cognitive 
impairment; < 10 severe cognitive impairment. 
 
F7. 
Beck Depression Inventory (BDI) 
 
The BDI is a self-reporting inventory that measures characteristic attitudes and symptoms of 
depression, including physical symptoms. Twenty-one questions have four responses each (rated 
0 to 3) with a total cumulative score scale ranging from 1-10 considered normal) > 40 (extreme 
depression). 
 
F8. 
Montgomery and Asberg Depression rating scale (MADRS) 
 
The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. 
Ten core symptoms and cognitive features are rated on a severity scale of 0 to 6. Higher scores 
indicate increasing depressive symptoms. 


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F9. 
Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
 
Timed motor tests are simple, objective, quantitative measures for the assessment of Parkinson’s 
disease. They include, in an on-medication and an off-medication state, timed recorded physical 
movements. 
 
 
 
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VIII. STATISTICAL CONSIDERATIONS 
A. 
Statistical Analysis 
 
In this subject-controlled, open label study the incidence of drug related SAEs in addition to 
changes from baseline to Month 3 for disease-relevant peripheral and CNS biomarkers as well as 
clinical measures will be calculated for each subject. 
 
A1. 
Analysis Populations 
 
Demographic characteristics and baseline efficacy data will be presented and summarized by 
treatment group for all subjects in the efficacy intent to treat (EITT) population. Demographic 
information will also be summarized by treatment group for the Safety population. No formal 
statistical comparisons will be made for either the EITT or Safety populations. 
 
B. 
Efficacy Analysis 
B1. 
Efficacy Variables 
 
The efficacy variables in this study are: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Safety Analysis 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
Assessment of safety will include calculating the overall number of subjects (by absolute number 
and percentage) with a particular AE. Safety will also be evaluated through examining clinical 
laboratory data (including chemistry and hematology and coagulation information) and physical 
examination findings, including vital signs obtained throughout the course of the study. A 
medical monitor will provide study oversight. 


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D. 
Sample Size 
 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 idiopathic PD 
subjects). Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker-responsive idiopathic PD subjects to achieve a higher number 
of subjects in whom we could understand the biochemical effects of the investigative drug and 
its potential clinical impact as assessed by the same study protocol and outcome metrics. 
 
 
 
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IX. STUDY MEDICATION 
A. 
Description 
 
EPI-589 is presented as an immediate release film-coated tablet. Each tablet contains 250 mg of 
EPI-589 and the following compendial excipients: lactose, microcrystalline cellulose, 
polyvinylpyrrolidone, crospovidone and magnesium stearate. Each tablet is film-coated with 
Opadry® II yellow. The tablets are yellow-colored and oval-shaped with a total target weight of 
824 mg. The tablets are packaged at 28 tablets per bottle in high-density polyethylene (HDPE) 
pharmaceutical wide mouth containers, induction sealed, and closed with a child-resistant 
closure. Each container is labeled with appropriate product information meeting current 
regulatory requirements. 
 
B. 
Packaging 
B1. 
Labeling 
 
Each container is labeled with appropriate product information meeting current regulatory 
requirements, in compliance with 21 CFR 312.6 and Eudralex Vol. 4 EU Guidelines to Good 
Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 13 
 
B2. 
Dosage Form 
 
The EPI-589 drug product will be provided in a 250-mg tablet formulation. 
 
B3. 
Dispensing 
 
Tablets are packaged in white round HPDE wide mouth containers. Each container holds 28 
tablets without desiccant. Each container is sealed with an induction seal held in place with a 
child-resistant closure. The packaged tablets are stored at controlled room temperature 20° to 
25°C (68° to 77°F). (See United States Pharmacopeia [USP]). 
 
C. 
Treatment Compliance and Adherence 
 
Study medication will be counted to assess compliance during each scheduled clinic visit. 
Subjects who take ≥ 80 percent of the prescribed doses and no more than 100 percent will be 
considered compliant. Subjects who fall outside the boundaries of these thresholds will be 
counseled and re-instructed on proper dosing procedures. Medication compliance will be 
recorded on the CRF for each visit after verification with subject-completed diary cards and 
returned used drug supply. 
 
D. 
Drug Accountability 
 
Dosing information will be captured on a subject Dosing Diary Form. This form is part of the 
source documentation and will be utilized as a source for the completion of CRFs associated 
with dosing and for reconciliation of study drug administered and returned to the study site for 


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accounting and destruction. Adequate records of study drug receipt and disposition should be 
maintained by pharmacy records of receipts, investigational drug orders, dispensing records, and 
disposition forms. The Study Monitor will also assess drug accountability and will 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 either be returned to the Sponsor or designee 
or destroyed per study site guidelines for destruction of investigational product immediately after 
drug accountability is performed by the study monitor. 
 
 
 
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X. 
SAFETY MANAGEMENT 
A. 
Clinical Adverse Events 
 
Clinical AEs will be monitored throughout the study. All AEs, whether observed by the 
Investigator, reported by the subject, from clinically significant laboratory findings, or other 
means, will be recorded in the CRF. 
 
B. 
Adverse Event Reporting 
 
All SAEs will be reported to the IRB in accordance with the IRB policies and as detailed below. 
AEs that are not serious will be summarized in narrative or other format and submitted to the 
IRB at the time of continuing review. 
 
B1. 
Safety Guidance 
 
Based on the known clinical manifestations of Parkinson’s disease, we expect that many AEs 
could occur during the course of the trial that are well documented to occur as the results of the 
natural history of this disease. These include, but are not limited to worsening neuromuscular 
function, depression, decline in cognitive function, loss of vision and other ophthalmological 
symptoms, loss of coordination and loss of speech. 
 
As there are no data available regarding EPI-589 phototoxicity, investigators are to advise 
subjects to take measures to minimize exposure to ultraviolet (UV) light for the duration of the 
study and for one week after the last dose. 
 
Edison Pharmaceuticals 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, Edison Pharmaceuticals should be provided with a copy 
of any post-mortem findings, including histopathology. 
 
C. 
Definition of an Adverse Event 
C1. Adverse Event 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
The AE may be: 
1. A new illness 


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2. Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 
3. An effect of the study medication, including comparator 
4. A combination of 2 or more of these factors 
No causal relationship with the study medication or with the clinical study itself is implied by the 
use of the term “adverse event” or “AE”. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs. 
 
Adverse events fall into the categories “non-serious” and “serious”. 
 
C2. Definition of a Serious Adverse Event (SAE) 
 
An SAE is one that at any dose results in any of the following: 
1. Death; 
2. A life-threatening adverse drug experience; 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability/incapacity; or 
5. A congenital anomaly/birth defect. 
ICH guidance also recommends that important medical events that may or may not be 
immediately life-threatening or result in death or hospitalization should also be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the serious definition. 
 
The term ”life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE. It does not refer to an SAE which 
hypothetically might have caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether other AEs, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject, require intervention to prevent one of the other 
outcomes listed 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. 
 
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 
has received 
study drug, 
should discontinue dosing, complete all end-of-study procedures, and be 
followed to determine the outcome of the pregnancy; follow-up of the pregnancy, fetus, and 
child will continue for at least 8 weeks after delivery. While pregnancy itself is not considered an 


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AE or SAE, all pregnancies should be reported using the same process as for SAEs. Any 
pregnancy complications or an outcome other than a healthy, normal outcome will be recorded 
as an AE or SAE. 
 
Clarification on the difference in meaning between “severe” and “serious”: The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as “serious,” which is based on the outcome or 
action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
C3. Non-serious Adverse Event 
 
A non-serious AE is any AE not meeting the SAE criteria. 
 
C4. Definition of Relationship to Study Medication 
 
Association or relatedness to the study medication will be graded as either “probably”, 
“possibly”, or “unlikely”. Determination of relatedness includes: 
 
PROBABLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Abates upon discontinuation of the drug and reappears with re-introduction of the drug 
3. Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state 
POSSIBLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
UNLIKELY – The adverse event: 
1. Does not follow a reasonable temporal sequence from drug administration 
2. Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
C5. Definition of Severity 
 
All AEs will be graded if possible by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. The severity of AEs that cannot be graded by CTCAE v4.03 will be categorized 
as follows: 
 
Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy indicated. 


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Grade 2 – Moderate limitation in activity, some assistance may be needed; minimal noninvasive 
medical intervention/therapy indicated. 
 
Grade 3 – Severe limitation in activity, assistance usually required; medical intervention/therapy 
required; hospitalization or prolongation of hospitalization indicated; disabling. 
 
Grade 4 – Extreme limitation in activity, significant assistance required; urgent medical 
intervention/therapy required; life-threatening consequences. 
 
Grade 5 – Death 
 
C6. Definition of Unexpected Adverse Event 
 
Any AE, the specificity or severity of which is not consistent with those listed in the current 
investigator’s brochure is considered “unexpected.” 
 
C7. Notification of SAEs 
 
The Investigator is responsible for promptly notifying the IRB/IEC of all study on-site SAEs and 
other unanticipated problems related to research. 
 
External SAEs that are unexpected and related to the study intervention should be reported as 
they are received using the MedWatch or CIOMs form (as appropriate). 
 
SAEs (whether unexpected or expected AEs) must be documented on the designated SAE form. 
The SAE must be reported to the medical expert and appropriate Edison or Edison-assigned 
pharmacovigilance staff within 24 hours, according to regulatory, Sponsor, or ICH-E6 Good 
Clinical Practice, followed by the SAE form within two calendar days. The designated SAE form 
and the instructions are provided in the Investigator’s site file. 
 
The SAE contact information will be provided separately from the protocol. 
 
The Investigator and/or Medical Expert must also inform the Study Monitor and the Sponsor in 
all cases. Any SAEs must also be reported to the IRB/IEC. The Sponsor or designee will ensure 
that all legal reporting requirements are met. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and the 
study medication. 
 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up SAE forms. 
 
The instructions to sites for the completion of SAE reports give detailed guidance on the 
reporting of SAEs and AEs initially reported as non-serious that become serious. When a non- 


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serious event becomes serious, details must be forwarded immediately to the Medical expert and 
Edison or Edison-assigned pharmacovigilance staff first for assessment and then submitted to the 
Sponsor on the designated SAE form within 24 hours. 
 
All relevant information about suspected unexpected serious adverse reactions (SUSARs) that 
are fatal or life-threatening are to be recorded and reported to the relevant competent authorities. 
 
In the US, all fatal or life-threatening suspected unexpected serious adverse events assessed as 
possibly or probably related to study drug by the Sponsor must be reported to the FDA as soon as 
possible (i.e., by telephone or facsimile transmission), but no later than 7 calendar days after first 
knowledge by the Sponsor that a report qualifies as a suspected unexpected fatal or life- 
threatening reaction. All unexpected serious adverse events, other than fatal or life-threatening, 
assessed as possibly or probably related to study drug by the Sponsor must be reported to the 
FDA within 15 calendar days from the day the Sponsor determines that the information qualifies 
as a SUSAR. 
 
In the UK, the Sponsor or trial investigator must act immediately or at least within 24 hours after 
becoming aware of a SUSAR by informing the MHRA’s Clinical Trial Unit by telephone. The 
MHRA must then be informed in writing within 3 days of the incident. All SUSARs originating 
in the UK or originating outside the UK involving the same medicinal product are to be reported. 
Fatal or life-threatening SUSARs are to be reported as soon as possible, but no later than after 7 
days. Any additional relevant information must be sent within 8 days of the report. Non-fatal or 
non-life-threatening SUSARs are to be reported as soon as possible but no later than 15 days 
after becoming aware of the reaction. 
 
C8. Follow-up Report 
 
If an SAE has not resolved at the time of the initial report, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. All SAEs should be followed until either resolved or stable. 
 
C9. Dose Modification Guidelines 
 
In the event that any patient develops elevated INR ≥ grade 2 in severity (> 1.5-2.5 x ULN) per CTCAE 
criteria version 4.0 thought to be related to treatment with EPI-743, administration of EPI-589 will be 
reduced by 1/2 to 50 percent of the starting dose. Should the INR toxicity not resolve to at least grade 1 in 
severity within two weeks of the initial dose reduction, administration of EPI-589 may either be further 
reduced or discontinued. 
 
Once a patient’s dose is reduced due to elevated INR thought to be related to study drug administration, 
their dose should not be re-escalated. 


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D. 
Medical Emergencies 
 
In medical emergencies, the Investigator should use medical judgment and remove the subject 
from the immediate hazard. The Medical Expert and the IRB/ IEC must be notified regarding the 
type of emergency and course of action taken and the procedures for SAE reporting must be 
followed. 
 
D1. Emergency Sponsor Contact 
 
In emergency situations, the Investigator should contact the Medical Monitor: 
 
 
D2. Emergency Treatment 
 
At present, the threshold and extent of clinical adverse effects are not known as only limited 
information is available in healthy volunteers. It is anticipated in the planned study that any 
effects will be minimal and laboratory measurements will detect study drug effects before they 
become clinically significant. 
 
 
 
 
 
 
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Version: Amendment 3.0 
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XI. STUDY ADMINISTRATION 
A. 
Treatment Assignment Methods 
 
This is an open-label study. 
 
B. 
Data Collection and Management 
 
Monitoring and auditing procedures, developed or endorsed by Edison will be followed in order 
to comply with GCP guidelines. Direct access to on-site study documentation including all 
source data, documentation and medical records should be ensured. 
 
The study will be monitored by Edison. Throughout the course of the study, the Study Monitor 
will make frequent contact with the Investigator. This will include telephone calls and on-site 
visits. During the on-site visits, the completed CRF will be compared to the source 
documentation for completeness, accuracy and adherence to the protocol. As part of the data 
audit, source documents must be made available to the Study Monitor for review. The Study 
Monitor will also perform drug accountability checks and will review the Investigator study file 
to assure completeness of documentation in all respects of clinical study conduct. 
 
Upon completion of the study, the Study Monitor will arrange for a final review of the study 
files, after which the files should be secured for the appropriate time period. The Investigator, or 
appointed delegate, will meet with the Study Monitor during the on-site visits and will cooperate 
in providing the documents for inspection and responding to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of Edison or 
the regulatory agencies. 
 
US and other competent regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. Medical records and other 
study documents may be copied during audit or inspection provided that subject names are 
obliterated on the copies to ensure confidentiality. 
 
C. 
Data Quality Assurance 
 
As a final step in the data management process, a 100% audit will be performed on the key 
safety and critical efficacy parameters. In addition, a random subject sample (10%) will be 
selected in order to perform a partial audit of remaining data. The purpose of this audit is to 
detect systematic and random errors. Any errors found from this audit will be corrected and, if 
the error rate is greater than 1 error per 1,000 fields (0.001%), a systematic review of the 
database will be undertaken and corrections will be made to achieve an error rate of less than 
0.001%. 
 
AEs will be coded using MedDRA, version (14.3). Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary, March 2014. 


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Version: Amendment 3.0 
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D. 
Retention of Study Records 
 
The following records must be retained by the Investigator for a minimum of 2 years after the 
Sponsor has notified the FDA or other competent authority that investigations have been 
discontinued, or after the FDA or other competent authority has approved the new drug 
application. In accordance with European regulatory requirements (Directive 2005/28/EC and 
Annex 17 and 2001/83/EC and Annex1), the Sponsor may request retention for a longer period 
of time. 
1. Signed informed consent documents for all subjects 
2. Subject identification code list, screening log (if applicable), and enrollment log 
3. Record of all communications between the Investigator and the IRB/IEC 
4. Composition of the IRB/IEC or other applicable statement 
5. Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
6. List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in the 
study and their signatures 
7. Copies of CRFs and of documentation of corrections for all subjects 
8. Drug accountability records 
9. Record of any body fluids or tissue samples retained 
10. All other source documents (subject records, hospital records, laboratory records, etc.) 
11. All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. 
 
Normally, these records will be held in the Investigator's archives. If the Investigator is unable to 
meet this obligation, 
or 
must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 
E. 
Confidentiality 
 
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the Sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be told that representatives of the Sponsor, IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection and privacy laws, including the Health Insurance 
Portability and Accountability Act (HIPAA) Guidelines, and the General Data Protection 
Regulation (GDPR). 


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The Investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
F. 
Documentation of Study Results 
 
A CRF will be provided for each enrolled subject. 
 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the CRF. Details of CRF completion and correction will be 
explained to the Investigator. If the Investigator authorizes other persons to make entries in the 
CRF, the names, positions, signatures, and initials of these persons must be supplied to the 
Sponsor. 
 
The Investigator, or designated representative, should complete the CRF pages as soon as 
possible after information is collected, preferably on the same day that a study subject is seen for 
an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
 
By signing the completed CRFs, the Investigator or Subinvestigator attests to the accuracy, 
completeness, legibility, and timeliness of the data collected on the CRF and casebooks. 
 
The Sponsor will retain the originals of all CRFs. The Investigator will retain a copy of all 
completed CRF pages. 
 
G. 
Regulatory and Ethical Considerations 
G1. Risk Assessment 
 
Based on the safety results of Study EPI-589-14-01 as summarized in the Clinical Study Report, 
it is not foreseen that subjects will endure any risks greater than minimal at the 500-mg BID dose 
selected for this study. 
 
G2. Potential Benefits of Trial Participation 
 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 
benefit in subjects with PD. Therefore, we cannot assure that subjects will benefit from treatment 
with EPI-589. Potential benefits may manifest in a variety of ways, such as in disease-related 
parameters, functioning, and quality of life. 
 
G3. Risk-Benefit Assessment 
 
There are no effective and/or approved disease modifying treatments available for PD, although 
a number of clinical interventions are being researched. Based on disease mechanism, EPI-589 
mechanism of action and pre-clinical studies, EPI-589 may hold benefit for patients with PD. 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 


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Protocol EPI589-15-002 
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Page 47 of 53 
 
 
 
benefit in subjects with PD. In order to further minimize risks, subjects will be closely monitored 
with a variety of safety measures. 
 
H. 
Informed Consent 
 
Before being enrolled in the clinical study, subjects must provide written consent to participate 
after the nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them. The Investigator will not undertake any measures specifically 
required only for the clinical study until valid consent has been obtained. 
 
An informed consent document that includes both information about the study and the consent 
form will be prepared and given to the subject. This document will contain all the elements 
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements 
required by local regulations and must be in a language understandable to the subject. Where 
required by local law, the person who informs the subject must be a physician. It should be 
signed and dated by all the parties concerned including the subject, legal guardian (where 
applicable), witness (where applicable) and the person obtaining the consent. 
 
A copy of the signed consent document must be given to the subject. The original signed consent 
document will be retained by the Investigator. 
 
The Investigator must inform the subject’s primary physician about the subject’s participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
 
 
 
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XII. PUBLICATION 
A. Use of Study Results 
 
All information concerning the product, as well as any matter concerning the operation of Edison 
(such as clinical indications for the drug, its formula, methods of manufacture, and other 
scientific data relating to it, that have been provided by Edison and are unpublished), are 
confidential and must remain the sole property of Edison. The Investigator will agree to use the 
information only for the purposes of carrying out this study and for no other purpose unless prior 
written permission from Edison is obtained. The Sponsor has full ownership of the CRFs 
completed as part of the study. 
 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by Edison. If necessary, the authorities will be notified 
of the Investigator's name, address, qualifications, and extent of involvement. 
 
This Study is part of a multicenter clinical research study. Accordingly, Sponsor will act as 
coordinator and referee with respect to publications of the data generated thereunder. Principal 
Investigator shall not publish or disclose any data, result or information with respect to any 
matters resulting from work performed under this Protocol while this Study is being conducted at 
other center/s. Only after the completion of this Study at all other centers, provision of the data to 
the FDA or EMA for review and comment, and publishing the combined data from all of the 
centers, may the Principal Investigator publish/present the individual results of the Study in 
accordance with this paragraph. 
 
Principal Investigator may publish provided, however, that no publication, abstract, 
announcement or disclosure (“Publication”) shall be made until the Principal Investigator 
submits to Sponsor any proposed Publication for Sponsor’s review. Sponsor shall have a period 
of sixty (60) days to review such Publication. If Sponsor determines during the review period 
that the Publication contains patentable subject matter, then the above sixty (60) days shall be 
extended to one hundred twenty (120) days in order to allow for the preparation of patent 
applications covering said patentable subject matter. Unless Sponsor approves in writing, no 
Publication may contain any Confidential Information (other than data and results generated 
under the Study). 
 
Without limiting the foregoing, Institution and Principal Investigator, and all other study 
investigators in other study institutions, shall give due regard to Sponsor’s legitimate interests, 
such as manuscript authorship, coordinating and maintaining the proprietary nature of 
submissions to health authorities, and coordinating with other ongoing studies in the same field, 
and agree to accept Sponsor’s reasonable comments and suggestions with respect to such 
Publications. 
 
If the Investigator is to be an author of a publication manuscript prepared by Edison, Edison will 
allow the Investigator or CRO 60 days for full review of the manuscript before publication. 


Edison Pharmaceuticals, Inc 
Protocol EPI589-15-002 
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Version: Amendment 3.0 
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10Oct2016 
Edison Pharmaceuticals Inc. 
Page 49 of 53 
 
 
 
XIII. LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AR 
accumulation ratio 
BDI 
Beck Depression Inventory 
BID 
twice daily 
BSO 
L-buthionine-(S,R)-sulfoximine 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatinine kinase 
CNS 
central nervous system 
CoQ10 
Coenzyme Q 10 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DaT 
dopamine transporters 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EITT 
efficacy intent-to-treat 
EPDA 
European Parkinson’s Disease Association 
EU 
European Union 
%F 
percent fluctuation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GCRC 
good clinical research practice 
GDPR 
General Data Protection Regulation 
GSH 
glutathione 
GSSG 
glutathione disulfide 
HDPE 
high density polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HMPAO 
hexamethylpropylene amine oxime 
ICF 
informed consent form 
ICH 
International Committee on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 


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kg 
kilogram 
Λz 
apparent terminal constant 
LFT 
liver function test 
MAD 
multiple ascending (oral) dose 
MADRS 
Montgomery and Asberg Depression rating scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale 
mg 
milligram 
mL 
milliliter 
MoCA 
Montreal Cognitive Assessment 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
MPV 
mean platelet volume 
mtDNA 
mitochondrial DNA 
N/A 
not applicable 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NF 
National Formulary 
nM 
nanomolar 
NMSS 
Non-motor Symptoms Scale 
NOAEL 
no observed adverse effect level 
NQ01 
NAD(P)H Quinone oxidoreductase 1 
OD 
once daily 
OTC 
over-the-counter 
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PO 
by mouth 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 
PVP 
polyvinylpyrrolidone 
QT 
interval between the start of the Q wave and the end of the T wave 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAD 
single ascending (oral) dose 
SAE 
serious adverse event 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
Tmax 
time to peak concentration 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
UV 
ultraviolet 


 
 
 
 
 
Edison Pharmaceuticals, lnc 
Protocol EPI589-15-002 
EPI-589 
Version: Amendment 3.0 
 
XIV. SIGNATURE OF SPONSOR 
 
A. Declaration of Sponsor 
 
This study protocol was subject to critical review and the information it contains is consistent 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP as described in 21 CFRparts 50, 54, 56, and 
312. 
 
The Investigator will be supplied with details of any significant or new findings on EPJ-589, 
including AEs. 
 
 
 
Date: [3 Oc( 2o:'  
ignature: 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Ave 
Mountain View, CA 94043 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
10Oct2016 
Edison Pharmaceuticals Inc. 
Page 51 of53 


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XV. REFERENCES 
 
Ashrafi G, Schlehe JS, LaVoie MJ, Schwartz TL. Mitophagy of damaged mitochondria occurs 
locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014; 1;206(5):655- 
70. 
 
Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces 
features of Parkinson's disease. Nat Neurosci. 2000; 3(12): 1301-1306. 
 
Dauer W and Przedborski S. Parkinson's disease: mechanisms and models, Neuron 2003; 39: 
889–909. 
 
de Lau LM and Breteler MM. Epidemology of Parkinson’s Disease. Lancet Neur.2006; 5: 525- 
35. 
 
EPDA-European Parkinson’s Disease Association. http://www.epda.eu.com/en/resources/life- 
with-parkinsons/part-1/prevalence-of-parkinsons-disease/ (consulted 04 December 2014). 
 
Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, et al. Biochemical and pathological 
characterization of Lrrk2. Ann Neurol. 2006: 59(2): 315-22. 
 
Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, 
environment and mitochondria. Parkinsonism Relat. Disord. 2003; 9 (Suppl 2): S59–S64. 
 
Holmay, MJ, Terpstra M, Coles LD, et al. N-acetylcysteine Boosts Brain and Blood Glutathione 
in Gaucher and Parkinson Diseases. Clin. Neuropharm. 2013; 36, 4: 103-106. 
 
Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, et al. Glutathione Depletion in PC12 Results in 
Selective Inhibition of Mitochondrial Complex I Activity. Implications for Parkinson’s disease. J 
Biol Chem. 2000; 25;275 (34): 26096-101. 
 
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product 
of meperidine-analog synthesis. Science. 1983; 219: 979–980. 
 
Lin MT and Beal FB. Mitochondrial dysfunction and oxidative stress in neurodegenerative 
diseases. Nature. 2006; 443: 787-795. 
 
Maarouf CL, Beach TG, Adler CH, Shill HA, Sabbagh MN, et al. Cerebrospinal fluid 
biomarkers of neuropathologically diagnosed Parkinson's disease subjects. Neurol Res. 2012; 
34:669–676. 
 
Mao P and Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and 
mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and 
therapeutics. Biochim. Biophys. Acta. 2011; 1812: 1359-1370. 


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Narendra, DP and Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and parkin in 
mitochondrial quality control. Antioxi. Redox Signal. 2011; 14: 1929-1938. 
 
The Parkinson’s Disease Foundation. http://www.pdf.org/en/parkinson_statistics (consulted 27 
April 2015). 
 
Pinto M, Pickrell AM, Moraes CT. Regional susceptibilities to mitochondrial dysfunctions in the 
CNS. Biol. Chem. 2012; 393: 275-281. 
 
Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, et al. Transition metals, ferritin, 
glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 1989; Feb;52(2): 515-20. 
 
Winklhofer KF and Haass C. Mytochondrial dysfunction in Parkinson’s disease. Biochimica et 
Biophysica Acta. 2010; 1802: 29-44. 
 
Zhu X, Babar A, Siedlak SL, Yang Q, Ito G, et al. LRRK2 in Parkinson's disease and dementia 
with Lewy bodies. Mol Neurodegener. 2006;1:17. 


Edison Pharmaceuticals, Inc. 
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Page 1 of 10 
 
 
 
 
 
Summary of Changes 
Amendment 3.0 
EPI589-15-002 
A Phase 2A Safety and Biomarker Study of EPI-589 
in Mitochondrial Subtype and Idiopathic Parkinson’s 
Disease Subjects 
 
Protocol Number 
EPI589-15-002 
Original Protocol Date 
27 April 2015 
Amendment 1.0 Date 
09 September 2015 
Amendment 2.0 Date 
04 January 2016 
Amendment 3.0 Date 
10 October 2016 
Study Sponsor 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Sponsor’s Representative 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
 
 
The information contained in this document is confidential and will not be disclosed to others without written authorization from Edison 
Pharmaceuticals, except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered or 
for discussions with local regulatory authorities, Ethics Committee/Investigational Review Boards, or people participating in the conduct of 
the study. 


Edison Pharmaceuticals, Inc. 
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Version: Amendment 3.0 
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Edison Pharmaceuticals Inc. 
Page 2 of 10 
 
 
 
 
KEY CHANGES TO THE PROTOCOL 
 
Amendment 3.0 provides the following changes and their rationales: 
 
Change 
Rationale 
• Added the new list of investigators and 
investigative sites 
• To complete the list of investigators and sites 
• Revision of inclusion and exclusion criteria 
regarding disease severity and prohibited meds 
• To allow for the study of drug safety, tolerability and 
biomarkers in a larger cohort of idiopathic Parkinson’s 
disease subjects 
• Added the term “for idiopathic subjects” to 
DaTscan , “fasting” for blood-based glutathione 
cycle biomarkers in schedule of assessments 
• For better clarity 
• Changed the MDS-UPDRS assessment from run- 
in to screening visit 
• Hoehn and Yahr is a screening assessment and is part of 
MDS-UPDRS assessment 
• Changes in laboratory evaluations, NIH common 
terminology criteria, etc 
• To clarify aspects of the protocol which have been 
previously documented in administrative letters 
• Dose modifications guidelines 
• To clearly define guidelines for dose modifications 
 
DESCRIPTION OF CHANGES TO THE PROTOCOL 
 
Changes to the protocol by section appear in the table below. Administrative and editorial 
clarifications, corrections or adjustments may not be individually identified. 
 
In this summary document, bold italic font indicates additions to existing text, and strikethrough 
font indicates deleted text. The actual amended protocol does not include bold or strikethrough 
font to indicate changes. 


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Protocol Section 
Modification 
Synopsis 
Investigators and Investigative Sites: 
• 
Germany 
• 
UK 
• 
USA 
• 
USA 
• 
USA 
Synopsis 
Planned number of subjects 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 drug 
naïve idiopathic PD subjects). (Adaptive design component allows enrollment of up 
to 20 additional subjects with idiopathic PD to try to achieve a total of 20 subjects 
that have a biomarker response to EPI-589.) 
Synopsis 
Inclusion Criteria (for all subjects) 
1.Hoehn and Yahr stage ≤ 2.5 3.0 
5. If on medications and supplements for PD drugs, then medication regimen must be 
stable for 60 days prior to enrollment 
Stable medication regimen of PD drugs for 30 days (except 60 days for rasagiline) prior 
to enrollment. 
For Idiopathic Subjects: 
7. For idiopathic subjects: a diagnosis of early idiopathic PD confirmed by the presence 
of bradykinesia plus one or both of the following symptoms: rigidity or resting tremor; 
and with an abnormal DaTscan consistent with a dopaminergic deficit 
8. For idiopathic subjects must not yet require symptomatic medications for PD and not 
expected to require such treatment before the end of the study 
9. For idiopathic subjects: age 40 to 75 years 
10. For idiopathic subjects: within 5 years of diagnosis of Parkinson’s disease 
For Genetic Subtype Subjects: 
11. For genetic subtype subjects: a confirmed diagnosis of PD plus a genetic diagnosis 
consistent with PD, specifically PINK1, parkin, LARK2 LRRK2 or other mitochondrial 
genetic subtype 
12. For genetic subtype subjects: stable medication regimen of PD drugs for 30 days 
(except 60 days for rasagiline) prior to enrollment  


Edison Pharmaceuticals, Inc. 
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Page4 oflO 
 
 
 
Synopsis 
Exclusion Criteria 
 
2. Use of afltio Eiea:Bts, Sfl@eifieally v Vitamins E and C beyond the recommended daily 
allowance 
 
ol'laiotiataie  £uej@ets 
 
le.01·i:EHOfl1HIHe suej@ets: us@ of 
M. ,,Q iebiei:t.01·s, amaetaaiB@ 01· ota@1·ElfHgs tii·@s6fi:e@Ei :fEH· 
€Of'@ S;'ffifltOIHS Of:PadaBSOB'S EHS@as@ fo1· i:EHOflatBi:e suej@ets 
I +0.  1·i:EHOfl1HIHe suej@ets: us@ Of Bo1·tfi:ti tbB@ 01·i}UJ,zo Eami:B@ eQ Elays tifi:01·to @m·oUm@Bt 
 
II. Schedule of 
Assessments and 
Dosing Schedule 
Tests 
-2 to -1 Months 
DayO 
Month 1 Month
2 
Month3
End of 
Treatme 
nt Visit 
Post- 
Treatment 
Follow-up 
Screening 
Run-in 
(upto 30 
days from 
screening) 
Baseline (27- 
33 days from
run-in) 
Day29 
(±3 
days) 
Day 
57d 
(±3 
days) 
Day85 
(±3 
days) 
Up to30 
Days after 
Last Dose• 
Infonued consent 
Dayl 
First 
Dose 
Inclusion/Exclusi 
on criteria 
Past Medical 
histo1y 
Previous genetic 
testing review 
Physical exam & 
Vital signs 
Height & weight 
• 
12-leadECG 
• 
Hematology 
(including 
coagulation 
panel) 
• 
f 
f 
Semm Chemistiy 
• 
f 
f 
Pregnancy testb 
C-SSRS 
Montreal 
Cognitive 
Assessment 
DaTscan (for 
idiopathic 
subjects) 
Revised Hamilton 
Rating Scale for 
Depression 
Subject enrolls in 
study 
X 
Fasting blood- 
based glutathione 
cycle biomarkers 
Lumbar puncnu·e 
(CNS 
biomarkers) 
Urine-based 
biomarkers 


Edison Pharmaceuticals, Inc. 
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Page5 oflO 
 
 
 
MDS-UPDRS 
+- 
Timed motor tests 
(for subjects on 
dopamine 
therapy) 
NMSS, PDQ-39, 
EQ-5D 
BDI,MADRS 
Dmgplasma 
concentration< 
< 
< 
AE/SAE 
assessment 
• 
• 
• 
• d,• 
d,• 
• 
Concomitant 
medications 
assessment 
d 
d 
• 
Post-Treatment 
Assessments• 
• 
a. 
Screening values can be used if done within one month of baseline and if completed under fasted conditions 
- Female subjects of childbearing potential must have a negative pregnancy test. 
C. 
Full plasma concentration profile w-ill be obtained at Time= 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours aft.er dosing 
from the fast 10 subjects to complete 1 month of therapy at each site.12 hour PK can be obtained at time 0. 
d. 
Month 2 assessments can be donebytelephone. Any new AEs and associated concomitant medications repo1ted 
at Month 3 must be followed for 30 days; this follow up may be conducted by telephone. 
e. 
AE/SAE and concomitant medication assessments conducted by telephone at least 10 days after last dose. 
Additional assessments determined at Investigator discretion. SAEs are tra.cked from the time ICF is signed 
and all other AEs are tracked from the time first dose is administered; 
r. 
The baseline and all subsequent laboratory assessments should be obtained under fasting conditions. 
IV. 
Investigational Plan 
A. General Schema of Study Design 
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effeets ef tfie i:B:resttgMt¥e 9fYg 8:fte tfs 13eteftfta:l ehBtea:ltfftj38ef a-s assesses ej' the smey 
9'..-¼f89H¼9 mea·i:es. e:PI ௭g9 • .ii:Uee aemi:Btsfe1·ee :Ee!' :-113 f9 J IB9Bfhs Eg௭ BajlS .I. J BajlSj 
:-mless etseeftfttt:-¼ee :EE)f' sa::fefy er telera:etldy tSSHes. 
I/we determine that there are a subset of idiopathic PD patients-whether due to 
disease stage or baseline biomarker profile-who are more likely to be EPI-589 
responsive, we will seek to enroll additional numbers of these subjects in the adaptive 
phase so that we can increase the number of likely biomarker responsive subjects. 
EPI-589 will be administered/or up to 3 months (85 days± 3 days) unless 
discontinued for safety or tolerability issues. 


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C. Study Duration, Enrollment and Number of Sites 
 
Duration of Subject Treatment 
Subjects will participate in a 30-day run-in phase to establish biomarker and clinical 
baseline measurements. EPI-589 will then be administered for 3 months (85 days ± 3 
days) unless discontinued for safety or tolerability issues. A post-treatment follow-up 
will be conducted at least 10 days and up to 30 days after last dose. 
 
Total Number of Study Sites/Total Number of Subjects Projected 
This study will be conducted at two five study sites: 
 
• 
Germany 
• 
• 
USA 
• 
USA 
• 
 
UK 
 
 
USA 
 
Approximately 40 subjects with PD are projected: 
 
20 with genetically-defined subtypes 
20 PD drug naïve idiopathic PD 
D. Study Population 
 
D1. Inclusion Criteria 
Inclusion Criteria (for all subjects) 
 
1.Hoehn and Yahr stage ≤ 2.5 3.0 
 
5. If on medications and supplements for PD drugs, then medication regimen must be 
stable for 60 days prior to enrollment 
 
Stable medication regimen of PD drugs for 30 days (except 60 days for rasagiline) prior 
to enrollment. 
 
For Idiopathic Subjects: 
 
7. For idiopathic subjects: A diagnosis of early idiopathic PD confirmed by the presence 
of bradykinesia plus one or both of the following symptoms: rigidity or resting tremor; 
and with an abnormal DaTscan consistent with a dopaminergic deficit 
8. For idiopathic subjects must not yet require symptomatic medications for PD and not 
expected to require such treatment before the end of the study 
9. For idiopathic subjects: Age 40 to 75 years 
10. For idiopathic subjects: within 5 years of diagnosis of Parkinson’s disease 


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For Genetic Subtype Subjects 
11. For genetic subtype subjects: a confirmed diagnosis of PD plus a genetic diagnosis 
consistent with PD, specifically PINK1, parkin, LARK2 LRRK2 or other mitochondrial 
genetic subtype 
12. For genetic subtype subjects: stable medication regimen of PD drugs for 30 days 
(except 60 days for rasagiline) prior to enrollment  
D2. Exclusion Criteria 
2. Use of antioxidants, specifically v Vitamins E and C beyond the recommended daily 
allowance 
For Idiopathic Subjects 
16. For idiopathic subjects: use of any MAO inhibitors, amantadine or other drugs 
prescribed for core symptoms of Parkinson’s disease for idiopathic subjects 
17. For idiopathic subjects: use of nortriptyline or fluvoxamine 60 days prior to 
enrollment 
VI. 
Study Procedures 
A. Screening Visit 
9. MDS—UPDRS 
13. AE/ SAE Assessments 
A1. Run-in Assessments 
4. MDS UPDRS 
5. AE/ SAE Assessments 
B1. Baseline Assessments 
13. AE/ SAE Assessments 
* Screening results for these assessments may be used if obtained within 1 month of 
Baseline and if they are completed under fasted conditions. 
G. Prohibited Medications 
The following are prohibited while the subject is on study treatment: 


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Edison Pharmaceuticals Inc. 
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1. Use of antioxidants, specifically v Vitamins E and C beyond the recommended daily 
allowance 
2. Participation 3 months prior to and for the duration of the study in a trial of a device, 
drug or other therapy for PD 
3. Use of MAO inhibitors, amantadine or other drugs prescribed for core symptoms of 
Parkinson’s disease for idiopathic subjects 
4. Use of nortriptyline or fluvoxamine 
 
H. Subject Withdrawals 
2. If a subject experiences an serious or severe adverse event that is deemed related to 
treatment with EPI-589 and in the Investigator’s or the Sponsor’s medical judgment 
continuation of treatment would be detrimental to the subject. 
5. Use of prohibited medications such as vitamins E and C beyond the recommended 
daily allowance. nortriptyline or fluvoxamine; and, for idiopathic subjects, MAO 
inhibitors, amantadine or other drugs prescribed for core symptoms of Parkinson’s 
disease 
VII. 
Study End Points and Evaluations 
D3. Laboratory Evaluations 
The following variables will be collected at various times (as detailed in Section I). 
1. 
Hematology 
1. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean 
corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration 
(MCHC), mean corpuscular volume (MCV), red cell distribution width (RDW) 
2. Leukocytes: white blood cell count (WBC) and differential (basophils, 
eosinophils, lymphocytes, monocytes, and neutrophils) reported as absolute 
values 
3. Platelets: platelet count, mean platelet volume (MPV) 
4. Coagulation: prothrombin time (PT) with INR, partial thromboplastin time 
(PTT), activated (aPTT) 
2. 
Serum chemistry 
1. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic pyruvic transaminase 
[SGPT]), AST (serum glutamic oxaloacetic transaminase [SGOT]), bilirubin 


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(total and direct), gamma glutamyl transferase (GGT), and lactate dehydrogenase 
(LDH) 
2. Renal: blood urea nitrogen (BUN), and creatinine 
3. Electrolytes: sodium, potassium, chloride, and carbon dioxide (CO2) as 
bicarbonate 
4. General: creatine phosphokinase (CPK), creatine kinase (CK), and troponin (at 
baseline only); total protein, albumin, calcium, magnesium, glucose, phosphate 
5. Lipids: cholesterol (total), high density lipoprotein (HDL) cholesterol, low 
density lipoprotein (LDL) cholesterol, cholesterol/HDL Ratio (calculated), non 
HDL cholesterol (calculated), and triglycerides 
D3. Laboratory Evaluations 
The following variables will be collected at various times (as detailed in Section I). 
1. Hematology 
a. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, , mean corpuscular 
volume (MCV) 
b. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) 
c. Platelets: platelet count 
d. Coagulation: prothrombin time (PT) with INR, and partial thromboplastin time (PTT) 
2.  Serum chemistry 
a. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total and 
direct), gamma-glutamyl transferase (GGT), and lactic dehydrogenase (LDH) 
b. Renal: blood urea nitrogen (BUN), and creatinine 
c. Electrolytes: sodium, potassium, chloride and carbon dioxide (CO2 ) 
d. General: creatine phosphokinase (CPK), total protein, albumin, calcium, magnesium, 
glucose, phosphate 
e. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL), cholesterol, and triglycerides 
Diagnoses associated with any NIH Common Terminology Criteria for Adverse Events 
(CTC v4.03) Grade 3 or 4 laboratory abnormalities will be recorded as adverse events 
(AEs) on the CRF. Repeated and verified ≥ Grade 3 laboratory tests will be reported as 
an AE SAE to the Sponsor and the IRB per institutional requirements. The recorded 
event should indicate the underlying abnormality or diagnosis (e.g., renal insufficiency) 
if known, as opposed to the observed deviation in laboratory results (e.g., elevated 
creatinine). Any additional relevant laboratory results obtained by the Investigator during 
the study will be supplied to the Sponsor 


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VIII. 
Statistical Considerations 
D. Sample Size 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 PD drug 
naïve idiopathic PD subjects). Under an adaptive design strategy, additional subjects (up 
to 20) may be added to increase the number of biomarker-responsive idiopathic PD 
subjects to achieve a higher number of subjects in whom we could understand the 
biochemical effects of the investigative drug and its potential clinical impact as assessed 
by the same study protocol and outcome metrics. 
IX 
B. Packaging 
Labeling 
Each container is labeled with appropriate product information meeting current regulatory 
requirements, in compliance with 21 CFR 312.6 and Eudralex Vol. 4 EU Guidelines to 
Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 
13 
X. 
Safety Management 
C9. Dose Modification Guidelines 
In the event that any patient develops elevated INR ≥ grade 2 in severity (> 1.5-2.5 x ULN) 
per CTCAE criteria version 4.0 thought to be related to treatment with EPI-743, 
administration of EPI-589 will be reduced by 1/3rd 1/2 to 66 50 percent of the starting dose. 
Should the INR toxicity not resolve to at least grade 1 in severity within two weeks of the 
initial dose reduction, administration of EPI-589 may either be further reduced or 
discontinued. 
Once a patient’s dose is reduced due to elevated INR thought to be related to study drug 
administration, their dose should not be re-escalated. 
 
End of Document 
#### 


 
 
 
 
 
 
EPI589-15-002 
A Phase 2A Safety 
and Biomarker Study of 
EPI-589 in Mitochondrial 
Subtype and Idiopathic 
Parkinson’s Disease Subjects 
 
Original Protocol: 
27 April 2015 
Protocol Amendment 1.0: 
09 September 2015 
Protocol Amendment 2.0: 
04 January 2016 
 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
The information contained in this document is confidential and will not be disclosed to others without 
written authorization from Edison, except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the study. 


Edison Pharmaceuticals, Inc 
Protocol EPI589-15-002 
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Version: Amendment 2.0 
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Table of Contents 
PROTOCOL SYNOPSIS ........................................................................................................ 6 
I. SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE ................................ 12 
II. INTRODUCTION ........................................................................................................... 13 
A. Background Information and Rationale................................................................... 13 
B. Rationale for the Study of EPI-589 in Parkinson’s Disease .................................... 14 
C. Name and Description of Investigational Product ................................................... 14 
D. Findings from Non-Clinical and Clinical Studies .................................................... 15 
D1. Non-Clinical Studies .................................................................................................. 15 
D2. Clinical Studies ........................................................................................................... 17 
E. Human Pharmacokinetics ............................................................................................ 17 
F. 
Clinical Study .............................................................................................................. 18 
G. Selection of Drugs and Dosages ................................................................................. 18 
H. Compliance Statement ................................................................................................ 18 
I. 
Relevant Literature and Data .................................................................................... 18 
III. STUDY OBJECTIVES ................................................................................................... 19 
A. Primary Objective ...................................................................................................... 19 
B. Secondary Objectives .................................................................................................. 19 
IV. INVESTIGATIONAL PLAN ......................................................................................... 20 
A. General Schema of Study Design .............................................................................. 20 
A1. Screening Phase ......................................................................................................... 20 
A2. 30-Day Run-in Phase ................................................................................................. 20 
A3. Baseline ...................................................................................................................... 20 
A4. Treatment Phase ........................................................................................................ 20 
A5. End of Treatment........................................................................................................ 21 
A6. Post-Treatment Follow-up ......................................................................................... 21 
B. Randomization and Blinding ..................................................................................... 21 
C. Study Duration, Enrollment and Number of Sites .................................................. 21 
C1. Duration of Subject Treatment ................................................................................... 21 
C2. Total Number of Study Sites/Total Number of Subjects Projected ............................ 21 
D. Study Population ......................................................................................................... 22 
D1. Inclusion Criteria ....................................................................................................... 22 


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D2. Exclusion Criteria ...................................................................................................... 22 
V. STUDY PROCEDURES ................................................................................................. 24 
A. Screening Visit ............................................................................................................ 24 
A1. Run-in Assessments ..................................................................................................... 24 
B. Treatment Phase ......................................................................................................... 24 
B1. Baseline Assessments .................................................................................................. 25 
B2. Study Visit Assessments .............................................................................................. 25 
B3. Pharmacokinetics ....................................................................................................... 26 
B4. Early Termination Study Visit .................................................................................... 26 
C. End of Treatment Visit ............................................................................................... 26 
D. Post-Treatment Follow-up ......................................................................................... 27 
E. Unscheduled Visits ...................................................................................................... 27 
F. 
Concomitant Medication ............................................................................................ 27 
G. Prohibited Medications .............................................................................................. 27 
H. Subject Withdrawals .................................................................................................. 27 
VI. STUDY ENDPOINTS AND EVALUATIONS .............................................................. 29 
A. Primary Endpoint ....................................................................................................... 29 
B. Secondary Endpoints (Efficacy) ............................................................................... 29 
C. Secondary Endpoints (Safety) ................................................................................... 29 
D. Screening and Baseline Evaluation ............................................................................ 29 
D1. Physical Examination................................................................................................. 29 
D2. Height and Weight ..................................................................................................... 30 
D3. Laboratory Evaluations ............................................................................................. 30 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) .................................................... 31 
E. Sample Collection Procedures, Bioanalytical Methods and Sample Shipment .... 31 
F. 
Efficacy Evaluations ................................................................................................... 31 
F1. Glutathione Cycle Biomarkers ................................................................................... 31 
F2. Parkinson’s Disease Rating (MDS-UPDRS) ............................................................. 31 
F3. Non-motor Symptoms (NMSS) ................................................................................... 32 
F4. Parkinson’s Disease Questionnaire (PDQ-39) ......................................................... 32 
F5. EQ-5D ........................................................................................................................ 32 
F6. Montreal Cognitive Assessment (MoCA) ................................................................... 32 


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F7. Beck Depression Inventory (BDI) .............................................................................. 32 
F8. Montgomery and Asberg Depression rating scale (MADRS) .................................... 32 
F9. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) ........... 33 
VII. STATISTICAL CONSIDERATIONS ........................................................................... 34 
A. Statistical Analysis ...................................................................................................... 34 
A1. Analysis Populations ................................................................................................... 34 
B. Efficacy Analysis ......................................................................................................... 34 
B1. Efficacy Variables ...................................................................................................... 34 
C. Safety Analysis ............................................................................................................ 34 
D. Sample Size .................................................................................................................. 35 
VIII. 
STUDY MEDICATION ........................................................................................... 36 
A. Description ................................................................................................................... 36 
B. Packaging .................................................................................................................... 36 
B1. Labeling ..................................................................................................................... 36 
B2. Dosage Form .............................................................................................................. 36 
B3. Dispensing.................................................................................................................. 36 
C. Treatment Compliance and Adherence .................................................................... 36 
D. Drug Accountability ................................................................................................... 36 
IX. SAFETY MANAGEMENT ............................................................................................ 38 
A. Clinical Adverse Events ............................................................................................. 38 
B. Adverse Event Reporting ........................................................................................... 38 
B1. Safety Guidance ......................................................................................................... 38 
C. Definition of an Adverse Event .................................................................................. 38 
C1. Adverse Event ............................................................................................................. 38 
C2. Definition of a Serious Adverse Event (SAE) ............................................................. 39 
C3. Non-serious Adverse Event ........................................................................................ 40 
C4. Definition of Relationship to Study Medication .......................................................... 40 
C5. Definition of Severity ................................................................................................. 40 
C6. Definition of Unexpected Adverse Event .................................................................... 41 
C7. Notification of SAEs ................................................................................................... 41 
C8. Follow-up Report ....................................................................................................... 42 
D. Medical Emergencies .................................................................................................. 42 


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D1. Emergency Sponsor Contact ...................................................................................... 42 
D2. Emergency Treatment ................................................................................................. 43 
X. STUDY ADMINISTRATION ........................................................................................ 44 
A. Treatment Assignment Methods ............................................................................... 44 
B. Data Collection and Management .............................................................................. 44 
C. Data Quality Assurance ............................................................................................. 44 
D. Retention of Study Records ....................................................................................... 45 
E. Confidentiality ............................................................................................................. 45 
F. 
Documentation of Study Results ............................................................................... 46 
G. Regulatory and Ethical Considerations .................................................................... 46 
G1. Risk Assessment .......................................................................................................... 46 
G2. Potential Benefits of Trial Participation .................................................................... 46 
G3. Risk-Benefit Assessment ............................................................................................. 46 
H. Informed Consent ....................................................................................................... 47 
XI. PUBLICATION ............................................................................................................... 48 
A. Use of Study Results ................................................................................................... 48 
XII. LIST OF ABBREVIATIONS ......................................................................................... 49 
XIII. 
SIGNATURE OF SPONSOR ................................................................................. 51 
A. Declaration of Sponsor ................................................................................................ 51 
XIV. 
REFERENCES ........................................................................................................ 52 
 
 
 
 
 
Space intentionally left blank 


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PROTOCOL SYNOPSIS 
Title of study 
A Phase 2A Safety and Biomarker Study of EPI-589 in 
Mitochondrial Subtype and Idiopathic Parkinson’s 
Disease Subjects 
Protocol number 
EPI589-15-002 
IND number 
126,795 
EudraCT number 
2015-001786-10 
Original Protocol Date 
27 April 2015 
Protocol Amendment 1.0 Date 
09 September 2015 
Protocol Amendment 2.0 Date 
04 January 2016 
Investigative Drug 
EPI-589 
Study Sponsor 
Edison Pharmaceuticals Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Investigators and Investigative 
• 
Sites 
USA 
• 
UK 
Study population 
Approximately 40 subjects with Parkinson’s disease 
(PD) including 20 subjects with genetically-defined 
subtypes 
Rationale for Study 
Mitochondrial pathophysiology 
It is now well appreciated that defects in mitochondrial 
function contribute to the pathophysiology of PD both in 
subjects with defined genetic defects as well as those 
with idiopathic forms of the disease. 
High morbidity 
Despite the available therapies for symptomatic relief, 
PD remains a highly morbid disease. There are no 
approved treatments for PD capable of modifying 
disease progression. 
Pre-clinical efficacy data 
EPI-589 is a redox active molecule that has 
demonstrated potency (EC50 < 100nM) and efficacy 
(>80% rescue from oxidative stress-induced cell death) 


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in cells derived from patients diagnosed with idiopathic 
and familial PD subtypes including PINK1, parkin and 
LRRK2. 
Study objectives 
Primary Objective 
To evaluate the effects of EPI-589 on safety as assessed 
by occurrence of drug-related serious adverse events in 
subjects with PD. 
Secondary Objectives 
To evaluate the effects of EPI-589 in subjects with PD 
on: 
1. Glutathione cycle biomarkers as measured in 
blood, cerebral spinal fluid, and urine 
2. Clinical disease state as assessed by the 
Movement Disorder Society-sponsored revision 
of the Unified Parkinson's Disease Rating Scale 
(MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor 
Symptoms Scale (NMSS), PDQ-39 and EQ-5D 
4. Cognitive function as assessed by Montreal 
Cognitive Assessment (MoCA) and 
5. Mood as assessed by the Beck Depression 
Inventory (BDI) and the Montgomery and 
Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 
Study design 
Open-label study with 30-day run-in phase. 
Planned number of subjects 
Approximately 40 subjects (20 with genetically-defined 
subtypes of PD and 20 drug-naïve idiopathic PD 
subjects). (Adaptive design component allows 
enrollment of up to 20 additional subjects with 
idiopathic PD to try to achieve a total of 20 subjects that 
have a biomarker response to EPI-589.) 
Study duration 
3 months (85 days ± 3 days) of study treatment preceded 
by a 1-month baseline parameter run-in period. 
Test product, mode of 
administration, and dose 
Test product 
EPI-589 in a tablet formulation at a strength of 250 mg 


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Mode of Administration 
Oral with meal 
Dose 
EPI-589 500-mg BID 
Reference therapy, dose, and 
mode of administration 
None 
Safety monitoring 
Clinical 
1. Physical exam and vital signs 
2. Evaluation of adverse events 
3. 12-lead Electrocardiogram 
4. Columbia Suicide Severity Rating Scale (C- 
SSRS) 
Laboratory 
1. Routine serum chemistries 
2. Routine hematology tests and coagulation tests 
Inclusion criteria 
1. Hoehn and Yahr stage ≤ 2.5 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners 
must agree to use medically accepted methods of 
contraception (e.g., hormonal methods, including 
oral, subcutaneous, and intrauterine; barrier 
methods, including 
condom, 
condom, or diaphragm with spermicidal gel) 
during the course of the study and for 3 months 
after the last dose of study treatment. 
4. Willingness and ability to comply with study 
procedures 
5. Stable regimen of dietary supplements for 30 
days prior to enrollment 
6. Abstention from use of other investigative or 
non-approved drugs for the duration of the trial 
For Idiopathic Subjects 
7. For idiopathic subjects: a diagnosis of early 
idiopathic PD confirmed by the presence of 
bradykinesia plus one or both of the following 
symptoms: rigidity or resting tremor; and with an 
abnormal DaTscan consistent with a 


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dopaminergic deficit 
8. For idiopathic subjects: must not yet require 
symptomatic medications for PD and not 
expected to require such treatment before the end 
of the study 
9. For idiopathic subjects: age 40 to 75 years 
10. For idiopathic subjects: within 5 years of 
diagnosis of Parkinson’s disease 
For Genetic Subtype Subjects 
11. For genetic subtype subjects: a confirmed 
diagnosis of PD plus a genetic diagnosis 
consistent with PD, specifically PINK1, parkin, 
LARK2 or other mitochondrial genetic subtype 
12. For genetic subtype subjects: age 21 to 75 years 
13. For genetic subtype subjects: stable medication 
regimen of PD drugs for 30 days (except 60 days 
for rasagiline) prior to enrollment 
Exclusion criteria 
1. Allergy to EPI-589 or other components of the 
EPI-589 tablet formulation 
2. Use of antioxidant supplements, specifically 
vitamins E and C beyond the recommended daily 
allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 
11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant 
neurologic disease that will confound the 
assessment of effect of study drug on disease 
progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast 
feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests 


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(LFTs) > 3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 
1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for 
duration of study in a trial of a device, drug or 
other therapy for PD 
For Idiopathic Subjects 
16. For idiopathic subjects: use of any MAO 
inhibitors, amantadine or other drugs prescribed 
for core symptoms of Parkinson’s disease for 
idiopathic subjects 
17. For idiopathic subjects: use of nortriptyline or 
fluvoxamine 60 days prior to enrollment 
Treatment 
Following study enrollment, baseline assessments will 
be performed. Subjects will participate in a 30-day run- 
in phase to establish biomarker and clinical baseline 
measurements. EPI-589 will then be administered for up 
to 3 months (85 days ± 3 days) unless discontinued for 
safety or tolerability issues. Post-treatment follow-up 
will be at least 10 days and up to 30 days after last dose. 
Efficacy variables 
1. Blood-based glutathione biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. Non-motor Symptoms Scale (NMSS) 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. Beck Depression Inventory (BDI) 
10. Montgomery & Asberg Depression rating scale 
(MADRS) 
11. Timed motor tests in ON and OFF state (for 
subjects on dopamine therapy) 
12. Pharmacokinetics 


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Safety variables 
Clinical 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
4. C-SSRS 
5. Laboratory 
6. Routine serum chemistries with liver function 
tests 
7. Routine hematology tests with coagulation tests 
Statistical Considerations 
Data Analysis 
This is a within-subject, controlled open-label study 
seeking to determine the safety and tolerability of EPI- 
589 in patients with PD as well as to determine if EPI- 
589 can alter the biochemical signature of PD as 
assessed by peripheral blood biomarkers, CNS 
biomarkers, brain imaging biomarkers, and urine 
biomarker analysis. In addition, data on a number of 
disease-relevant clinical measures will be collected. 
 
 
 
 
 
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I. 
SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE 
 
Tests 
-2 to -1 Months 
Day 0 
Month 1 
Month 2 
Month 3 
End of 
Treatment Visit 
Post-Treatment 
Follow-up 
Screening 
Run-in 
(± 30 days) 
Baseline 
Day 29 
(± 3 days) 
Day 57d 
(± 3 days) 
Day 85 
(± 3 days) 
Up to 30 Days 
after Last Dosee 
Informed consent 
 
Inclusion/Exclusion criteria 
 
Past Medical history 
 
Previous genetic testing 
review 
 
Physical exam & Vital signs 
 
 
 
 
Height & weight 
 
a 
 
 
12-lead ECG 
 
a 
 
 
Hematology (including 
coagulation panel) 
 
a 
 
 
Serum Chemistry 
 
a 
 
 
Pregnancy testb 
 
 
 
 
C-SSRS 
 
 
 
Montreal Cognitive 
Assessment 
 
 
DaTscan 
 
Revised Hamilton Rating 
Scale for Depression 
 
Subject enrolls in study 
X 
Blood-based glutathione cycle 
biomarkers 
 
 
 
 
Lumbar puncture (CNS 
biomarkers) 
 
 
Urine-based biomarkers 
 
 
 
 
MDS-UPDRS 
 
 
 
 
Timed motor tests (for 
subjects on dopamine therapy) 
 
 
 
NMSS, PDQ-39, EQ-5D 
 
 
BDI, MADRS 
 
 
Drug plasma concentrationc 
c 
c 
AE/SAE assessmentd 
 
d 
d 
e 
Concomitant medications 
assessment 
 
 
 
 
d 
d 
e 
Post-Treatment Assessmentse 
e 
a. Screening values can be used if done within one month of baseline. 
b. Female subjects of childbearing potential must have a negative pregnancy test. 
c. Full plasma concentration profile will be obtained at Time = 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours after dosing from the first 10 subjects to 
complete 1 month of therapy at each site. 
d. Month 2 assessments can be done by telephone. Any new AEs and associated concomitant medications reported at Month 3 must be followed for 
30 days; this follow up may be conducted by telephone. 
e. AE/SAE and concomitant medication assessments conducted by telephone at least 10 days after last dose. Additional assessments determined at 
Investigator discretion. 
Dosing Schedule 
Month 1 
Month 2 
Month 3 
Post-Treatment 
EPI-589 500-mg BID 
 
 
 


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II. 
INTRODUCTION 
A. 
Background Information and Rationale 
 
Parkinson’s disease (PD) is a highly morbid neurodegenerative movement disorder that has a 
number of neuromuscular, cognitive and neuropsychiatric manifestations as well as non- 
neurological symptoms. PD is the second most common neurodegenerative disorder with an 
estimated prevalence of 6.3 million people worldwide (EPDA). 
 
PD has long been considered a non-genetic (idiopathic) disease; however, about 5% of patients 
have an identifiable mutation. Disease onset typically occurs after age 50, however, in a subset of 
patients, disease onset can occur at a younger age. The primary motor symptoms result from 
death of dopamine-producing cells in the pars compacta region of the substantia nigra. However, 
the mechanisms underlying this cell death and disease pathology remain poorly understood. 
There is no approved treatment for PD capable of modifying disease progression. Current 
therapies partially address disease motor symptoms through levodopa or dopamine agonists or 
other agents, and other disease symptoms (e.g. neuropsychiatric symptoms), but disability tends 
to increase over time despite these treatments. 
 
The association of PD with mitochondrial pathology and high levels of oxidative stress are well 
established. Increased levels of oxidative stress have been consistently measured in post-mortem 
specimens from PD patients (Maarouf 2012, Reale 2012). The occurrence of PD-like symptoms 
in heroin addicts exposed to MPTP in the 1980s established a first link between PD and 
mitochondrial injury (Langston 1983, Dauer and Przedborski 2003). MPTP inhibits complex 1 of 
the mitochondrial respiratory chain and induces degeneration of dopaminergic cells through 
oxidative stress-mediated injury. The link between mitochondrial injury and PD was further 
strengthened by the induction of PD symptoms following exposure to another neurotoxic 
complex 1 inhibitor, rotenone (Betarbet et al 2000, Greenamyre et al. 2003), which like MPTP 
has come to be used in pre-clinical testing for its phenotypic similarities to PD. 
 
Furthermore, the identification of genetic mutations such as PINK1, parkin, LRRK2 and others 
in mitochondrial genes in familial PD patients provided the strongest link between the 
mitochondria and PD (Winklhofer and Haass 2010). Normally these genes influence oxidative 
balance and provide neural protection of the dopaminergic neurons that are affected by PD. 
PINK1 and parkin are involved in protecting against oxidative stress (OS) and overabundant 
reactive oxygen species (ROS), and are implicated in cell morphology and dynamics, as well as 
in the preferential degradation of dysfunctional mitochondria or “mitophagy” (Ashrafi et al. 
2014). Mutant LRRK2 leads to the accumulation of misfolding intracellular protein 
accumulations, cell stress and apoptosis (Giasson et al. 2006, Zhu et al. 2006). 
 
The importance of oxidative stress in PD pathology is further substantiated by the measurement 
of decreased levels of reduced glutathione in the brains of patients with PD (Holmay et al. 2013). 
Glutathione levels are low at very early stages of PD and correlate with disease severity 
(Riederer et al. 1989), and experimental induction of glutathione depletion leads to mitochondrial 
complex I dysfunction (Jha et al, 2000;). Reduced glutathione is an essential intermediary 


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metabolite that serves as the primary native cellular antioxidant. In a state of high oxidative 
stress, elevated levels of ROS outstrip the supply of glutathione (GSH) resulting in depletion of 
GSH and ROS-mediated cell death. 
 
Given the important role of oxidative stress and mitochondrial pathology in PD, a redox-active 
therapy that could target key pathways in cellular OS response pathways may hold promise for 
the treatment of PD. 
 
B. 
Rationale for the Study of EPI-589 in Parkinson’s Disease 
 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 <100nM ) and efficacy 
(>80% rescue from oxidative stress-induced cell death) in cells derived from patients diagnosed 
with idiopathic and familial PD genetic subtypes including PINK1, parkin and LRRK2. 
In these cell-based assays, primary fibroblasts from patients (and control) were pre-incubated 
with and without test compound, then treated with L-buthionine-(S,R)-sulfoximine (BSO), a 
GSH synthesis inhibitor, to initiate depletion of cellular GSH. GSH depletion has been shown to 
lead to OS and disruption of calcium homeostasis resulting in loss of the mitochondrial 
membrane potential and cell death. Under these conditions, the control cells are resistant to the 
stress and the fibroblast cells from patients with disease indications die within 36 to 48 hours. 
Pretreatment of cells with EPI-589 prior to initiation of GSH depletion potently protected against 
oxidative stress-mediated cell death, with EC50 response concentrations of 16 to 52 nM. (Table 
1). 
Table 1: 
Cell Line Rescue with EPI-589 in Parkinson’s Disease Genetic Subtypes 
 
EPI-589 
EC50 (nM range) 
PINK1 
26-36 
LRRK2 
16-18 
parkin 
42-52 
 
C. 
Name and Description of Investigational Product 
The IUPAC name of EPI-589 is: 
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide. 
 
A common chemical name of EPI-589 is (R)-troloxamide quinone. EPI-589 is derived from 
resolved (R)-Trolox®, a derivative of vitamin E in the form of a pale yellow to yellow solid. The 
EPI-589 drug product will be provided in a 250-mg tablet formulation. 


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The Investigator will ensure that all study drugs are stored and dispensed in accordance with the 
Food and Drug Administration (FDA) and local regulations concerning the storage and 
administration of investigational drugs. 
 
D. 
Findings from Non-Clinical and Clinical Studies 
D1. Non-Clinical Studies 
 
EPI-589 is an orally available compound that has been demonstrated in vitro and in vivo to cross 
the blood-brain-barrier. In 28-day and 91-day repeat-dose toxicity studies in rat and cynomolgus 
monkey, the no observed adverse effect level (NOAEL) was 300 mg/kg/day, corresponding to 
combined mean Cmax values of 37,717 to 56,500 ng/mL (rat) and 14,300 to 16,417 ng/mL 
(monkey), and a combined mean area under the plasma concentration-time curve from time zero 
to the last measurable concentration (AUClast) value of 149,495 to 297,000 ng.h/mL (rat) and 
47,300 to 67,656 ng.h/mL (monkey) (Studies 1660-038, 1660-039, 1660-063, and 1660-064). 
 
A phase 1 clinical study demonstrated that healthy subjects administered 500 mg EPI-589 BID 
for 14 days showed a mean Cmax value of 1,890 ng/mL and a mean AUClast value of 5,240 
ng.h/mL (Study EPI589-14-01). These plasma concentrations are well below the mean exposure 
values in monkey associated with the NOAEL in the toxicity studies, corresponding to safety 
margins of approximately 7- to 8-fold for the mean Cmax and 9- to 12-fold for the mean AUC. 
 
During the 28-day repeat-dose toxicity studies, rat and monkey were exposed to up to 1,000 
mg/kg/day EPI-589 PO (Studies 1660-039 and 1660-038). The NOAEL for both studies was 300 
mg/kg/day. Rats exposed to 1,000 mg/kg/day exhibited adverse test-article related effects on 
hematology parameters consistent with hemolysis and bone marrow regeneration, mild to 
moderately enlarged spleens, and increased organ weights with some organs showing 
corresponding microscopic pathology. The majority of these findings were resolved following 
the 28-day recovery period. Monkeys exposed to 1,000 mg/kg/day showed significant test-article 
related morbundity that resulted in half the animals in the high dose group being euthanized on 
Days 3 and 4 and the remaining animals being euthanized on Day 9. These animals exhibited 
significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
values, and microscopic findings in the kidney, liver, skeletal muscle, heart, and lymphoid 
tissues. In several of the animals the primary cause of morbidity was determined to be test-article 
related renal tubular degeneration/necrosis. 
 
During the 91-day repeat-dose toxicity studies, rat and monkey were exposed to up to 300 
mg/kg/day EPI-589 PO (Studies 1660-063 and 1660-064). The NOAEL for the rat study was 300 
mg/kg/day and the no observed effect level (NOEL) for the monkey study was 300 mg/kg/day. 
rats exposed to 300 mg/kg/day and 
rats exposed to ≥ 100 mg/kg/day exhibited mild 
test-article related effects on hematology parameters consistent with hemolysis and bone marrow 
regeneration. These findings were not considered adverse. 
 
Development and reproductive toxicology studies were conducted in rat and rabbit at doses up to 
1,000 mg/kg/day EPI-589 PO (Studies 1660-069, 1660-067, and 1660-068). The NOAEL for 
reproductive toxicity in rat was demonstrated to be 1,000 mg/kg/day (1660-069). The NOAEL 


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for developmental toxicity in rat and rabbit during the embryofetal studies was deemed to be 300 
mg/kg/day (Studies 1660-067 and 1660-068). Rats exposed to 1,000 mg/kg/day exhibited 
decreased maternal body weights, decreased food consumption, and decreased fetal body 
weights. There was no teratogenic potential in rat at doses up to 1,000 mg/kg/day. Rabbits 
exposed to 1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, decreased number of viable fetuses, decreased litter size, increased 
postimplantation loss, increased resorptions (early and late), and increased fetal skeletal 
malformations. The margin of exposure between healthy humans exposed to 500 mg BID EPI- 
589 (relevant clinical dose) for 14 days (Study EPI589-14-01) and rabbits exposed to 1,000 and 
300 mg/kg/day EPI-589 is approximately 179- to 236-fold and 47- to 50-fold, respectively. 
Based on these data, EPI-589 is not anticipated to increase the risk of adverse developmental or 
reproductive outcomes in humans when used in accordance with dosing information. 
 
EPI-589 was negative for mutagenic response in the in vitro Ames bacterial reverse mutation 
assay (Study AD58AS.502ICH.BTL); equivocal for the induction of structural and negative for 
the induction of numerical chromosomal aberrations in the in vitro chromosome aberration assay 
in Chinese hamster ovary (CHO) cells (Study AD58AS.331ICH.BTL); and negative in the in 
vivo micronucleus assay in rat (Study AD58AS.125012ICH.BTL). These data indicate a low 
clinical mutagenicity risk. 
 
Primary pharmacodynamics studies demonstrated that EPI-589 is a potent rescue agent in 
cellular models of diseases of energy metabolism and oxidative stress. In vitro cellular models 
utilizing primary human fibroblasts from patients with ALS, Parkinson’s disease and other 
diseases characterized by high levels of oxidative stress, or striatal cells derived from mouse 
models of Huntingdon’s disease were used to assess the potential of EPI-589 to mitigate the 
harmful effects of oxidative stress (Studies EPI-BA-000216, EPI-BA-000363, and EPI-BA- 
000362). Pretreatment of patient cells with EPI-589 potently protected against oxidative stress- 
mediated cell death in a concentration dependent manner. Furthermore, EPI-589 normalized 3- 
nitrosotyrosine (3NT) levels, a biomarker of oxidative stress, and increased glutathione levels in 
mouse striatal cells under oxidative stress conditions. 
 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, EPI-589 did not 
significantly affect off-target molecular targets (Study EPI-BA-159). In safety pharmacology 
studies, EPI-589 did not significantly affect ion channel current in the hERG assay (Study 
130719.FEK); did not affect ECG parameters during the 28-day and 3-month repeat-dose 
toxicology studies in monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for 
animals administered 1,000 mg/kg/day and up to Day 91 data collected for animals administered 
up to 300 mg/kg/day) (Studies 1660-038 and 1660-064); and did not change respiratory function 
or adversely impact neurobehavioral function in rat at doses up to 1,000 mg/kg (Studies 1660- 
051, 1660-050, and 1660-063). 
 
In single dose exposure PK studies, EPI-589 was absorbed rapidly in rat, dog, and monkey, with 
mean Tmax values ranging from .08 to 1 hour and mean T1/2 values ranging from 3.7 to 5.0 hours 
(Studies EPI-BA-53, EPI-BA-59, EPI-BA-72, and EPI-BA-302). EPI-589 does not significantly 
induce cytochrome P450 (CYP) enzymes and appears to be metabolized by reductases in the 


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liver cytosol and microsomal subcellular fractions and to a lesser extent by the family of CYP 
enzymes (Studies MC12M-0037 and MC14M-0018). 
 
EPI-589 exhibited weak direct inhibition of CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (both 
midazolam and testosterone as probe substrates) with estimated IC50 (µM) values and R values 
based on free plasma concentrations (shown in parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 34 
(1.21), and 53 (1.13), respectively (Study MC14M-0020)Based on these data, EPI-589 is not 
anticipated to increase the risk of adverse developmental or reproductive outcomes in humans 
when used in accordance with dosing information. 
 
D2. Clinical Studies 
 
Phase I Study EPI589-13-022 evaluated the pharmacokinetics, safety and tolerability of single 
ascending oral doses (SADs) of EPI-589 in healthy subjects and a preliminary evaluation of 
safety and tolerability data was performed. Sixteen AEs were reported in the 36 subjects who 
received administration of EPI-589. Ten subjects (27.8%) who received EPI-589 (and 2 subjects, 
20% on placebo) reported AEs that were assessed as related. All were mild and resolved during 
the study, with the exception of a common cold (1 subject) and cold sore (1 subject). None of the 
vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant change 
compared to baseline. From all preliminary data available from this SAD study it may be 
concluded that there is no objection to proceed with treatment with 50 mg, 100 mg, 250 mg or 
500 mg of EPI-589. 
 
Phase I Study EPI589-14-01 evaluated the pharmacokinetics, safety and tolerability of multiple 
ascending oral doses (MAD) of EPI-589 in healthy subjects, and an evaluation of safety and 
tolerability data was performed. No severe or serious adverse events were observed. Twenty-six 
subjects (65.0%) on EPI-589, and 8 subjects (80%) on placebo reported AEs. Twenty-four of 34 
AEs were considered by the Investigator to be related to EPI-589. Nineteen subjects (47.5%) on 
EPI-589, and 6 subjects (60%) on placebo reported AEs that were assessed as related. All 
adverse events were mild, except for 1 AE which was moderate (unrelated brain contusion). All 
AEs were resolved during the study, with the exception of one, which was a common cold. None 
of the vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant 
change compared to baseline. From all preliminary data available from the MAD study it may be 
concluded that there is no objection to proceed with treatment with 250-mg, or 500-mg doses of 
EPI-589. 
 
E. 
Human Pharmacokinetics 
 
EPI-589 was fast absorbed following oral administration in SAD Study EPI589-13-022. The 
median Cmax was attained approximately within 1 hour under fasted conditions after dosing. The 
median Tmax values were attained in 0.50 to 1.00 hours over the dose range of 50 to 1000 mg 
under fasted conditions and 3.01 hours at the 500 mg dose level under fed conditions. Mean half- 
life ranged from 5.55 to 10.7 hours over the dose range of 50 to 1000 mg under fasted conditions 
and 4.91 hours at the 500 mg dose level under fed conditions. Half-life was independent of the 
dose levels over the dose range of 50 to 1000 mg under fasted conditions. The rate of EPI-589 
absorption, as measured by Cmax, was decreased by 24.07% under fed conditions at the 500 mg 


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dose level. The extent of absorption as measured by AUCs (AUC0-t or AUC0-inf) was not affected 
under fed conditions in the 500 mg dose groups. 
 
In MAD study EPI589-14-01, EPI-589 was rapidly absorbed following oral administration and 
the median Cmax was attained within 1 hour (0.50 to 0.76 hours) under fasted conditions after 
single or multiple dosing among these five cohorts. The mean half-life of EPI-589 ranged from 
5.64 to 8.47 hours among these five cohorts. In general, the mean values of the time to peak 
concentration (Tmax), half-life (t½), apparent terminal constant (λz), accumulation ratio (AR), 
percent fluctuation (%F) and accumulation index (AI) of EPI-589 were similar among the five 
cohorts of various ages and smoking status. No significant effects of age or smoking on EPI-589 
pharmacokinetics were observed in this study. Dose proportionality existed in the exposures 
(AUC0-tau, Cmax, Cmin and Cavg) over the dose range of 250 to 500-mg BID EPI-589 under fasted 
conditions. 
 
F. 
Clinical Study 
 
EPI589-15-002: A Phase 2A Safety and Biomarker Study of EPI-589 in in Mitochondrial 
Subtype and Idiopathic Parkinson’s Disease Subjects. 
 
G. 
Selection of Drugs and Dosages 
 
The study drug in this trial is EPI-589: common chemical name (R)-troloxamide quinone. 
 
Each tablet contains 250 mg of EPI-589. The study dose is 500-mg BID, to be maintained in the 
absence of treatment-emergent toxicity. EPI-589 tablets must be taken with meals. 
 
H. 
Compliance Statement 
 
This study will be conducted in full accordance with all applicable research policies and 
procedures, the EU Clinical Trials Directive, all applicable EU and US federal and local laws 
and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312 and 314, and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonization (ICH). Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
will report AEs in accordance with local institutional policies and procedures and all EU and US 
federal requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the study. 
 
I. 
Relevant Literature and Data 
 
Literature references have been provided in Section XIV. Additional information can be found in 
the Investigator’s Brochure. 


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III. STUDY OBJECTIVES 
A. 
Primary Objective 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
B. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with PD on: 
1. Glutathione cycle biomarkers as measured in blood, cerebral spinal fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society-sponsored revision 
of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale (NMSS), PDQ-39 and 
EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment (MoCA) 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the Montgomery & 
Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 
 
 
 
 
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IV. INVESTIGATIONAL PLAN 
A. 
General Schema of Study Design 
 
Following study enrollment, baseline assessments will be performed. Subjects will participate in 
a 30-day run-in phase to establish biomarker and clinical baseline measurements. EPI-589 will 
then be administered for up to 3 months (85 days ± 3 days) unless discontinued for safety or 
tolerability issues. 
 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. Given that the investigational drug 
targets an enzyme key to glutathione synthesis and that glutathione depletion has been found to 
be associated with PD, we are seeking to determine the safety and potential biochemical benefit 
of EPI-589 in PD subjects as assessed by glutathione cycle biomarkers. If we determine that 
there are a subset of subjects with normal levels of glutathione who do not demonstrate 
biochemical changes following drug administration, and a subset of subjects with low levels of 
reduced glutathione who do respond to drug treatment, we would seek to enroll additional 
idiopathic PD subjects with low glutathione levels to achieve a higher number of subjects in 
whom we could understand the biochemical effects of the investigative drug and its potential 
clinical impact as assessed by the study outcome metrics. EPI-589 will be administered for up to 
3 months (85 days ± 3 days) unless discontinued for safety or tolerability issues. 
 
A1. 
Screening Phase 
 
Suitable candidates for the trial will receive a short overview of the study by the Investigator’s 
staff and, if interested, will undergo Screening. The Investigator will inform each prospective 
subject of the nature and details of the study, explain the potential risks and must obtain written 
informed consent from the subject or their legally authorized representative prior to performing 
any study related procedures. 
 
A2. 
30-Day Run-in Phase 
 
Once eligibility is confirmed, the subject will be enrolled in the study and the run-in scans, CNS, 
blood-based biomarker, urine-based biomarker and clinical measurements will be collected. 
 
A3. 
Baseline 
 
Baseline assessments, scans, blood-based biomarker, urine biomarker, and clinical measurements 
will be collected. 
 
A4. 
Treatment Phase 
 
EPI-589 dosing will start on Day 1. Subjects will self-administer EPI-589 at a dose of 500-mg 
BID. 


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Blood-based biomarker, urine biomarker, and clinical measurements will be collected at Day 29 
(± 3 days) and Day 85 (± 3 days). 
 
A5. 
End of Treatment 
 
End of treatment data will be collected at the last study visit Day 85 (± 3 days). 
 
AEs reported as ongoing at Day 85 (± 3 days) and/or any concomitant medications associated 
with such events 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. 
 
A6. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose: AE/SAE and 
concomitant medication assessments conducted by telephone. Additional assessments to be 
determined at Investigator discretion. 
 
 
B. 
Randomization and Blinding 
 
This is an open-label study. 
 
C. 
Study Duration, Enrollment and Number of Sites 
C1. Duration of Subject Treatment 
 
Subjects will participate in a 30-day run-in phase to establish biomarker and clinical baseline 
measurements. EPI-589 will then be administered for 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. A post-treatment follow-up will be conducted up to 
30 days after last dose. 
 
C2. 
Total Number of Study Sites/Total Number of Subjects Projected 
 
This study will be conducted at two study sites: 
• 
UK 
• 
USA. 
Approximately 40 subjects with PD are projected: 
• 20 with genetically-defined subtypes 
• 20 PD drug-naïve 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects to achieve a higher number of subjects in 
whom we could understand the biochemical effects of the investigative drug and its potential 
clinical impact as assessed by the same study protocol and outcome metrics. 


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D. 
Study Population 
D1. Inclusion Criteria 
 
1. Hoehn and Yahr stage ≤ 2.5 
2. Ambulatory with or without assistance 
3. Sexually active fertile subjects and their partners must agree to use medically accepted 
methods of contraception (e.g., hormonal methods, including oral, subcutaneous, and 
intrauterine; barrier methods, including 
condom, 
condom, or diaphragm with 
spermicidal gel) during the course of the study and for 3 months after the last dose of 
study treatment. 
4. Willingness and ability to comply with study procedures 
5. Stable regimen of dietary supplements for 30 days prior to enrollment 
6. Abstention from use of other investigative or non-approved drugs for the duration of the 
trial 
For Idiopathic Subjects 
7. For idiopathic subjects: a diagnosis of early idiopathic PD confirmed by the presence of 
bradykinesia plus one or both of the following symptoms: rigidity or resting tremor; and 
with an abnormal DaTscan consistent with a dopaminergic deficit 
8. For idiopathic subjects: must not yet require symptomatic medications for PD and not 
expected to require such treatment before the end of the study 
9. For idiopathic subjects: age 40 to 75 years 
10. For idiopathic subjects: within 5 years of diagnosis of Parkinson’s disease 
 
For Genetic Subtype Subjects 
11. For genetic subtype subjects: a confirmed diagnosis of PD plus a genetic diagnosis 
consistent with PD, specifically PINK1, parkin, LARK2 or other mitochondrial genetic 
subtype 
12. For genetic subtype subjects: age 21 to 75 years 
13. For genetic subtype subjects: stable medication regimen of PD drugs for 30 days (except 
60 days for rasagiline) prior to enrollment 
 
D2. Exclusion Criteria 
 
1. Allergy to EPI-589 or other components of the EPI-589 tablet formulation 
2. Use of antioxidant supplements, specifically vitamins E and C beyond the recommended 
daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that will confound the 
assessment of effect of study drug on disease progression 
8. Malignancy within past two years 


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9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial of a device, drug or 
other therapy for PD 
For Idiopathic Subjects 
16. For idiopathic subjects: use of any MAO inhibitors, amantadine or other drugs prescribed 
for core symptoms of Parkinson’s disease for idiopathic subjects 
17. For idiopathic subjects: use of nortriptyline or fluvoxamine 60 days prior to enrollment 
 
 
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V. 
STUDY PROCEDURES 
A. 
Screening Visit 
 
Screening evaluations will be performed within two months of first dose. The Investigator will 
inform each prospective subject of the nature of the study, explain the potential risks, and must 
obtain written informed consent from the subject prior to performing any study-related 
procedures and prior to the administration of study drug. Screening evaluations consist of the 
following: 
1. Assessment of eligibility 
2. Medical history, chart review 
3. Receipt and review of previous testing including genetic tests 
4. Physical examination including vital signs 
5. Height and weight 
6. 12-lead ECG 
7. Laboratory assessments for hematology, coagulation, and serum chemistry (See Sections 
VI.D3.a and VI.D3.b) 
8. Urine pregnancy test (women of childbearing potential must have a negative urine 
pregnancy test; see Section VI.D3.c) 
9. MoCA 
10. DaTscan 
11. Revised Hamilton Rating Scale for Depression 
12. Concomitant medications assessment (last 60 days prior to enrollment) 
 
A1. 
Run-in Assessments 
 
If the subject is eligible for the study following all screening procedures and is still willing to 
participate in the study, the subject must return to the clinic within one month for Run-in 
assessments. These will be performed 30 days (± 3 days) prior to baseline after eligibility is 
confirmed and subject is enrolled in the study. Run-in evaluations consist of the following: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers (lumbar puncture) 
3. Urine biomarkers 
4. MDS-UPDRS 
5. Timed motor tests (for subjects on dopamine therapy) 
6. Concomitant medications review 
 
B. 
Treatment Phase 
 
After the Run-in phase, the subject must return to the clinic within 30 days (± 3 days) for 
baseline assessments. In-clinic study visits are scheduled at Month 1 and Month 3. The Month 2 
study assessments can be conducted via telephone. End of treatment assessments will be 
conducted at the Month 3 study visit. Pharmacokinetic sampling takes place at Month 1 and 
Month 3. 


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B1. 
Baseline Assessments 
 
The following will be assessed or performed at this visit. 
1. Physical examination including vital signs 
2. Height and weight* 
3. 12-Lead ECG* 
4. Blood-based GSH cycle biomarkers 
5. Urine-based biomarkers 
6. Laboratory assessments for hematology, coagulation and serum chemistry* 
7. Urine pregnancy test (females of child bearing potential) 
8. C-SSRS (Columbia Suicide Severity Rating Scale) 
9. MDS-UPDRS 
10. NMSS, PDQ-39, EQ-5D 
11. BDI, MADRS 
12. Timed motor tests (for subjects on dopamine therapy) 
13. Concomitant medications review 
* Screening results for these assessments may be used if obtained within 1 month of Baseline. 
 
B2. 
Study Visit Assessments 
 
• Month 1 Clinic Visit (Day 29 ± 3 days): 
 
The following will be assessed or performed at the Month 1 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. MDS-UPDRS 
10. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
11. AE assessments 
12. Concomitant medications review 
• Month 2 Visit (Day 57 ± 3 days) 
 
Month 2 assessments can be conducted by telephone and must include review of: 
1. Concomitant medication 
2. AEs 


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• Month 3 Clinic Visit (Day 85 ± 3 days) 
 
The following will be assessed or performed at the Month 3 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. CNS biomarkers 
10. MDS-UPDRS 
11. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
12. AE assessments 
13. Concomitant medications review 
14. MoCA 
15. NMSS, PDQ-39, EQ-5D 
16. BDI, MADRS 
17. Timed motor tests (for subjects on dopamine therapy) 
 
B3. 
Pharmacokinetics 
 
Plasma concentration samples will be collected from the first 10 subjects to complete 1 month of 
therapy at each site, at the following time points: 
• Month 1 (Day 29 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
• Month 3 (Day 85 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
 
B4. 
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. 
 
C. 
End of Treatment Visit 
 
End of treatment visit takes place at Month 3 (Day 85 ± 3 days) and includes the assessments 
listed in Section VB2 Study Visit Assessments. 
 
Subjects who have an ongoing AE at the time of study completion will be followed for up to 30 
days, until the event resolves, or until the Sponsor and the Investigator agree that further follow- 
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D. 
Post-Treatment Follow-up 
 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose, with 
AE/SAE and concomitant medication assessments conducted by telephone. Additional 
assessments to be determined at Investigator discretion. 
 
E. 
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 case report form (CRF) using the supplemental visit CRF pages. 
 
F. 
Concomitant Medication 
 
Any medication taken by a subject ≤ 60 days prior to enrollment and during the course of the 
study and the reason for use of the medication will be recorded on the 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 [OTC] medications) without consulting the Investigator. 
 
G. 
Prohibited Medications 
 
The following are prohibited while the subject is on study treatment: 
1. Use of antioxidants, specifically vitamins E and C beyond the recommended daily 
allowance 
2. Participation 3 months prior to and for the duration of the study in a trial of a device, drug 
or other therapy for PD 
3. Use of MAO inhibitors, amantadine or other drugs prescribed for core symptoms of 
Parkinson’s disease for idiopathic subjects 
4. Use of nortriptyline or fluvoxamine 
 
H. 
Subject Withdrawals 
 
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 a serious or severe adverse event that is deemed related to 
treatment with EPI-589 and in the Investigator’s or the Sponsor’s medical judgment 
continuation of treatment would be detrimental to the subject. 
3. At the specific request of a regulatory agency for termination of treatment of an 
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4. Subject participation in another clinical study using an investigational agent or 
investigational medical device 
5. Use of prohibited medications such as vitamins E and C beyond the recommended daily 
allowance; nortriptyline or fluvoxamine; and, for idiopathic subjects, MAO inhibitors, 
amantadine or other drugs prescribed for core symptoms of Parkinson’s disease 
6. Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use medically accepted methods of contraception 
7. If a subject becomes pregnant. 
8. Significant noncompliance with the protocol in the opinion of the Investigator or the 
Sponsor 
In all cases, the reason for withdrawal must be recorded in the 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 
IX.B. 
 
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. 
 
Every effort will be made to follow subjects who have an ongoing AE at the time of withdrawal 
until the event resolves, or until the Sponsor and the Investigator agree that further follow-up is 
not medically necessary. 
 
 
 
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VI. STUDY ENDPOINTS AND EVALUATIONS 
A. 
Primary Endpoint 
 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of drug-related serious 
adverse events in subjects with PD. 
 
B. 
Secondary Endpoints (Efficacy) 
 
1. Blood-based biomarkers 
2. CNS-based biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Secondary Endpoints (Safety) 
 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Routine serum chemistries with liver function tests 
4. C-SSRS 
5. Routine hematology tests with coagulation tests 
6. Electrocardiogram 
 
D. 
Screening and Baseline Evaluation 
D1. Physical Examination 
 
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. 
 
Vital sign measurements (pulse rate, blood pressure and respiration rate) will be obtained in the 
sitting position (after the subject has been sitting for five minutes). 
 
Medical history and demographics including age, gender, race, height and weight will be 
collected at Screening. 


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D2. Height and Weight 
 
Weight (kg) will be measured in ordinary indoor clothing (i.e., street clothes, scrubs, etc.) with 
shoes off. Height will be recorded in centimeters (cm). 
 
If clinically significant findings, as determined by the Investigator, are recorded for a particular 
symptom, sign or abnormal measurement, that measurement will be repeated at medically 
appropriate intervals until the value returns to an acceptable range, a specific diagnosis is 
established, or the condition is otherwise explained. 
 
D3. Laboratory Evaluations 
 
Subjects will have less than 100 mL of blood drawn over the course of the study. 
The following variables will be collected at various times (as detailed in Section I). 
a. 
Hematology 
 
1. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), red cell distribution width (RDW) 
2. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) reported as absolute values 
3. Platelets: platelet count, mean platelet volume (MPV) 
4. Coagulation: prothrombin time (PT) with INR, partial thromboplastin time (PTT), 
activated (aPTT) 
 
b. Serum chemistry 
 
1. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total and 
direct), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH) 
2. Renal: blood urea nitrogen (BUN), and creatinine 
3. Electrolytes: sodium, potassium, chloride, and carbon dioxide (CO2) as bicarbonate 
4. General: creatine phosphokinase (CPK), creatine kinase (CK), and troponin (at baseline 
only); total protein, albumin, calcium, magnesium, glucose, phosphate 
5. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL) cholesterol, cholesterol/HDL Ratio (calculated), non-HDL cholesterol 
(calculated), and triglycerides 
 
c. 
Urine pregnancy test 
1. Human chorionic gonadotropin (HCG) beta subunit will be measured on all female 
subjects of childbearing potential. 


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Laboratory tests that result in significantly abnormal values should be repeated for verification. 
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, or to monitor the course of an AE, should be obtained when clinically indicated. 
In particular, if a clinically significant abnormal result is observed that is not resolved by the 
final study visit, repeat tests should be performed to document resolution or stability of the 
abnormality. 
 
Diagnoses associated with any NIH Common Terminology Criteria for Adverse Events (CTC 
v4.03) Grade 3 or 4 laboratory abnormalities will be recorded as SAEs on the CRF. Repeated 
and verified ≥ Grade 3 laboratory tests will be reported as an SAE to the Sponsor and the IRB 
per institutional requirements. The recorded event should indicate the underlying abnormality or 
diagnosis (e.g., renal insufficiency) if known, as opposed to the observed deviation in laboratory 
results (e.g., elevated creatinine). Any additional relevant laboratory results obtained by the 
Investigator during the study will be supplied to the Sponsor. 
 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a semi-structured tool for assessing suicidal ideation (Questions 1-5) and 
behavior (Questions 6-10) through a series of questions. 
 
E. 
Sample Collection Procedures, Bioanalytical Methods and Sample Shipment 
 
Subject samples will be identified by unique sample codes. 
 
Blood, urine, and cerebral spinal fluid samples will be collected for determination of levels of 
GSH cycle markers. Additional information about the collection, handling, storage, and 
shipment of the GSH cycle marker samples will be provided separately prior to start of the study. 
 
F. 
Efficacy Evaluations 
F1. 
Glutathione Cycle Biomarkers 
 
Blood, urine, and CNS levels of oxidized and reduced GSH as well as GSH metabolites will be 
used to evaluate EPI-589 target engagement and ability to correct a key biochemical aspect of 
disease pathology. 
 
F2. 
Parkinson’s Disease Rating (MDS-UPDRS) 
 
The MDS-UPDRS is a tool for monitoring the impact of PD, the degree of disability caused, and 
complications from treatment. Part I evaluates nonmotor experiences of daily living; Part II 
evaluates motor experiences of daily living; Part III is a motor examination and includes the 
Hoehn and Yahr scale; Part IV examines motor complications (e.g., motor fluctuations and 
dyskinesias). 
 
Several questions from Part I and all questions from Part II are designed to be amenable to a 
patient/caregiver questionnaire format; the remaining interview (Part I and Part III) and 


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examination (Part IV) are designed with the expectation they can be completed within 30 
minutes. Each item is measured on a five-point scale. 
 
F3. 
Non-motor Symptoms (NMSS) 
 
Non-motor symptoms are evaluated using the NMSS which is divided into 30 questions in 9 
different domains including such symptoms as dribbling saliva, constipation, depression, sleep 
disorders, apathy, hallucinations and dementia. Symptoms are quantified based on their severity 
(using a scale of 0 to 3) and frequency (using a scale of 0 to 4). The final cumulative scores are 
derived from adding up the product of the frequency score times severity score for each of the 30 
questions. 
 
F4. 
Parkinson’s Disease Questionnaire (PDQ-39) 
 
PDQ-39 is a self-administered questionnaire for patients with PD that has 39 questions relating 
to eight key areas of health and daily activities, including both motor and non-motor symptoms. 
It is scored on a scale of 0 to 100, with lower scores indicating better health, and high scores 
more severe symptoms. 
 
F5. 
EQ-5D 
 
EQ-5D is a questionnaire designed to provide measures of health-related quality of life states, 
consisting in five domains (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). 
 
F6. 
Montreal Cognitive Assessment (MoCA) 
 
MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive 
domains: attention and concentration, executive functions, memory, language, visuo- 
constructional skills, conceptual thinking, calculations, and orientation. Severity ranges are 
approximately: 26 to 30 normal; 18 to 26 mild cognitive impairment; 10-17 moderate cognitive 
impairment; < 10 severe cognitive impairment. 
 
F7. 
Beck Depression Inventory (BDI) 
 
The BDI is a self-reporting inventory that measures characteristic attitudes and symptoms of 
depression, including physical symptoms. Twenty-one questions have four responses each (rated 
0 to 3) with a total cumulative score scale ranging from 1-10 considered normal) > 40 (extreme 
depression). 
 
F8. 
Montgomery and Asberg Depression rating scale (MADRS) 
 
The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. 
Ten core symptoms and cognitive features are rated on a severity scale of 0 to 6. Higher scores 
indicate increasing depressive symptoms. 


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F9. 
Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
 
Timed motor tests are simple, objective, quantitative measures for the assessment of Parkinson’s 
disease. They include, in an on-medication and an off-medication state, timed recorded physical 
movements. 
 
 
 
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VII. STATISTICAL CONSIDERATIONS 
A. 
Statistical Analysis 
 
In this subject-controlled, open label study the incidence of drug related SAEs in addition to 
changes from baseline to Month 3 for disease-relevant peripheral and CNS biomarkers as well as 
clinical measures will be calculated for each subject. 
 
A1. 
Analysis Populations 
 
Demographic characteristics and baseline efficacy data will be presented and summarized by 
treatment group for all subjects in the efficacy intent to treat (EITT) population. Demographic 
information will also be summarized by treatment group for the Safety population. No formal 
statistical comparisons will be made for either the EITT or Safety populations. 
 
B. 
Efficacy Analysis 
B1. 
Efficacy Variables 
 
The efficacy variables in this study are: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Safety Analysis 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
Assessment of safety will include calculating the overall number of subjects (by absolute number 
and percentage) with a particular AE. Safety will also be evaluated through examining clinical 
laboratory data (including chemistry and hematology and coagulation information) and physical 
examination findings, including vital signs obtained throughout the course of the study. A 
medical monitor will provide study oversight. 


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D. 
Sample Size 
 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 PD drug-naïve 
subjects). Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker-responsive idiopathic PD subjects to achieve a higher number 
of subjects in whom we could understand the biochemical effects of the investigative drug and 
its potential clinical impact as assessed by the same study protocol and outcome metrics. 
 
 
 
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VIII. STUDY MEDICATION 
A. 
Description 
 
EPI-589 is presented as an immediate release film-coated tablet. Each tablet contains 250 mg of 
EPI-589 and the following compendial excipients: lactose, microcrystalline cellulose, 
polyvinylpyrrolidone, crospovidone and magnesium stearate. Each tablet is film-coated with 
Opadry® II yellow. The tablets are yellow-colored and oval-shaped with a total target weight of 
824 mg. The tablets are packaged at 28 tablets per bottle in high-density polyethylene (HDPE) 
pharmaceutical wide mouth containers, induction sealed, and closed with a child-resistant 
closure. Each container is labeled with appropriate product information meeting current 
regulatory requirements. 
 
B. 
Packaging 
B1. 
Labeling 
 
Each container is labeled with appropriate product information meeting current regulatory 
requirements, in compliance with 21 CRF 312.6. 
 
B2. 
Dosage Form 
 
The EPI-589 drug product will be provided in a 250-mg tablet formulation. 
 
B3. 
Dispensing 
 
Tablets are packaged in white round HPDE wide mouth containers. Each container holds 28 
tablets without desiccant. Each container is sealed with an induction seal held in place with a 
child-resistant closure. The packaged tablets are stored at controlled room temperature 20° to 
25°C (68° to 77°F). (See United States Pharmacopeia [USP]). 
 
C. 
Treatment Compliance and Adherence 
 
Study medication will be counted to assess compliance during each scheduled clinic visit. 
Subjects who take ≥ 80 percent of the prescribed doses and no more than 100 percent will be 
considered compliant. Subjects who fall outside the boundaries of these thresholds will be 
counseled and re-instructed on proper dosing procedures. Medication compliance will be 
recorded on the CRF for each visit after verification with subject-completed diary cards and 
returned used drug supply. 
 
D. 
Drug Accountability 
 
Dosing information will be captured on a subject Dosing Diary Form. This form is part of the 
source documentation and will be utilized as a source for the completion of CRFs associated 
with dosing and for reconciliation of study drug administered and returned to the study site for 
accounting and destruction. Adequate records of study drug receipt and disposition should be 


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maintained by pharmacy records of receipts, investigational drug orders, dispensing records, and 
disposition forms. The Study Monitor will also assess drug accountability and will 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 either be returned to the Sponsor or designee 
or destroyed per study site guidelines for destruction of investigational product immediately after 
drug accountability is performed by the study monitor. 
 
 
 
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IX. SAFETY MANAGEMENT 
A. 
Clinical Adverse Events 
 
Clinical AEs will be monitored throughout the study. All AEs, whether observed by the 
Investigator, reported by the subject, from clinically significant laboratory findings, or other 
means, will be recorded in the CRF. 
 
B. 
Adverse Event Reporting 
 
All SAEs will be reported to the IRB in accordance with the IRB policies and as detailed below. 
AEs that are not serious will be summarized in narrative or other format and submitted to the 
IRB at the time of continuing review. 
 
B1. 
Safety Guidance 
 
Based on the known clinical manifestations of Parkinson’s disease, we expect that many AEs 
could occur during the course of the trial that are well documented to occur as the results of the 
natural history of this disease. These include, but are not limited to worsening neuromuscular 
function, depression, decline in cognitive function, loss of vision and other ophthalmological 
symptoms, loss of coordination and loss of speech. 
 
As there are no data available regarding EPI-589 phototoxicity, investigators are to advise 
subjects to take measures to minimize exposure to ultraviolet (UV) light for the duration of the 
study and for one week after the last dose. 
 
Edison Pharmaceuticals 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, Edison Pharmaceuticals should be provided with a copy 
of any post-mortem findings, including histopathology. 
 
C. 
Definition of an Adverse Event 
C1. Adverse Event 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
The AE may be: 
1. A new illness 


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2. Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 
3. An effect of the study medication, including comparator 
4. A combination of 2 or more of these factors 
No causal relationship with the study medication or with the clinical study itself is implied by the 
use of the term “adverse event” or “AE”. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs. 
 
Adverse events fall into the categories “non-serious” and “serious”. 
 
C2. Definition of a Serious Adverse Event (SAE) 
 
An SAE is one that at any dose results in any of the following: 
1. Death; 
2. A life-threatening adverse drug experience; 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability/incapacity; or 
5. A congenital anomaly/birth defect. 
ICH guidance also recommends that important medical events that may or may not be 
immediately life-threatening or result in death or hospitalization should also be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the serious definition. 
 
The term ”life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE. It does not refer to an SAE which 
hypothetically might have caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether other AEs, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject, require intervention to prevent one of the other 
outcomes listed 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. 
 
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 
has received 
study drug, 
should discontinue dosing, complete all end-of-study procedures, and be 
followed to determine the outcome of the pregnancy; follow-up of the pregnancy, fetus, and 
child will continue for at least 8 weeks after delivery. While pregnancy itself is not considered an 


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AE or SAE, all pregnancies should be reported using the same process as for SAEs. Any 
pregnancy complications or an outcome other than a healthy, normal outcome will be recorded 
as an AE or SAE. 
 
Clarification on the difference in meaning between “severe” and “serious”: The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as “serious,” which is based on the outcome or 
action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
C3. Non-serious Adverse Event 
 
A non-serious AE is any AE not meeting the SAE criteria. 
 
C4. Definition of Relationship to Study Medication 
 
Association or relatedness to the study medication will be graded as either “probably”, 
“possibly”, or “unlikely”. Determination of relatedness includes: 
 
PROBABLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Abates upon discontinuation of the drug and reappears with re-introduction of the drug 
3. Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state 
POSSIBLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
UNLIKELY – The adverse event: 
1. Does not follow a reasonable temporal sequence from drug administration 
2. Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
C5. Definition of Severity 
 
All AEs will be graded if possible by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. The severity of AEs that cannot be graded by CTCAE v4.03 will be categorized 
as follows: 
 
Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy indicated. 


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Grade 2 – Moderate limitation in activity, some assistance may be needed; minimal noninvasive 
medical intervention/therapy indicated. 
 
Grade 3 – Severe limitation in activity, assistance usually required; medical intervention/therapy 
required; hospitalization or prolongation of hospitalization indicated; disabling. 
 
Grade 4 – Extreme limitation in activity, significant assistance required; urgent medical 
intervention/therapy required; life-threatening consequences. 
 
Grade 5 – Death 
 
C6. Definition of Unexpected Adverse Event 
 
Any AE, the specificity or severity of which is not consistent with those listed in the current 
investigator’s brochure is considered “unexpected.” 
 
C7. Notification of SAEs 
 
The Investigator is responsible for promptly notifying the IRB/IEC of all study on-site SAEs and 
other unanticipated problems related to research. 
 
External SAEs that are unexpected and related to the study intervention should be reported as 
they are received using the MedWatch or CIOMs form (as appropriate). 
 
SAEs (whether unexpected or expected AEs) must be documented on the designated SAE form. 
The SAE must be reported to the medical expert and appropriate Edison or Edison-assigned 
pharmacovigilance staff within 24 hours, according to regulatory, Sponsor, or ICH-E6 Good 
Clinical Practice, followed by the SAE form within two calendar days. The designated SAE form 
and the instructions are provided in the Investigator’s site file. 
 
The SAE contact information will be provided separately from the protocol. 
 
The Investigator and/or Medical Expert must also inform the Study Monitor and the Sponsor in 
all cases. Any SAEs must also be reported to the IRB/IEC. The Sponsor or designee will ensure 
that all legal reporting requirements are met. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and the 
study medication. 
 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up SAE forms. 
 
The instructions to sites for the completion of SAE reports give detailed guidance on the 
reporting of SAEs and AEs initially reported as non-serious that become serious. When a non- 


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serious event becomes serious, details must be forwarded immediately to the Medical expert and 
Edison or Edison-assigned pharmacovigilance staff first for assessment and then submitted to the 
Sponsor on the designated SAE form within 24 hours. 
 
All relevant information about suspected unexpected serious adverse reactions (SUSARs) that 
are fatal or life-threatening are to be recorded and reported to the relevant competent authorities. 
 
In the US, all fatal or life-threatening suspected unexpected serious adverse events assessed as 
possibly or probably related to study drug by the Sponsor must be reported to the FDA as soon as 
possible (i.e., by telephone or facsimile transmission), but no later than 7 calendar days after first 
knowledge by the Sponsor that a report qualifies as a suspected unexpected fatal or life- 
threatening reaction. All unexpected serious adverse events, other than fatal or life-threatening, 
assessed as possibly or probably related to study drug by the Sponsor must be reported to the 
FDA within 15 calendar days from the day the Sponsor determines that the information qualifies 
as a SUSAR. 
 
In the UK, the Sponsor or trial investigator must act immediately or at least within 24 hours after 
becoming aware of a SUSAR by informing the MHRA’s Clinical Trial Unit by telephone. The 
MHRA must then be informed in writing within 3 days of the incident. All SUSARs originating 
in the UK or originating outside the UK involving the same medicinal product are to be reported. 
Fatal or life-threatening SUSARs are to be reported as soon as possible, but no later than after 7 
days. Any additional relevant information must be sent within 8 days of the report. Non-fatal or 
non-life-threatening SUSARs are to be reported as soon as possible but no later than 15 days 
after becoming aware of the reaction. 
 
C8. 
Follow-up Report 
 
If an SAE has not resolved at the time of the initial report, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. All SAEs should be followed until either resolved or stable. 
 
D. 
Medical Emergencies 
 
In medical emergencies, the Investigator should use medical judgment and remove the subject 
from the immediate hazard. The Medical Expert and the IRB/ IEC must be notified regarding the 
type of emergency and course of action taken and the procedures for SAE reporting must be 
followed. 
 
D1. Emergency Sponsor Contact 
 
In emergency situations, the Investigator should contact the Medical Monitor: 
 


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D2. Emergency Treatment 
 
At present, the threshold and extent of clinical adverse effects are not known as only limited 
information is available in healthy volunteers. It is anticipated in the planned study that any 
effects will be minimal and laboratory measurements will detect study drug effects before they 
become clinically significant. 
 
 
 
 
 
 
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X. 
STUDY ADMINISTRATION 
A. 
Treatment Assignment Methods 
 
This is an open-label study. 
 
B. 
Data Collection and Management 
 
Monitoring and auditing procedures, developed or endorsed by Edison will be followed in order 
to comply with GCP guidelines. Direct access to on-site study documentation including all 
source data, documentation and medical records should be ensured. 
 
The study will be monitored by Edison. Throughout the course of the study, the Study Monitor 
will make frequent contact with the Investigator. This will include telephone calls and on-site 
visits. During the on-site visits, the completed CRF will be compared to the source 
documentation for completeness, accuracy and adherence to the protocol. As part of the data 
audit, source documents must be made available to the Study Monitor for review. The Study 
Monitor will also perform drug accountability checks and will review the Investigator study file 
to assure completeness of documentation in all respects of clinical study conduct. 
 
Upon completion of the study, the Study Monitor will arrange for a final review of the study 
files, after which the files should be secured for the appropriate time period. The Investigator, or 
appointed delegate, will meet with the Study Monitor during the on-site visits and will cooperate 
in providing the documents for inspection and responding to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of Edison or 
the regulatory agencies. 
 
US and other competent regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. Medical records and other 
study documents may be copied during audit or inspection provided that subject names are 
obliterated on the copies to ensure confidentiality. 
 
C. 
Data Quality Assurance 
 
As a final step in the data management process, a 100% audit will be performed on the key 
safety and critical efficacy parameters. In addition, a random subject sample (10%) will be 
selected in order to perform a partial audit of remaining data. The purpose of this audit is to 
detect systematic and random errors. Any errors found from this audit will be corrected and, if 
the error rate is greater than 1 error per 1,000 fields (0.001%), a systematic review of the 
database will be undertaken and corrections will be made to achieve an error rate of less than 
0.001%. 
 
AEs will be coded using MedDRA, version (14.3). Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary, March 2014. 


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D. 
Retention of Study Records 
 
The following records must be retained by the Investigator for a minimum of 2 years after the 
Sponsor has notified the FDA or other competent authority that investigations have been 
discontinued, or after the FDA or other competent authority has approved the new drug 
application. In accordance with European regulatory requirements (Directive 2005/28/EC and 
Annex 17 and 2001/83/EC and Annex1), the Sponsor may request retention for a longer period 
of time. 
1. Signed informed consent documents for all subjects 
2. Subject identification code list, screening log (if applicable), and enrollment log 
3. Record of all communications between the Investigator and the IRB/IEC 
4. Composition of the IRB/IEC or other applicable statement 
5. Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
6. List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in the 
study and their signatures 
7. Copies of CRFs and of documentation of corrections for all subjects 
8. Drug accountability records 
9. Record of any body fluids or tissue samples retained 
10. All other source documents (subject records, hospital records, laboratory records, etc.) 
11. All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. 
 
Normally, these records will be held in the Investigator's archives. If the Investigator is unable to 
meet this obligation, 
or 
must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 
E. 
Confidentiality 
 
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the Sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be told that representatives of the Sponsor, IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection and privacy laws, including the Health Insurance 
Portability and Accountability Act (HIPAA) Guidelines, and the General Data Protection 
Regulation (GDPR). 


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The Investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
F. 
Documentation of Study Results 
 
A CRF will be provided for each enrolled subject. 
 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the CRF. Details of CRF completion and correction will be 
explained to the Investigator. If the Investigator authorizes other persons to make entries in the 
CRF, the names, positions, signatures, and initials of these persons must be supplied to the 
Sponsor. 
 
The Investigator, or designated representative, should complete the CRF pages as soon as 
possible after information is collected, preferably on the same day that a study subject is seen for 
an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
 
By signing the completed CRFs, the Investigator or Subinvestigator attests to the accuracy, 
completeness, legibility, and timeliness of the data collected on the CRF and casebooks. 
 
The Sponsor will retain the originals of all CRFs. The Investigator will retain a copy of all 
completed CRF pages. 
 
G. 
Regulatory and Ethical Considerations 
G1. Risk Assessment 
 
Based on the safety results of Study EPI-589-14-01 as summarized in the Clinical Study Report, 
it is not foreseen that subjects will endure any risks greater than minimal at the 500-mg BID dose 
selected for this study. 
 
G2. Potential Benefits of Trial Participation 
 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 
benefit in subjects with PD. Therefore, we cannot assure that subjects will benefit from treatment 
with EPI-589. Potential benefits may manifest in a variety of ways, such as in disease-related 
parameters, functioning, and quality of life. 
 
G3. Risk-Benefit Assessment 
 
There are no effective and/or approved disease modifying treatments available for PD, although 
a number of clinical interventions are being researched. Based on disease mechanism, EPI-589 
mechanism of action and pre-clinical studies, EPI-589 may hold benefit for patients with PD. 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 


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benefit in subjects with PD. In order to further minimize risks, subjects will be closely monitored 
with a variety of safety measures. 
 
H. 
Informed Consent 
 
Before being enrolled in the clinical study, subjects must provide written consent to participate 
after the nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them. The Investigator will not undertake any measures specifically 
required only for the clinical study until valid consent has been obtained. 
 
An informed consent document that includes both information about the study and the consent 
form will be prepared and given to the subject. This document will contain all the elements 
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements 
required by local regulations and must be in a language understandable to the subject. Where 
required by local law, the person who informs the subject must be a physician. It should be 
signed and dated by all the parties concerned including the subject, legal guardian (where 
applicable), witness (where applicable) and the person obtaining the consent. 
 
A copy of the signed consent document must be given to the subject. The original signed consent 
document will be retained by the Investigator. 
 
The Investigator must inform the subject’s primary physician about the subject’s participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
 
 
 
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XI. PUBLICATION 
A. Use of Study Results 
 
All information concerning the product, as well as any matter concerning the operation of Edison 
(such as clinical indications for the drug, its formula, methods of manufacture, and other 
scientific data relating to it, that have been provided by Edison and are unpublished), are 
confidential and must remain the sole property of Edison. The Investigator will agree to use the 
information only for the purposes of carrying out this study and for no other purpose unless prior 
written permission from Edison is obtained. The Sponsor has full ownership of the CRFs 
completed as part of the study. 
 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by Edison. If necessary, the authorities will be notified 
of the Investigator's name, address, qualifications, and extent of involvement. 
 
This Study is part of a multicenter clinical research study. Accordingly, Sponsor will act as 
coordinator and referee with respect to publications of the data generated thereunder. Principal 
Investigator shall not publish or disclose any data, result or information with respect to any 
matters resulting from work performed under this Protocol while this Study is being conducted at 
other center/s. Only after the completion of this Study at all other centers, provision of the data to 
the FDA or EMA for review and comment, and publishing the combined data from all of the 
centers, may the Principal Investigator publish/present the individual results of the Study in 
accordance with this paragraph. 
 
Principal Investigator may publish provided, however, that no publication, abstract, 
announcement or disclosure (“Publication”) shall be made until the Principal Investigator 
submits to Sponsor any proposed Publication for Sponsor’s review. Sponsor shall have a period 
of sixty (60) days to review such Publication. If Sponsor determines during the review period 
that the Publication contains patentable subject matter, then the above sixty (60) days shall be 
extended to one hundred twenty (120) days in order to allow for the preparation of patent 
applications covering said patentable subject matter. Unless Sponsor approves in writing, no 
Publication may contain any Confidential Information (other than data and results generated 
under the Study). 
 
Without limiting the foregoing, Institution and Principal Investigator, and all other study 
investigators in other study institutions, shall give due regard to Sponsor’s legitimate interests, 
such as manuscript authorship, coordinating and maintaining the proprietary nature of 
submissions to health authorities, and coordinating with other ongoing studies in the same field, 
and agree to accept Sponsor’s reasonable comments and suggestions with respect to such 
Publications. 
 
If the Investigator is to be an author of a publication manuscript prepared by Edison, Edison will 
allow the Investigator or CRO 60 days for full review of the manuscript before publication. 


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XII. LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AR 
accumulation ratio 
BDI 
Beck Depression Inventory 
BID 
twice daily 
BSO 
L-buthionine-(S,R)-sulfoximine 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatinine kinase 
CNS 
central nervous system 
CoQ10 
Coenzyme Q 10 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DaT 
dopamine transporters 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EITT 
efficacy intent-to-treat 
EPDA 
European Parkinson’s Disease Association 
EU 
European Union 
%F 
percent fluctuation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GCRC 
good clinical research practice 
GDPR 
General Data Protection Regulation 
GSH 
glutathione 
GSSG 
glutathione disulfide 
HDPE 
high density polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HMPAO 
hexamethylpropylene amine oxime 
ICF 
informed consent form 
ICH 
International Committee on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 


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kg 
kilogram 
λz 
apparent terminal constant 
LFT 
liver function test 
MAD 
multiple ascending (oral) dose 
MADRS 
Montgomery and Asberg Depression rating scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale 
mg 
milligram 
mL 
milliliter 
MoCA 
Montreal Cognitive Assessment 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
MPV 
mean platelet volume 
mtDNA 
mitochondrial DNA 
N/A 
not applicable 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NF 
National Formulary 
nM 
nanomolar 
NMSS 
Non-motor Symptoms Scale 
NOAEL 
no observed adverse effect level 
NQ01 
NAD(P)H Quinone oxidoreductase 1 
OD 
once daily 
OTC 
over-the-counter 
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PO 
by mouth 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 
PVP 
polyvinylpyrrolidone 
QT 
interval between the start of the Q wave and the end of the T wave 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAD 
single ascending (oral) dose 
SAE 
serious adverse event 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
Tmax 
time to peak concentration 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
UV 
ultraviolet 


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Protocol EPI589- l 5-002 
Version: Amendment 2.0 
 
 
XIII. SIGNATURE OF SPONSOR 
 
A. Declaration of Sponsor 
 
This study protocol was subject to critical review and the information it contains is consistent 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP as described in 21 CFR parts 50, 54, 56, and 
312. 
 
The Investigator will be supplied with details of any significant or new findings on EPI-589, 
including AEs. 
 
 
 
Date: 0 J /\JVCJ 1 \Signature: 
 
Edison Phaimaceuticals, Inc. 
350 North Bernardo Ave 
Mountain View, CA 94043 


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XIV. REFERENCES 
 
Ashrafi G, Schlehe JS, LaVoie MJ, Schwartz TL. Mitophagy of damaged mitochondria occurs 
locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014; 1;206(5):655- 
70. 
 
Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces 
features of Parkinson's disease. Nat Neurosci. 2000; 3(12): 1301-1306. 
 
Dauer W and Przedborski S. Parkinson's disease: mechanisms and models, Neuron 2003; 39: 
889–909. 
 
de Lau LM and Breteler MM. Epidemology of Parkinson’s Disease. Lancet Neur.2006; 5: 525- 
35. 
 
EPDA-European Parkinson’s Disease Association. http://www.epda.eu.com/en/resources/life- 
with-parkinsons/part-1/prevalence-of-parkinsons-disease/ (consulted 04 December 2014). 
 
Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, et al. Biochemical and pathological 
characterization of Lrrk2. Ann Neurol. 2006: 59(2): 315-22. 
 
Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, 
environment and mitochondria. Parkinsonism Relat. Disord. 2003; 9 (Suppl 2): S59–S64. 
 
Holmay, MJ, Terpstra M, Coles LD, et al. N-acetylcysteine Boosts Brain and Blood Glutathione 
in Gaucher and Parkinson Diseases. Clin. Neuropharm. 2013; 36, 4: 103-106. 
 
Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, et al. Glutathione Depletion in PC12 Results in 
Selective Inhibition of Mitochondrial Complex I Activity. Implications for Parkinson’s disease. J 
Biol Chem. 2000; 25;275 (34): 26096-101. 
 
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product 
of meperidine-analog synthesis. Science. 1983; 219: 979–980. 
 
Lin MT and Beal FB. Mitochondrial dysfunction and oxidative stress in neurodegenerative 
diseases. Nature. 2006; 443: 787-795. 
 
Maarouf CL, Beach TG, Adler CH, Shill HA, Sabbagh MN, et al. Cerebrospinal fluid 
biomarkers of neuropathologically diagnosed Parkinson's disease subjects. Neurol Res. 2012; 
34:669–676. 
 
Mao P and Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and 
mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and 
therapeutics. Biochim. Biophys. Acta. 2011; 1812: 1359-1370. 


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Narendra, DP and Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and parkin in 
mitochondrial quality control. Antioxi. Redox Signal. 2011; 14: 1929-1938. 
 
The Parkinson’s Disease Foundation. http://www.pdf.org/en/parkinson_statistics (consulted 27 
April 2015). 
 
Pinto M, Pickrell AM, Moraes CT. Regional susceptibilities to mitochondrial dysfunctions in the 
CNS. Biol. Chem. 2012; 393: 275-281. 
 
Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, et al. Transition metals, ferritin, 
glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 1989; Feb;52(2): 515-20. 
 
Winklhofer KF and Haass C. Mytochondrial dysfunction in Parkinson’s disease. Biochimica et 
Biophysica Acta. 2010; 1802: 29-44. 
 
Zhu X, Babar A, Siedlak SL, Yang Q, Ito G, et al. LRRK2 in Parkinson's disease and dementia 
with Lewy bodies. Mol Neurodegener. 2006;1:17. 


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Summary of Changes 
Amendment 2.0 
EPI589-15-002 
A Phase 2A Safety and Biomarker Study of EPI-589 
in Mitochondrial Subtype and Idiopathic Parkinson’s 
Disease Subjects 
 
 
 
 
Protocol Number 
EPI589-15-002 
Original Protocol Date 
27 April 2015 
Amendment 1.0 Date 
09 September 2015 
Amendment 2.0 Date 
04 January 2016 
Study Sponsor 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Sponsor’s Representative 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
 
 
 
 
 
 
 
The information contained in this document is confidential and will not be disclosed to others without written authorization from Edison 
Pharmaceuticals, except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered or 
for discussions with local regulatory authorities, Ethics Committee/Investigational Review Boards, or people participating in the conduct of 
the study. 


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1. KEY CHANGES TO THE PROTOCOL 
 
Amendment 2.0 provides the following changes and their rationales: 
 
Change 
Rationale 
Numerically indicated the ± day range of study 
drug administration 
To clarify study drug administration duration 
Additional detail for adaptive design rationale 
To provide additional details on the purpose of 
and criteria for adaptive design component of 
protocol 
Added examples of contraception 
To provide more specific guidelines for 
methods of contraception 
Added a post-treatment follow-up visit 
To specify post-treatment follow-up and its 
time window to allow for assessment for 
events following discontinuation of study drug 
Added details of study withdrawal criteria 
To provide specific details for subject 
withdrawal from the study 
Added warning about possible drug-associated 
phototoxicity since no data are yet available 
To provide a warning of a potential side effect 
which has yet to be fully evaluated in 
preclinical studies 
 
2. DESCRIPTION OF CHANGES TO THE PROTOCOL 
 
Changes to the protocol by section appear in the table below. Administrative and editorial 
clarifications, corrections or adjustments may not be individually identified. 
 
In this summary document, bold italic font indicates additions to existing text, and strikethrough 
font indicates deleted text. The actual amended protocol does not include bold or strikethrough 
font to indicate changes. 
 
Protocol Section 
Modification 
Synopsis 
Study design 
Open-label study with 30-day run-in phase and adaptive design component to include 
more subjects if deemed appropriate by investigators. 
Synopsis 
Planned number of subjects 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 drug- 
naïve idiopathic PD subjects). (Adaptive design component allows enrollment of up 
to 20 additional subjects with idiopathic PD to try to achieve a total of 20 subjects 
that have a biomarker response to EPI-589.) 
Synopsis 
Study duration 
3 months (85 days ± 3 days) of study treatment preceded by a 1-month baseline 
parameter run-in period. 
Synopsis; 
Section IV.D1 
Inclusion criteria 
3. Sexually active fertile subjects and their partners must agree to use medically 
accepted methods of contraception (e.g., hormonal methods, including oral, 


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EPI-589 
Version: Amendment 2.0 
Confidential 
Edison Pharmaceuticals Inc. 
Page 3 of 5 
 
 
 
subcutaneous and intrauterine; barrier methods, including 
condom, 
condom, or diaphragm with spermicidal gel) during the course of the study and for 
3 months after the last dose of study treatment.Agreement to use contraception if 
within reproductive years 
Synopsis 
Treatment 
EPI-589 will then be administered for up to 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. Post-treatment follow-up will be at 
least 10 days and up to 30 days after last dose. 
Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker responsive idiopathic PD subjects. 
I. Schedule of 
Assessments and 
Dosing Schedule 
Month 3 
End of StudyTreatment Visit 
Post-Treatment Follow-up 
Day 85 
(± 3 days) 
Up to 30 Days after Last Dosee 
AE/SAE assessmentd 
e 
Concomitant medications 
assessment 
e 
Post-Treatment 
Assessmentse 
e 
e AE/SAE and concomitant medication assessments conducted by telephone at least 10 days after 
last dose. Additional assessments to be determined at Investigator discretion. 
Dosing Schedule 
Month 3 
Post-Treatment 
IV.A 
EPI-589 will then be administered for up to 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. 
Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker responsive idiopathic PD subjects. Given that the 
investigational drug targets an enzyme key to glutathione synthesis and that 
glutathione depletion has been found to be associated with PD, we are seeking to 
determine the safety and potential biochemical benefit of EPI-589 in PD subjects 
as assessed by glutathione cycle biomarkers. If we determine that there are a subset 
of subjects with normal levels of glutathione who do not demonstrate biochemical 
changes following drug administration, and a subset of subjects with low levels of 
reduced glutathione who do respond to drug treatment, we would seek to enroll 
additional idiopathic PD subjects with low glutathione levels to achieve a higher 
number of subjects in whom we could understand the biochemical effects of the 
investigative drug and its potential clinical impact as assessed by the study outcome 
metrics. EPI-589 will be administered for up to 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. 
IV.A5 
A5. End of StudyTreatment 
End of study treatment data will be collected at the last study visit Day 85 (± 3 days). 
AEs reported as ongoing at Day 85 (± 3 days), and/or any concomitant medications 
associated with such events 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. 
IV.A6 
A6. Post-Treatment Follow-up 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose: 
AE/SAE and concomitant medication assessments conducted by telephone. 
Additional assessments to be determined at Investigator discretion. 


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IV.C1 
EPI-589 will then be administered for 3 months (85 days ± 3 days) unless 
discontinued for safety or tolerability issues. A post-treatment follow-up will be 
conducted up to 30 days after last dose. 
IV.C2 
Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker responsive idiopathic PD subjects to achieve a 
higher number of subjects in whom we could understand the biochemical effects of 
the investigative drug and its potential clinical impact as assessed by the same study 
protocol and outcome metrics. 
V.B 
End of Studytreatment assessments will be conducted at the Month 3 study visit. 
Pharmacokinetic sampling takes place at Month 1 and Month 3. 
V.C 
C. End of StudyTreatment Visit 
End of Study treatment visit takes place at Month 3 (Day 85 ± 3 days) and includes 
the assessments listed in Section VB2 Study Visit Assessments. 
V.D 
D. Post-Treatment Follow-up 
Post-Treatment Follow-up will be at least 10 days and up to 30 days after last dose, 
with AE/SAE and concomitant medication assessments conducted by telephone. 
Additional assessments to be determined at Investigator discretion. 
V.H 
H. Subject Withdrawals 
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.Subjects may be withdrawn from the study at any time for reasons 
including the followingThe 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 in the Investigator’s opinion, continuation in the study would be 
detrimental to the subject’s well being a subject experiences a serious or 
severe adverse event that is deemed related to treatment with EPI-589 and 
in the Investigator’s or the Sponsor’s medical judgment continuation of 
treatment would be detrimental to the subject 
2. At the specific request of the Sponsor (or designee) 
3. At the specific request of a regulatory agency for termination of treatment 
of an individual subject or all subjects under the protocol 
4. Subject participation in another clinical study using an investigational 
agent or investigational medical device 
5. Use of prohibited medications such as vitamins E and C beyond the 
recommended daily allowance; nortriptyline or fluvoxamine; and, for 
idiopathic subjects, MAO inhibitors, amantadine or other drugs prescribed 
for core symptoms of Parkinson’s disease 
6. Refusal of sexually active fertile subjects (excluding subjects who have 
been sterilized) to use medically accepted methods of contraception 


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7. If a subject becomes pregnant. 
8. Significant noncompliance with the protocol in the opinion of the 
Investigator or the SponsorAdditional protocol specific reasons 
VII.D 
Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker-responsive idiopathic PD subjects to achieve a 
higher number of subjects in whom we could understand the biochemical effects of 
the investigative drug and its potential clinical impact as assessed by the same study 
protocol and outcome metrics. 
IX.B1 
These include, but are not limited to worsening neuromuscular function, depression, 
decline in cognitive function, loss of vision and other ophthalmological symptoms, 
loss of coordination and loss of speech. 
As there are no data available regarding EPI-589 phototoxicity, investigators are to 
advise subjects to take measures to minimize exposure to ultraviolet (UV) light for 
the duration of the study and for one week after the last dose. 
Edison Pharmaceuticals may request that the Investigator perform or arrange for the 
conduct of supplemental measurements and/or evaluations. 
IX.C2 
If a subject is found to be pregnant after 
has received study drug, 
should 
discontinue dosing, complete all end-of-study procedures, and be followed to 
determine the outcome of the pregnancy;. Generally, follow-up of the pregnancy, 
fetus, and child will be continue no longer than 6 tofor at least 8 weeks following 
the estimated delivery date. While pregnancy itself is not considered an AE or SAE, 
all pregnancies should be reported using the same process as for SAEs. 
XII 
UV 
ultraviolet 
 
 
 
End of Document 
#### 


 
 
 
 
 
 
EPI589-15-002 
A Phase 2A Safety 
and Biomarker Study of 
EPI-589 in Mitochondrial 
Subtype and Idiopathic 
Parkinson’s Disease Subjects 
 
Original Protocol: 
27 April 2015 
Protocol Amendment 1.0: 
09 September 2015 
 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
 
The information contained in this document is confidential and will not be disclosed to others without 
written authorization from Edison, except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the study. 


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Protocol EPI589-15-002 
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Table of Contents 
PROTOCOL SYNOPSIS ........................................................................................................ 6 
I. SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE ................................ 11 
II. INTRODUCTION ........................................................................................................... 12 
A. Background Information and Rationale................................................................... 12 
B. Rationale for the Study of EPI-589 in Parkinson’s Disease .................................... 13 
C. Name and Description of Investigational Product ................................................... 13 
D. Findings from Non-Clinical and Clinical Studies .................................................... 14 
D1. Non-Clinical Studies .................................................................................................. 14 
D2. Clinical Studies ........................................................................................................... 16 
E. Human Pharmacokinetics ............................................................................................ 16 
F. 
Clinical Study .............................................................................................................. 17 
G. Selection of Drugs and Dosages ................................................................................. 17 
H. Compliance Statement ................................................................................................ 17 
I. 
Relevant Literature and Data .................................................................................... 17 
III. STUDY OBJECTIVES ................................................................................................... 18 
A. Primary Objective ...................................................................................................... 18 
B. Secondary Objectives .................................................................................................. 18 
IV. INVESTIGATIONAL PLAN ......................................................................................... 19 
A. General Schema of Study Design .............................................................................. 19 
A1. Screening Phase ......................................................................................................... 19 
A2. 30-Day Run-in Phase ................................................................................................. 19 
A3. Baseline ...................................................................................................................... 19 
A4. Treatment Phase ........................................................................................................ 19 
A5. End of Study ............................................................................................................... 19 
B. Randomization and Blinding ..................................................................................... 20 
C. Study Duration, Enrollment and Number of Sites .................................................. 20 
C1. Duration of Subject Treatment ................................................................................... 20 
C2. Total Number of Study Sites/Total Number of Subjects Projected ............................ 20 
D. Study Population ......................................................................................................... 20 
D1. Inclusion Criteria ....................................................................................................... 20 
D2. Exclusion Criteria ...................................................................................................... 21 


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V. STUDY PROCEDURES ................................................................................................. 22 
A. Screening Visit ............................................................................................................ 22 
A1. Run-in Assessments ..................................................................................................... 22 
B. Treatment Phase ......................................................................................................... 22 
B1. Baseline Assessments .................................................................................................. 23 
B2. Study Visit Assessments .............................................................................................. 23 
B3. Pharmacokinetics ....................................................................................................... 24 
B4. Early Termination Study Visit .................................................................................... 24 
C. End of Study Visit ....................................................................................................... 24 
D. Unscheduled Visits ...................................................................................................... 25 
E. Concomitant Medication ............................................................................................ 25 
F. 
Prohibited Medications .............................................................................................. 25 
G. Subject Withdrawals .................................................................................................. 25 
VI. STUDY ENDPOINTS AND EVALUATIONS .............................................................. 27 
A. Primary Endpoint ....................................................................................................... 27 
B. Secondary Endpoints (Efficacy) ............................................................................... 27 
C. Secondary Endpoints (Safety) ................................................................................... 27 
D. Screening and Baseline Evaluation ............................................................................ 27 
D1. Physical Examination................................................................................................. 27 
D2. Height and Weight ..................................................................................................... 28 
D3. Laboratory Evaluations ............................................................................................. 28 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) .................................................... 29 
E. Sample Collection Procedures, Bioanalytical Methods and Sample Shipment .... 29 
F. 
Efficacy Evaluations ................................................................................................... 29 
F1. Glutathione Cycle Biomarkers ................................................................................... 29 
F2. Parkinson’s Disease Rating (MDS-UPDRS) ............................................................. 29 
F3. Non-motor Symptoms (NMSS) ................................................................................... 30 
F4. Parkinson’s Disease Questionnaire (PDQ-39) ......................................................... 30 
F5. EQ-5D ........................................................................................................................ 30 
F6. Montreal Cognitive Assessment (MoCA) ................................................................... 30 
F7. Beck Depression Inventory (BDI) .............................................................................. 30 
F8. Montgomery and Asberg Depression rating scale (MADRS) .................................... 30 


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F9. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) ........... 31 
VII. STATISTICAL CONSIDERATIONS ........................................................................... 32 
A. Statistical Analysis ...................................................................................................... 32 
A1. Analysis Populations ................................................................................................... 32 
B. Efficacy Analysis ......................................................................................................... 32 
B1. Efficacy Variables ...................................................................................................... 32 
C. Safety Analysis ............................................................................................................ 32 
D. Sample Size .................................................................................................................. 33 
VIII. 
STUDY MEDICATION ........................................................................................... 34 
A. Description ................................................................................................................... 34 
B. Packaging .................................................................................................................... 34 
B1. Labeling ..................................................................................................................... 34 
B2. Dosage Form .............................................................................................................. 34 
B3. Dispensing.................................................................................................................. 34 
C. Treatment Compliance and Adherence .................................................................... 34 
D. Drug Accountability ................................................................................................... 34 
IX. SAFETY MANAGEMENT ............................................................................................ 36 
A. Clinical Adverse Events ............................................................................................. 36 
B. Adverse Event Reporting ........................................................................................... 36 
B1. Safety Guidance ......................................................................................................... 36 
C. Definition of an Adverse Event .................................................................................. 36 
C1. Adverse Event ............................................................................................................. 36 
C2. Definition of a Serious Adverse Event (SAE) ............................................................. 37 
C3. Non-serious Adverse Event ........................................................................................ 38 
C4. Definition of Relationship to Study Medication .......................................................... 38 
C5. Definition of Severity ................................................................................................. 38 
C6. Definition of Unexpected Adverse Event .................................................................... 39 
C7. Notification of SAEs ................................................................................................... 39 
C8. Follow-up Report ....................................................................................................... 40 
D. Medical Emergencies .................................................................................................. 40 
D1. Emergency Sponsor Contact ...................................................................................... 40 
D2. Emergency Treatment ................................................................................................. 40 


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X. STUDY ADMINISTRATION ........................................................................................ 41 
A. Treatment Assignment Methods ............................................................................... 41 
B. Data Collection and Management .............................................................................. 41 
C. Data Quality Assurance ............................................................................................. 41 
D. Retention of Study Records ....................................................................................... 42 
E. Confidentiality ............................................................................................................. 42 
F. 
Documentation of Study Results ............................................................................... 43 
G. Regulatory and Ethical Considerations .................................................................... 43 
G1. Risk Assessment .......................................................................................................... 43 
G2. Potential Benefits of Trial Participation .................................................................... 43 
G3. Risk-Benefit Assessment ............................................................................................. 43 
H. Informed Consent ....................................................................................................... 44 
XI. PUBLICATION ............................................................................................................... 45 
A. Use of Study Results ................................................................................................... 45 
XII. LIST OF ABBREVIATIONS ......................................................................................... 46 
XIII. 
SIGNATURE OF SPONSOR ................................................................................. 48 
A. Declaration of Sponsor ................................................................................................ 48 
XIV. 
REFERENCES ........................................................................................................ 49 
 
 
 
 
 
Space intentionally left blank 


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PROTOCOL SYNOPSIS 
Title of study 
A Phase 2A Safety and Biomarker Study of EPI-589 in 
Mitochondrial Subtype and Idiopathic Parkinson’s Disease 
Subjects 
Protocol number 
EPI589-15-002 
IND number 
126,795 
EudraCT number 
2015-001786-10 
Original Protocol Date 
27 April 2015 
Protocol Amendment 
09 September 2015 
1.0 Date 
Investigative Drug 
EPI-589 
Study Sponsor 
Edison Pharmaceuticals Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Investigators and 
• 
Investigative Sites 
USA 
• 
UK 
Study population 
Approximately 40 subjects with Parkinson’s disease (PD) 
including 20 subjects with genetically-defined subtypes 
Rationale for Study 
Mitochondrial pathophysiology 
It is now well appreciated that defects in mitochondrial function 
contribute to the pathophysiology of PD both in subjects with 
defined genetic defects as well as those with idiopathic forms of 
the disease. 
High morbidity 
Despite the available therapies for symptomatic relief, PD 
remains a highly morbid disease. There are no approved 
treatments for PD capable of modifying disease progression. 
Pre-clinical efficacy data 
EPI-589 is a redox active molecule that has demonstrated 
potency (EC50 < 100nM) and efficacy (>80% rescue from 
oxidative stress-induced cell death) in cells derived from 
patients diagnosed with idiopathic and familial PD subtypes 


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including PINK1, parkin and LRRK2. 
Study objectives 
Primary Objective 
To evaluate the effects of EPI-589 on safety as assessed by 
occurrence of drug-related serious adverse events in subjects 
with PD. 
Secondary Objectives 
To evaluate the effects of EPI-589 in subjects with PD on: 
1. Glutathione cycle biomarkers as measured in blood, 
cerebral spinal fluid, and urine 
2. Clinical disease state as assessed by the Movement 
Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor 
Symptoms Scale (NMSS), PDQ-39 and EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive 
Assessment (MoCA) and 
5. Mood as assessed by the Beck Depression Inventory 
(BDI) and the Montgomery and Asberg Depression 
rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 
Study design 
Open-label study with 30-day run-in phase and adaptive design 
component to include more subjects if deemed appropriate by 
investigators. 
Planned number of 
subjects 
Approximately 40 subjects (20 with genetically-defined 
subtypes of PD and 20 drug-naïve idiopathic PD subjects). 
Study duration 
3 months of study treatment preceded by a 1-month baseline 
parameter run-in period. 
Test product, mode of 
administration, and 
dose 
Test product 
EPI-589 in a tablet formulation at a strength of 250 mg 
Mode of Administration 
Oral with meal 
Dose 
EPI-589 500-mg BID 
Reference therapy, 
dose, and mode of 
None 


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administration 
Safety monitoring 
Clinical 
1. Physical exam and vital signs 
2. Evaluation of adverse events 
3. 12-lead Electrocardiogram 
4. Columbia Suicide Severity Rating Scale (C-SSRS) 
Laboratory 
1. Routine serum chemistries 
2. Routine hematology tests and coagulation tests 
Inclusion criteria 
1. Hoehn and Yahr stage ≤ 2.5 
2. Ambulatory with or without assistance 
3. Agreement to use contraception if within reproductive 
years 
4. Willingness and ability to comply with study procedures 
5. Stable regimen of dietary supplements for 30 days prior 
to enrollment 
6. Abstention from use of other investigative or non- 
approved drugs for the duration of the trial 
For Idiopathic Subjects 
7. For idiopathic subjects: a diagnosis of early idiopathic 
PD confirmed by the presence of bradykinesia plus one 
or both of the following symptoms: rigidity or resting 
tremor; and with an abnormal DaTscan consistent with a 
dopaminergic deficit 
8. For idiopathic subjects: must not yet require 
symptomatic medications for PD and not expected to 
require such treatment before the end of the study 
9. For idiopathic subjects: age 40 to 75 years 
10. For idiopathic subjects: within 5 years of diagnosis of 
Parkinson’s disease 
For Genetic Subtype Subjects 
11. For genetic subtype subjects: a confirmed diagnosis of 
PD plus a genetic diagnosis consistent with PD, 
specifically PINK1, parkin, LARK2 or other 
mitochondrial genetic subtype 
12. For genetic subtype subjects: age 21 to 75 years 


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13. For genetic subtype subjects: stable medication regimen 
of PD drugs for 30 days (except 60 days for rasagiline) 
prior to enrollment 
Exclusion criteria 
1. Allergy to EPI-589 or other components of the EPI-589 
tablet formulation 
2. Use of antioxidant supplements, specifically vitamins E 
and C beyond the recommended daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic 
disease that will confound the assessment of effect of 
study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 
3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times 
normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of 
study in a trial of a device, drug or other therapy for PD 
For Idiopathic Subjects 
16. For idiopathic subjects: use of any MAO inhibitors, 
amantadine or other drugs prescribed for core symptoms 
of Parkinson’s disease for idiopathic subjects 
17. For idiopathic subjects: use of nortriptyline or 
fluvoxamine 60 days prior to enrollment 
Treatment 
Following study enrollment, baseline assessments will be 
performed. Subjects will participate in a 30-day run-in phase to 
establish biomarker and clinical baseline measurements. 
EPI-589 will then be administered for up to 3 months unless 
discontinued for safety or tolerability issues. Under an adaptive 


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design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker responsive idiopathic PD 
subjects. 
Efficacy variables 
1. Blood-based glutathione biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. Non-motor Symptoms Scale (NMSS) 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. Beck Depression Inventory (BDI) 
10. Montgomery & Asberg Depression rating scale 
(MADRS) 
11. Timed motor tests in ON and OFF state (for subjects on 
dopamine therapy) 
12. Pharmacokinetics 
Safety variables 
Clinical 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
4. C-SSRS 
5. Laboratory 
6. Routine serum chemistries with liver function tests 
7. Routine hematology tests with coagulation tests 
Statistical 
Considerations 
Data Analysis 
This is a within-subject, controlled open-label study seeking to 
determine the safety and tolerability of EPI-589 in patients with 
PD as well as to determine if EPI-589 can alter the biochemical 
signature of PD as assessed by peripheral blood biomarkers, 
CNS biomarkers, brain imaging biomarkers, and urine 
biomarker analysis. In addition, data on a number of disease- 
relevant clinical measures will be collected. 


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I. 
SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE 
 
Tests 
-2 to -1 Months 
Day 0 
Month 1 
Month 2 
Month 3 
End of Study 
Screening 
Run-in 
(± 30 days) 
Baseline 
Day 29 
(± 3 days) 
Day 57d 
(± 3 days) 
Day 85 
(± 3 days) 
Informed consent 
 
Inclusion/Exclusion criteria 
 
Past Medical history 
 
Previous genetic testing review 
 
Physical exam & Vital signs 
 
 
 
 
Height & weight 
 
a 
 
 
12-lead ECG 
 
a 
 
 
Hematology (including coagulation 
panel) 
 
a 
 
 
Serum Chemistry 
 
a 
 
 
Pregnancy testb 
 
 
 
 
C-SSRS 
 
 
 
Montreal Cognitive Assessment 
 
 
DaTscan 
 
Revised Hamilton Rating Scale for 
Depression 
 
Subject enrolls in study 
X 
Blood-based glutathione cycle 
biomarkers 
 
 
 
 
Lumbar puncture (CNS biomarkers) 
 
 
Urine-based biomarkers 
 
 
 
 
MDS-UPDRS 
 
 
 
 
Timed motor tests (for subjects on 
dopamine therapy) 
 
 
 
NMSS, PDQ-39, EQ-5D 
 
 
BDI, MADRS 
 
 
Drug plasma concentrationc 
c 
c 
AE/SAE assessmentd 
 
d 
d 
Concomitant medications assessment 
 
 
 
 
d 
d 
a. 
Screening values can be used if done within one month of baseline. 
b. Female subjects of childbearing potential must have a negative pregnancy test. 
c. 
Full plasma concentration profile will be obtained at Time = 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours after dosing from 
the first 10 subjects to complete 1 month of therapy at each site. 
d. Month 2 assessments can be done by telephone. Any new AEs and associated concomitant medications reported at 
Month 3 must be followed for 30 days; this follow up may be conducted by telephone. 
Dosing Schedule 
Month 1 
Month 2 
Month 3 
EPI-589 500-mg BID 
 
 
 


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II. 
INTRODUCTION 
A. 
Background Information and Rationale 
 
Parkinson’s disease (PD) is a highly morbid neurodegenerative movement disorder that has a 
number of neuromuscular, cognitive and neuropsychiatric manifestations as well as non- 
neurological symptoms. PD is the second most common neurodegenerative disorder with an 
estimated prevalence of 6.3 million people worldwide (EPDA). 
 
PD has long been considered a non-genetic (idiopathic) disease; however, about 5% of patients 
have an identifiable mutation. Disease onset typically occurs after age 50, however, in a subset of 
patients, disease onset can occur at a younger age. The primary motor symptoms result from 
death of dopamine-producing cells in the pars compacta region of the substantia nigra. However, 
the mechanisms underlying this cell death and disease pathology remain poorly understood. 
There is no approved treatment for PD capable of modifying disease progression. Current 
therapies partially address disease motor symptoms through levodopa or dopamine agonists or 
other agents, and other disease symptoms (e.g. neuropsychiatric symptoms), but disability tends 
to increase over time despite these treatments. 
 
The association of PD with mitochondrial pathology and high levels of oxidative stress are well 
established. Increased levels of oxidative stress have been consistently measured in post-mortem 
specimens from PD patients (Maarouf 2012, Reale 2012). The occurrence of PD-like symptoms 
in heroin addicts exposed to MPTP in the 1980s established a first link between PD and 
mitochondrial injury (Langston 1983, Dauer and Przedborski 2003). MPTP inhibits complex 1 of 
the mitochondrial respiratory chain and induces degeneration of dopaminergic cells through 
oxidative stress-mediated injury. The link between mitochondrial injury and PD was further 
strengthened by the induction of PD symptoms following exposure to another neurotoxic 
complex 1 inhibitor, rotenone (Betarbet et al 2000, Greenamyre et al. 2003), which like MPTP 
has come to be used in pre-clinical testing for its phenotypic similarities to PD. 
 
Furthermore, the identification of genetic mutations such as PINK1, parkin, LRRK2 and others 
in mitochondrial genes in familial PD patients provided the strongest link between the 
mitochondria and PD (Winklhofer and Haass 2010). Normally these genes influence oxidative 
balance and provide neural protection of the dopaminergic neurons that are affected by PD. 
PINK1 and parkin are involved in protecting against oxidative stress (OS) and overabundant 
reactive oxygen species (ROS), and are implicated in cell morphology and dynamics, as well as 
in the preferential degradation of dysfunctional mitochondria or “mitophagy” (Ashrafi et al. 
2014). Mutant LRRK2 leads to the accumulation of misfolding intracellular protein 
accumulations, cell stress and apoptosis (Giasson et al. 2006, Zhu et al. 2006). 
 
The importance of oxidative stress in PD pathology is further substantiated by the measurement 
of decreased levels of reduced glutathione in the brains of patients with PD (Holmay et al. 2013). 
Glutathione levels are low at very early stages of PD and correlate with disease severity 
(Riederer et al. 1989), and experimental induction of glutathione depletion leads to mitochondrial 
complex I dysfunction (Jha et al, 2000;). Reduced glutathione is an essential intermediary 


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metabolite that serves as the primary native cellular antioxidant. In a state of high oxidative 
stress, elevated levels of ROS outstrip the supply of glutathione (GSH) resulting in depletion of 
GSH and ROS-mediated cell death. 
 
Given the important role of oxidative stress and mitochondrial pathology in PD, a redox-active 
therapy that could target key pathways in cellular OS response pathways may hold promise for 
the treatment of PD. 
 
B. 
Rationale for the Study of EPI-589 in Parkinson’s Disease 
 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 <100nM ) and efficacy 
(>80% rescue from oxidative stress-induced cell death) in cells derived from patients diagnosed 
with idiopathic and familial PD genetic subtypes including PINK1, parkin and LRRK2. 
In these cell-based assays, primary fibroblasts from patients (and control) were pre-incubated 
with and without test compound, then treated with L-buthionine-(S,R)-sulfoximine (BSO), a 
GSH synthesis inhibitor, to initiate depletion of cellular GSH. GSH depletion has been shown to 
lead to OS and disruption of calcium homeostasis resulting in loss of the mitochondrial 
membrane potential and cell death. Under these conditions, the control cells are resistant to the 
stress and the fibroblast cells from patients with disease indications die within 36 to 48 hours. 
Pretreatment of cells with EPI-589 prior to initiation of GSH depletion potently protected against 
oxidative stress-mediated cell death, with EC50 response concentrations of 16 to 52 nM. (Table 
1). 
Table 1: 
Cell Line Rescue with EPI-589 in Parkinson’s Disease Genetic Subtypes 
 
EPI-589 
EC50 (nM range) 
PINK1 
26-36 
LRRK2 
16-18 
parkin 
42-52 
 
C. 
Name and Description of Investigational Product 
The IUPAC name of EPI-589 is: 
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide. 
 
A common chemical name of EPI-589 is (R)-troloxamide quinone. EPI-589 is derived from 
resolved (R)-Trolox®, a derivative of vitamin E in the form of a pale yellow to yellow solid. The 
EPI-589 drug product will be provided in a 250-mg tablet formulation. 


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The Investigator will ensure that all study drugs are stored and dispensed in accordance with the 
Food and Drug Administration (FDA) and local regulations concerning the storage and 
administration of investigational drugs. 
 
D. 
Findings from Non-Clinical and Clinical Studies 
D1. Non-Clinical Studies 
 
EPI-589 is an orally available compound that has been demonstrated in vitro and in vivo to cross 
the blood-brain-barrier. In 28-day and 91-day repeat-dose toxicity studies in rat and cynomolgus 
monkey, the no observed adverse effect level (NOAEL) was 300 mg/kg/day, corresponding to 
combined mean Cmax values of 37,717 to 56,500 ng/mL (rat) and 14,300 to 16,417 ng/mL 
(monkey), and a combined mean area under the plasma concentration-time curve from time zero 
to the last measurable concentration (AUClast) value of 149,495 to 297,000 ng.h/mL (rat) and 
47,300 to 67,656 ng.h/mL (monkey) (Studies 1660-038, 1660-039, 1660-063, and 1660-064). 
 
A phase 1 clinical study demonstrated that healthy subjects administered 500 mg EPI-589 BID 
for 14 days showed a mean Cmax value of 1,890 ng/mL and a mean AUClast value of 5,240 
ng.h/mL (Study EPI589-14-01). These plasma concentrations are well below the mean exposure 
values in monkey associated with the NOAEL in the toxicity studies, corresponding to safety 
margins of approximately 7- to 8-fold for the mean Cmax and 9- to 12-fold for the mean AUC. 
 
During the 28-day repeat-dose toxicity studies, rat and monkey were exposed to up to 1,000 
mg/kg/day EPI-589 PO (Studies 1660-039 and 1660-038). The NOAEL for both studies was 300 
mg/kg/day. Rats exposed to 1,000 mg/kg/day exhibited adverse test-article related effects on 
hematology parameters consistent with hemolysis and bone marrow regeneration, mild to 
moderately enlarged spleens, and increased organ weights with some organs showing 
corresponding microscopic pathology. The majority of these findings were resolved following 
the 28-day recovery period. Monkeys exposed to 1,000 mg/kg/day showed significant test-article 
related morbundity that resulted in half the animals in the high dose group being euthanized on 
Days 3 and 4 and the remaining animals being euthanized on Day 9. These animals exhibited 
significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
values, and microscopic findings in the kidney, liver, skeletal muscle, heart, and lymphoid 
tissues. In several of the animals the primary cause of morbidity was determined to be test-article 
related renal tubular degeneration/necrosis. 
 
During the 91-day repeat-dose toxicity studies, rat and monkey were exposed to up to 300 
mg/kg/day EPI-589 PO (Studies 1660-063 and 1660-064). The NOAEL for the rat study was 300 
mg/kg/day and the no observed effect level (NOEL) for the monkey study was 300 mg/kg/day. 
rats exposed to 300 mg/kg/day and 
rats exposed to ≥ 100 mg/kg/day exhibited mild 
test-article related effects on hematology parameters consistent with hemolysis and bone marrow 
regeneration. These findings were not considered adverse. 
 
Development and reproductive toxicology studies were conducted in rat and rabbit at doses up to 
1,000 mg/kg/day EPI-589 PO (Studies 1660-069, 1660-067, and 1660-068). The NOAEL for 
reproductive toxicity in rat was demonstrated to be 1,000 mg/kg/day (1660-069). The NOAEL 


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for developmental toxicity in rat and rabbit during the embryofetal studies was deemed to be 300 
mg/kg/day (Studies 1660-067 and 1660-068). Rats exposed to 1,000 mg/kg/day exhibited 
decreased maternal body weights, decreased food consumption, and decreased fetal body 
weights. There was no teratogenic potential in rat at doses up to 1,000 mg/kg/day. Rabbits 
exposed to 1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, decreased number of viable fetuses, decreased litter size, increased 
postimplantation loss, increased resorptions (early and late), and increased fetal skeletal 
malformations. The margin of exposure between healthy humans exposed to 500 mg BID EPI- 
589 (relevant clinical dose) for 14 days (Study EPI589-14-01) and rabbits exposed to 1,000 and 
300 mg/kg/day EPI-589 is approximately 179- to 236-fold and 47- to 50-fold, respectively. 
Based on these data, EPI-589 is not anticipated to increase the risk of adverse developmental or 
reproductive outcomes in humans when used in accordance with dosing information. 
 
EPI-589 was negative for mutagenic response in the in vitro Ames bacterial reverse mutation 
assay (Study AD58AS.502ICH.BTL); equivocal for the induction of structural and negative for 
the induction of numerical chromosomal aberrations in the in vitro chromosome aberration assay 
in Chinese hamster ovary (CHO) cells (Study AD58AS.331ICH.BTL); and negative in the in 
vivo micronucleus assay in rat (Study AD58AS.125012ICH.BTL). These data indicate a low 
clinical mutagenicity risk. 
 
Primary pharmacodynamics studies demonstrated that EPI-589 is a potent rescue agent in 
cellular models of diseases of energy metabolism and oxidative stress. In vitro cellular models 
utilizing primary human fibroblasts from patients with ALS, Parkinson’s disease and other 
diseases characterized by high levels of oxidative stress, or striatal cells derived from mouse 
models of Huntingdon’s disease were used to assess the potential of EPI-589 to mitigate the 
harmful effects of oxidative stress (Studies EPI-BA-000216, EPI-BA-000363, and EPI-BA- 
000362). Pretreatment of patient cells with EPI-589 potently protected against oxidative stress- 
mediated cell death in a concentration dependent manner. Furthermore, EPI-589 normalized 3- 
nitrosotyrosine (3NT) levels, a biomarker of oxidative stress, and increased glutathione levels in 
mouse striatal cells under oxidative stress conditions. 
 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, EPI-589 did not 
significantly affect off-target molecular targets (Study EPI-BA-159). In safety pharmacology 
studies, EPI-589 did not significantly affect ion channel current in the hERG assay (Study 
130719.FEK); did not affect ECG parameters during the 28-day and 3-month repeat-dose 
toxicology studies in monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for 
animals administered 1,000 mg/kg/day and up to Day 91 data collected for animals administered 
up to 300 mg/kg/day) (Studies 1660-038 and 1660-064); and did not change respiratory function 
or adversely impact neurobehavioral function in rat at doses up to 1,000 mg/kg (Studies 1660- 
051, 1660-050, and 1660-063). 
 
In single dose exposure PK studies, EPI-589 was absorbed rapidly in rat, dog, and monkey, with 
mean Tmax values ranging from .08 to 1 hour and mean T1/2 values ranging from 3.7 to 5.0 hours 
(Studies EPI-BA-53, EPI-BA-59, EPI-BA-72, and EPI-BA-302). EPI-589 does not significantly 
induce cytochrome P450 (CYP) enzymes and appears to be metabolized by reductases in the 


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liver cytosol and microsomal subcellular fractions and to a lesser extent by the family of CYP 
enzymes (Studies MC12M-0037 and MC14M-0018). 
 
EPI-589 exhibited weak direct inhibition of CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (both 
midazolam and testosterone as probe substrates) with estimated IC50 (µM) values and R values 
based on free plasma concentrations (shown in parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 34 
(1.21), and 53 (1.13), respectively (Study MC14M-0020)Based on these data, EPI-589 is not 
anticipated to increase the risk of adverse developmental or reproductive outcomes in humans 
when used in accordance with dosing information. 
 
D2. Clinical Studies 
 
Phase I Study EPI589-13-022 evaluated the pharmacokinetics, safety and tolerability of single 
ascending oral doses (SADs) of EPI-589 in healthy subjects and a preliminary evaluation of 
safety and tolerability data was performed. Sixteen AEs were reported in the 36 subjects who 
received administration of EPI-589. Ten subjects (27.8%) who received EPI-589 (and 2 subjects, 
20% on placebo) reported AEs that were assessed as related. All were mild and resolved during 
the study, with the exception of a common cold (1 subject) and cold sore (1 subject). None of the 
vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant change 
compared to baseline. From all preliminary data available from this SAD study it may be 
concluded that there is no objection to proceed with treatment with 50 mg, 100 mg, 250 mg or 
500 mg of EPI-589. 
 
Phase I Study EPI589-14-01 evaluated the pharmacokinetics, safety and tolerability of multiple 
ascending oral doses (MAD) of EPI-589 in healthy subjects, and an evaluation of safety and 
tolerability data was performed. No severe or serious adverse events were observed. Twenty-six 
subjects (65.0%) on EPI-589, and 8 subjects (80%) on placebo reported AEs. Twenty-four of 34 
AEs were considered by the Investigator to be related to EPI-589. Nineteen subjects (47.5%) on 
EPI-589, and 6 subjects (60%) on placebo reported AEs that were assessed as related. All 
adverse events were mild, except for 1 AE which was moderate (unrelated brain contusion). All 
AEs were resolved during the study, with the exception of one, which was a common cold. None 
of the vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant 
change compared to baseline. From all preliminary data available from the MAD study it may be 
concluded that there is no objection to proceed with treatment with 250-mg, or 500-mg doses of 
EPI-589. 
 
E. 
Human Pharmacokinetics 
 
EPI-589 was fast absorbed following oral administration in SAD Study EPI589-13-022. The 
median Cmax was attained approximately within 1 hour under fasted conditions after dosing. The 
median Tmax values were attained in 0.50 to 1.00 hours over the dose range of 50 to 1000 mg 
under fasted conditions and 3.01 hours at the 500 mg dose level under fed conditions. Mean half- 
life ranged from 5.55 to 10.7 hours over the dose range of 50 to 1000 mg under fasted conditions 
and 4.91 hours at the 500 mg dose level under fed conditions. Half-life was independent of the 
dose levels over the dose range of 50 to 1000 mg under fasted conditions. The rate of EPI-589 
absorption, as measured by Cmax, was decreased by 24.07% under fed conditions at the 500 mg 


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dose level. The extent of absorption as measured by AUCs (AUC0-t or AUC0-inf) was not affected 
under fed conditions in the 500 mg dose groups. 
 
In MAD study EPI589-14-01, EPI-589 was rapidly absorbed following oral administration and 
the median Cmax was attained within 1 hour (0.50 to 0.76 hours) under fasted conditions after 
single or multiple dosing among these five cohorts. The mean half-life of EPI-589 ranged from 
5.64 to 8.47 hours among these five cohorts. In general, the mean values of the time to peak 
concentration (Tmax), half-life (t½), apparent terminal constant (λz), accumulation ratio (AR), 
percent fluctuation (%F) and accumulation index (AI) of EPI-589 were similar among the five 
cohorts of various ages and smoking status. No significant effects of age or smoking on EPI-589 
pharmacokinetics were observed in this study. Dose proportionality existed in the exposures 
(AUC0-tau, Cmax, Cmin and Cavg) over the dose range of 250 to 500-mg BID EPI-589 under fasted 
conditions. 
 
F. 
Clinical Study 
 
EPI589-15-002: A Phase 2A Safety and Biomarker Study of EPI-589 in in Mitochondrial 
Subtype and Idiopathic Parkinson’s Disease Subjects. 
 
G. 
Selection of Drugs and Dosages 
 
The study drug in this trial is EPI-589: common chemical name (R)-troloxamide quinone. 
 
Each tablet contains 250 mg of EPI-589. The study dose is 500-mg BID, to be maintained in the 
absence of treatment-emergent toxicity. EPI-589 tablets must be taken with meals. 
 
H. 
Compliance Statement 
 
This study will be conducted in full accordance with all applicable research policies and 
procedures, the EU Clinical Trials Directive, all applicable EU and US federal and local laws 
and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312 and 314, and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonization (ICH). Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
will report AEs in accordance with local institutional policies and procedures and all EU and US 
federal requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the study. 
 
I. 
Relevant Literature and Data 
 
Literature references have been provided in Section XIV. Additional information can be found in 
the Investigator’s Brochure. 


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III. STUDY OBJECTIVES 
A. 
Primary Objective 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
B. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with PD on: 
1. Glutathione cycle biomarkers as measured in blood, cerebral spinal fluid, and urine 
2. Clinical disease state as assessed by the Movement Disorder Society-sponsored revision 
of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale (NMSS), PDQ-39 and 
EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment (MoCA) 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the Montgomery & 
Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
7. Hematology, blood chemistry, electrocardiogram 
 
 
 
 
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IV. INVESTIGATIONAL PLAN 
A. 
General Schema of Study Design 
 
Following study enrollment, baseline assessments will be performed. Subjects will participate in 
a 30-day run-in phase to establish biomarker and clinical baseline measurements. EPI-589 will 
then be administered for up to 3 months unless discontinued for safety or tolerability issues. 
 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. 
 
A1. 
Screening Phase 
 
Suitable candidates for the trial will receive a short overview of the study by the Investigator’s 
staff and, if interested, will undergo Screening. The Investigator will inform each prospective 
subject of the nature and details of the study, explain the potential risks and must obtain written 
informed consent from the subject or their legally authorized representative prior to performing 
any study related procedures. 
 
A2. 
30-Day Run-in Phase 
 
Once eligibility is confirmed, the subject will be enrolled in the study and the run-in scans, CNS, 
blood-based biomarker, urine-based biomarker and clinical measurements will be collected. 
 
A3. 
Baseline 
 
Baseline assessments, scans, blood-based biomarker, urine biomarker, and clinical measurements 
will be collected. 
 
A4. 
Treatment Phase 
 
EPI-589 dosing will start on Day 1. Subjects will self-administer EPI-589 at a dose of 500-mg 
BID. 
 
Blood-based biomarker, urine biomarker, and clinical measurements will be collected at Day 29 
(± 3 days) and Day 85 (± 3 days). 
 
A5. 
End of Study 
 
End of study data will be collected at the last study visit Day 85 (± 3 days). 
 
AEs reported as ongoing at Day 85, any associated concomitant medications associated with 
such events, and any events occurring within 30 days of last dose will be followed for 30 days. 


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B. 
Randomization and Blinding 
 
This is an open-label study. 
 
C. 
Study Duration, Enrollment and Number of Sites 
C1. Duration of Subject Treatment 
 
Subjects will participate in a 30 day run-in phase to establish biomarker and clinical baseline 
measurements. EPI-589 will then be administered for 3 months unless discontinued for safety or 
tolerability issues. 
 
C2. Total Number of Study Sites/Total Number of Subjects Projected 
 
This study will be conducted at two study sites: 
• 
UK 
• 
USA. 
Approximately 40 subjects with PD are projected: 
• 20 with genetically-defined subtypes 
• 20 PD drug-naïve 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. 
 
D. 
Study Population 
D1. Inclusion Criteria 
 
1. Hoehn and Yahr stage ≤ 2.5 
2. Ambulatory with or without assistance 
3. Agreement to use contraception if within reproductive years 
4. Willingness and ability to comply with study procedures 
5. Stable regimen of dietary supplements for 30 days prior to enrollment 
6. Abstention from use of other investigative or non-approved drugs for the duration of the 
trial 
For Idiopathic Subjects 
7. For idiopathic subjects: a diagnosis of early idiopathic PD confirmed by the presence of 
bradykinesia plus one or both of the following symptoms: rigidity or resting tremor; and 
with an abnormal DaTscan consistent with a dopaminergic deficit 
8. For idiopathic subjects: must not yet require symptomatic medications for PD and not 
expected to require such treatment before the end of the study 
9. For idiopathic subjects: age 40 to 75 years 
10. For idiopathic subjects: within 5 years of diagnosis of Parkinson’s disease 


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For Genetic Subtype Subjects 
11. For genetic subtype subjects: a confirmed diagnosis of PD plus a genetic diagnosis 
consistent with PD, specifically PINK1, parkin, LARK2 or other mitochondrial genetic 
subtype 
12. For genetic subtype subjects: age 21 to 75 years 
13. For genetic subtype subjects: stable medication regimen of PD drugs for 30 days (except 
60 days for rasagiline) prior to enrollment 
 
D2. Exclusion Criteria 
 
1. Allergy to EPI-589 or other components of the EPI-589 tablet formulation 
2. Use of antioxidant supplements, specifically vitamins E and C beyond the recommended 
daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that will confound the 
assessment of effect of study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial of a device, drug or 
other therapy for PD 
For Idiopathic Subjects 
16. For idiopathic subjects: use of any MAO inhibitors, amantadine or other drugs prescribed 
for core symptoms of Parkinson’s disease for idiopathic subjects 
17. For idiopathic subjects: use of nortriptyline or fluvoxamine 60 days prior to enrollment 
 
 
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V. 
STUDY PROCEDURES 
A. 
Screening Visit 
 
Screening evaluations will be performed within two months of first dose. The Investigator will 
inform each prospective subject of the nature of the study, explain the potential risks, and must 
obtain written informed consent from the subject prior to performing any study-related 
procedures and prior to the administration of study drug. Screening evaluations consist of the 
following: 
1. Assessment of eligibility 
2. Medical history, chart review 
3. Receipt and review of previous testing including genetic tests 
4. Physical examination including vital signs 
5. Height and weight 
6. 12-lead ECG 
7. Laboratory assessments for hematology, coagulation, and serum chemistry (See Sections 
VI.D3.a and VI.D3.b) 
8. Urine pregnancy test (women of childbearing potential must have a negative urine 
pregnancy test; see Section VI.D3.c) 
9. MoCA 
10. DaTscan 
11. Revised Hamilton Rating Scale for Depression 
12. Concomitant medications assessment (last 60 days prior to enrollment) 
 
A1. 
Run-in Assessments 
 
If the subject is eligible for the study following all screening procedures and is still willing to 
participate in the study, the subject must return to the clinic within one month for Run-in 
assessments. These will be performed 30 days (± 3 days) prior to baseline after eligibility is 
confirmed and subject is enrolled in the study. Run-in evaluations consist of the following: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers (lumbar puncture) 
3. Urine biomarkers 
4. MDS-UPDRS 
5. Timed motor tests (for subjects on dopamine therapy) 
6. Concomitant medications review 
 
B. 
Treatment Phase 
 
After the Run-in phase, the subject must return to the clinic within 30 days (± 3 days) for 
baseline assessments. In-clinic study visits are scheduled at Month 1 and Month 3. The Month 2 
study assessments can be conducted via telephone. End of Study assessments will be conducted 
at the Month 3 study visit. Pharmacokinetic sampling takes place at Month 1 and Month 3. 


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B1. 
Baseline Assessments 
 
The following will be assessed or performed at this visit. 
1. Physical examination including vital signs 
2. Height and weight* 
3. 12-Lead ECG* 
4. Blood-based GSH cycle biomarkers 
5. Urine-based biomarkers 
6. Laboratory assessments for hematology, coagulation and serum chemistry* 
7. Urine pregnancy test (females of child bearing potential) 
8. C-SSRS (Columbia Suicide Severity Rating Scale) 
9. MDS-UPDRS 
10. NMSS, PDQ-39, EQ-5D 
11. BDI, MADRS 
12. Timed motor tests (for subjects on dopamine therapy) 
13. Concomitant medications review 
* Screening results for these assessments may be used if obtained within 1 month of Baseline. 
 
B2. 
Study Visit Assessments 
 
• Month 1 Clinic Visit (Day 29 ± 3 days): 
 
The following will be assessed or performed at the Month 1 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. MDS-UPDRS 
10. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
11. AE assessments 
12. Concomitant medications review 
• Month 2 Visit (Day 57 ± 3 days) 
 
Month 2 assessments can be conducted by telephone and must include review of: 
1. Concomitant medication 
2. AEs 


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• Month 3 Clinic Visit (Day 85 ± 3 days) 
 
The following will be assessed or performed at the Month 3 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. CNS biomarkers 
10. MDS-UPDRS 
11. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
12. AE assessments 
13. Concomitant medications review 
14. MoCA 
15. NMSS, PDQ-39, EQ-5D 
16. BDI, MADRS 
17. Timed motor tests (for subjects on dopamine therapy) 
 
B3. 
Pharmacokinetics 
 
Plasma concentration samples will be collected from the first 10 subjects to complete 1 month of 
therapy at each site, at the following time points: 
• Month 1 (Day 29 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
• Month 3 (Day 85 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
 
B4. 
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 study visit assessments completed as soon as possible. 
 
C. 
End of Study Visit 
 
End of Study visit takes place at Month 3 (Day 85 ± 3 days) and includes the assessments listed 
in Section VB2 Study Visit Assessments. 
 
Subjects who have an ongoing AE at the time of study completion will be followed for up to 30 
days, until the event resolves, or until the Sponsor and the Investigator agree that further follow- 
up is not medically necessary. 


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D. 
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 case report form (CRF) using the supplemental visit CRF pages. 
 
E. 
Concomitant Medication 
 
Any medication taken by a subject ≤ 60 days prior to enrollment and during the course of the 
study and the reason for use of the medication will be recorded on the 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 [OTC] medications) without consulting the Investigator. 
 
F. 
Prohibited Medications 
 
The following are prohibited while the subject is on study treatment: 
1. Use of antioxidants, specifically vitamins E and C beyond the recommended daily 
allowance 
2. Participation 3 months prior to and for the duration of the study in a trial of a device, drug 
or other therapy for PD 
3. Use of MAO inhibitors, amantadine or other drugs prescribed for core symptoms of 
Parkinson’s disease for idiopathic subjects 
4. Use of nortriptyline or fluvoxamine 
 
G. 
Subject Withdrawals 
 
Subjects may be withdrawn from the study at any time for reasons including the following: 
1. At their own request or at the request of their legally authorized representative 
2. If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
subject’s well-being 
3. At the specific request of the Sponsor (or designee) 
4. Additional protocol specific reasons 
In all cases, the reason for withdrawal must be recorded in the 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 
IX.B. 
 
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. 


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Every effort will be made to follow subjects who have an ongoing AE at the time of withdrawal 
until the event resolves, or until the Sponsor and the Investigator agree that further follow-up is 
not medically necessary. 
 
 
 
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VI. STUDY ENDPOINTS AND EVALUATIONS 
A. 
Primary Endpoint 
 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of drug-related serious 
adverse events in subjects with PD. 
 
B. 
Secondary Endpoints (Efficacy) 
 
1. Blood-based biomarkers 
2. CNS-based biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Secondary Endpoints (Safety) 
 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Routine serum chemistries with liver function tests 
4. C-SSRS 
5. Routine hematology tests with coagulation tests 
6. Electrocardiogram 
 
D. 
Screening and Baseline Evaluation 
D1. Physical Examination 
 
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. 
 
Vital sign measurements (pulse rate, blood pressure and respiration rate) will be obtained in the 
sitting position (after the subject has been sitting for five minutes). 
 
Medical history and demographics including age, gender, race, height and weight will be 
collected at Screening. 


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D2. Height and Weight 
 
Weight (kg) will be measured in ordinary indoor clothing (i.e., street clothes, scrubs, etc.) with 
shoes off. Height will be recorded in centimeters (cm). 
 
If clinically significant findings, as determined by the Investigator, are recorded for a particular 
symptom, sign or abnormal measurement, that measurement will be repeated at medically 
appropriate intervals until the value returns to an acceptable range, a specific diagnosis is 
established, or the condition is otherwise explained. 
 
D3. Laboratory Evaluations 
 
Subjects will have less than 100 mL of blood drawn over the course of the study. 
The following variables will be collected at various times (as detailed in Section I). 
a. 
Hematology 
 
1. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), red cell distribution width (RDW) 
2. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) reported as absolute values 
3. Platelets: platelet count, mean platelet volume (MPV) 
4. Coagulation: prothrombin time (PT) with INR, partial thromboplastin time (PTT), 
activated (aPTT) 
 
b. Serum chemistry 
 
1. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total and 
direct), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH) 
2. Renal: blood urea nitrogen (BUN), and creatinine 
3. Electrolytes: sodium, potassium, chloride, and carbon dioxide (CO2) as bicarbonate 
4. General: creatine phosphokinase (CPK), creatine kinase (CK), and troponin (at baseline 
only); total protein, albumin, calcium, magnesium, glucose, phosphate 
5. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL) cholesterol, cholesterol/HDL Ratio (calculated), non-HDL cholesterol 
(calculated), and triglycerides 
 
c. 
Urine pregnancy test 
1. Human chorionic gonadotropin (HCG) beta subunit will be measured on all female 
subjects of childbearing potential. 


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Laboratory tests that result in significantly abnormal values should be repeated for verification. 
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, or to monitor the course of an AE, should be obtained when clinically indicated. 
In particular, if a clinically significant abnormal result is observed that is not resolved by the 
final study visit, repeat tests should be performed to document resolution or stability of the 
abnormality. 
 
Diagnoses associated with any NIH Common Terminology Criteria for Adverse Events (CTC 
v4.03) Grade 3 or 4 laboratory abnormalities will be recorded as SAEs on the CRF. Repeated 
and verified ≥ Grade 3 laboratory tests will be reported as an SAE to the Sponsor and the IRB 
per institutional requirements. The recorded event should indicate the underlying abnormality or 
diagnosis (e.g., renal insufficiency) if known, as opposed to the observed deviation in laboratory 
results (e.g., elevated creatinine). Any additional relevant laboratory results obtained by the 
Investigator during the study will be supplied to the Sponsor. 
 
D4. Columbia Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS is a semi-structured tool for assessing suicidal ideation (Questions 1-5) and 
behavior (Questions 6-10) through a series of questions. 
 
E. 
Sample Collection Procedures, Bioanalytical Methods and Sample Shipment 
 
Subject samples will be identified by unique sample codes. 
 
Blood, urine, and cerebral spinal fluid samples will be collected for determination of levels of 
GSH cycle markers. Additional information about the collection, handling, storage, and 
shipment of the GSH cycle marker samples will be provided separately prior to start of the study. 
 
F. 
Efficacy Evaluations 
F1. 
Glutathione Cycle Biomarkers 
 
Blood, urine, and CNS levels of oxidized and reduced GSH as well as GSH metabolites will be 
used to evaluate EPI-589 target engagement and ability to correct a key biochemical aspect of 
disease pathology. 
 
F2. 
Parkinson’s Disease Rating (MDS-UPDRS) 
 
The MDS-UPDRS is a tool for monitoring the impact of PD, the degree of disability caused, and 
complications from treatment. Part I evaluates nonmotor experiences of daily living; Part II 
evaluates motor experiences of daily living; Part III is a motor examination and includes the 
Hoehn and Yahr scale; Part IV examines motor complications (e.g., motor fluctuations and 
dyskinesias). 
 
Several questions from Part I and all questions from Part II are designed to be amenable to a 
patient/caregiver questionnaire format; the remaining interview (Part I and Part III) and 


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examination (Part IV) are designed with the expectation they can be completed within 30 
minutes. Each item is measured on a five-point scale. 
 
F3. 
Non-motor Symptoms (NMSS) 
 
Non-motor symptoms are evaluated using the NMSS which is divided into 30 questions in 9 
different domains including such symptoms as dribbling saliva, constipation, depression, sleep 
disorders, apathy, hallucinations and dementia. Symptoms are quantified based on their severity 
(using a scale of 0 to 3) and frequency (using a scale of 0 to 4). The final cumulative scores are 
derived from adding up the product of the frequency score times severity score for each of the 30 
questions. 
 
F4. 
Parkinson’s Disease Questionnaire (PDQ-39) 
 
PDQ-39 is a self-administered questionnaire for patients with PD that has 39 questions relating 
to eight key areas of health and daily activities, including both motor and non-motor symptoms. 
It is scored on a scale of 0 to 100, with lower scores indicating better health, and high scores 
more severe symptoms. 
 
F5. 
EQ-5D 
 
EQ-5D is a questionnaire designed to provide measures of health-related quality of life states, 
consisting in five domains (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). 
 
F6. 
Montreal Cognitive Assessment (MoCA) 
 
MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive 
domains: attention and concentration, executive functions, memory, language, visuo- 
constructional skills, conceptual thinking, calculations, and orientation. Severity ranges are 
approximately: 26 to 30 normal; 18 to 26 mild cognitive impairment; 10-17 moderate cognitive 
impairment; < 10 severe cognitive impairment. 
 
F7. 
Beck Depression Inventory (BDI) 
 
The BDI is a self-reporting inventory that measures characteristic attitudes and symptoms of 
depression, including physical symptoms. Twenty-one questions have four responses each (rated 
0 to 3) with a total cumulative score scale ranging from 1-10 considered normal) > 40 (extreme 
depression). 
 
F8. 
Montgomery and Asberg Depression rating scale (MADRS) 
 
The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. 
Ten core symptoms and cognitive features are rated on a severity scale of 0 to 6. Higher scores 
indicate increasing depressive symptoms. 


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F9. 
Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
 
Timed motor tests are simple, objective, quantitative measures for the assessment of Parkinson’s 
disease. They include, in an on-medication and an off-medication state, timed recorded physical 
movements. 
 
 
 
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VII. STATISTICAL CONSIDERATIONS 
A. 
Statistical Analysis 
 
In this subject-controlled, open label study the incidence of drug related SAEs in addition to 
changes from baseline to Month 3 for disease-relevant peripheral and CNS biomarkers as well as 
clinical measures will be calculated for each subject. 
 
A1. 
Analysis Populations 
 
Demographic characteristics and baseline efficacy data will be presented and summarized by 
treatment group for all subjects in the efficacy intent to treat (EITT) population. Demographic 
information will also be summarized by treatment group for the Safety population. No formal 
statistical comparisons will be made for either the EITT or Safety populations. 
 
B. 
Efficacy Analysis 
B1. 
Efficacy Variables 
 
The efficacy variables in this study are: 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
12. Pharmacokinetics 
 
C. 
Safety Analysis 
 
The primary objective of this study is to evaluate the effects of EPI-589 safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
Assessment of safety will include calculating the overall number of subjects (by absolute number 
and percentage) with a particular AE. Safety will also be evaluated through examining clinical 
laboratory data (including chemistry and hematology and coagulation information) and physical 
examination findings, including vital signs obtained throughout the course of the study. A 
medical monitor will provide study oversight. 


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D. 
Sample Size 
 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 PD drug-naïve 
subjects). Under an adaptive design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker responsive idiopathic PD subjects. 
 
 
 
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VIII. STUDY MEDICATION 
A. 
Description 
 
EPI-589 is presented as an immediate release film-coated tablet. Each tablet contains 250 mg of 
EPI-589 and the following compendial excipients: lactose, microcrystalline cellulose, 
polyvinylpyrrolidone, crospovidone and magnesium stearate. Each tablet is film-coated with 
Opadry® II yellow. The tablets are yellow-colored and oval-shaped with a total target weight of 
824 mg. The tablets are packaged at 28 tablets per bottle in high-density polyethylene (HDPE) 
pharmaceutical wide mouth containers, induction sealed, and closed with a child-resistant 
closure. Each container is labeled with appropriate product information meeting current 
regulatory requirements. 
 
B. 
Packaging 
B1. 
Labeling 
 
Each container is labeled with appropriate product information meeting current regulatory 
requirements, in compliance with 21 CRF 312.6. 
 
B2. 
Dosage Form 
 
The EPI-589 drug product will be provided in a 250-mg tablet formulation. 
 
B3. 
Dispensing 
 
Tablets are packaged in white round HPDE wide mouth containers. Each container holds 28 
tablets without desiccant. Each container is sealed with an induction seal held in place with a 
child-resistant closure. The packaged tablets are stored at controlled room temperature 20° to 
25°C (68° to 77°F). (See United States Pharmacopeia [USP]). 
 
C. 
Treatment Compliance and Adherence 
 
Study medication will be counted to assess compliance during each scheduled clinic visit. 
Subjects who take ≥ 80 percent of the prescribed doses and no more than 100 percent will be 
considered compliant. Subjects who fall outside the boundaries of these thresholds will be 
counseled and re-instructed on proper dosing procedures. Medication compliance will be 
recorded on the CRF for each visit after verification with subject-completed diary cards and 
returned used drug supply. 
 
D. 
Drug Accountability 
 
Dosing information will be captured on a subject Dosing Diary Form. This form is part of the 
source documentation and will be utilized as a source for the completion of CRFs associated 
with dosing and for reconciliation of study drug administered and returned to the study site for 
accounting and destruction. Adequate records of study drug receipt and disposition should be 


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maintained by pharmacy records of receipts, investigational drug orders, dispensing records, and 
disposition forms. The Study Monitor will also assess drug accountability and will 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 either be returned to the Sponsor or designee 
or destroyed per study site guidelines for destruction of investigational product immediately after 
drug accountability is performed by the study monitor. 
 
 
 
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IX. SAFETY MANAGEMENT 
A. 
Clinical Adverse Events 
 
Clinical AEs will be monitored throughout the study. All AEs, whether observed by the 
Investigator, reported by the subject, from clinically significant laboratory findings, or other 
means, will be recorded in the CRF. 
 
B. 
Adverse Event Reporting 
 
All SAEs will be reported to the IRB in accordance with the IRB policies and as detailed below. 
AEs that are not serious will be summarized in narrative or other format and submitted to the 
IRB at the time of continuing review. 
 
B1. 
Safety Guidance 
 
Based on the known clinical manifestations of Parkinson’s disease, we expect that many AEs 
could occur during the course of the trial that are well documented to occur as the results of the 
natural history of this disease. These include, but are not limited to worsening neuromuscular 
function, depression, decline in cognitive function, loss of vision and other ophthalmological 
symptoms, loss of coordination and loss of speech. 
 
Edison Pharmaceuticals 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, Edison Pharmaceuticals should be provided with a copy 
of any post-mortem findings, including histopathology. 
 
C. 
Definition of an Adverse Event 
C1. Adverse Event 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
The AE may be: 
1. A new illness 
2. Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 
3. An effect of the study medication, including comparator 
4. A combination of 2 or more of these factors 


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No causal relationship with the study medication or with the clinical study itself is implied by the 
use of the term “adverse event” or “AE”. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs. 
 
Adverse events fall into the categories “non-serious” and “serious”. 
 
C2. Definition of a Serious Adverse Event (SAE) 
 
An SAE is one that at any dose results in any of the following: 
1. Death; 
2. A life-threatening adverse drug experience; 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability/incapacity; or 
5. A congenital anomaly/birth defect. 
ICH guidance also recommends that important medical events that may or may not be 
immediately life-threatening or result in death or hospitalization should also be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the serious definition. 
 
The term ”life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE. It does not refer to an SAE which 
hypothetically might have caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether other AEs, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject, require intervention to prevent one of the other 
outcomes listed 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. 
 
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 
has received 
study drug, 
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. While pregnancy itself is not considered an 
AE or SAE, all pregnancies should be reported using the same process as for SAEs. Any 
pregnancy complications or an outcome other than a healthy, normal outcome will be recorded 
as an AE or SAE. 


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Clarification on the difference in meaning between “severe” and “serious”: The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as “serious,” which is based on the outcome or 
action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
C3. Non-serious Adverse Event 
 
A non-serious AE is any AE not meeting the SAE criteria. 
 
C4. Definition of Relationship to Study Medication 
 
Association or relatedness to the study medication will be graded as either “probably”, 
“possibly”, or “unlikely”. Determination of relatedness includes: 
 
PROBABLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Abates upon discontinuation of the drug and reappears with re-introduction of the drug 
3. Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state 
POSSIBLY – The adverse event: 
1. Follows a reasonable temporal sequence from drug administration 
2. Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
UNLIKELY – The adverse event: 
1. Does not follow a reasonable temporal sequence from drug administration 
2. Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
C5. Definition of Severity 
 
All AEs will be graded if possible by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. The severity of AEs that cannot be graded by CTCAE v4.03 will be categorized 
as follows: 
 
Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy indicated. 
 
Grade 2 – Moderate limitation in activity, some assistance may be needed; minimal noninvasive 
medical intervention/therapy indicated. 


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Grade 3 – Severe limitation in activity, assistance usually required; medical intervention/therapy 
required; hospitalization or prolongation of hospitalization indicated; disabling. 
 
Grade 4 – Extreme limitation in activity, significant assistance required; urgent medical 
intervention/therapy required; life-threatening consequences. 
 
Grade 5 – Death 
 
C6. Definition of Unexpected Adverse Event 
 
Any AE, the specificity or severity of which is not consistent with those listed in the current 
investigator’s brochure is considered “unexpected.” 
 
C7. Notification of SAEs 
 
The Investigator is responsible for promptly notifying the IRB/IEC of all study on-site SAEs and 
other unanticipated problems related to research. 
 
External SAEs that are unexpected and related to the study intervention should be reported as 
they are received using the MedWatch or CIOMs form (as appropriate). 
 
SAEs (whether unexpected or expected AEs) must be documented on the designated SAE form. 
The SAE must be reported to the medical expert and appropriate Edison or Edison-assigned 
pharmacovigilance staff within 24 hours, according to regulatory, Sponsor, or ICH-E6 Good 
Clinical Practice, followed by the SAE form within two calendar days. The designated SAE form 
and the instructions are provided in the Investigator’s site file. 
 
The SAE contact information will be provided separately from the protocol. 
 
The Investigator and/or Medical Expert must also inform the Study Monitor and the Sponsor in 
all cases. Any SAEs must also be reported to the IRB/IEC. The Sponsor or designee will ensure 
that all legal reporting requirements are met. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and the 
study medication. 
 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up SAE forms. 
 
The instructions to sites for the completion of SAE reports give detailed guidance on the 
reporting of SAEs and AEs initially reported as non-serious that become serious. When a non- 
serious event becomes serious, details must be forwarded immediately to the Medical expert and 
Edison or Edison-assigned pharmacovigilance staff first for assessment and then submitted to the 
Sponsor on the designated SAE form within 24 hours. 


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All relevant information about suspected unexpected serious adverse reactions (SUSARs) that 
are fatal or life-threatening are to be recorded and reported to the relevant competent authorities. 
 
In the US, all fatal or life-threatening suspected unexpected serious adverse events assessed as 
possibly or probably related to study drug by the Sponsor must be reported to the FDA as soon as 
possible (i.e., by telephone or facsimile transmission), but no later than 7 calendar days after first 
knowledge by the Sponsor that a report qualifies as a suspected unexpected fatal or life- 
threatening reaction. All unexpected serious adverse events, other than fatal or life-threatening, 
assessed as possibly or probably related to study drug by the Sponsor must be reported to the 
FDA within 15 calendar days from the day the Sponsor determines that the information qualifies 
as a SUSAR. 
 
In the UK, the Sponsor or trial investigator must act immediately or at least within 24 hours after 
becoming aware of a SUSAR by informing the MHRA’s Clinical Trial Unit by telephone. The 
MHRA must then be informed in writing within 3 days of the incident. All SUSARs originating 
in the UK or originating outside the UK involving the same medicinal product are to be reported. 
Fatal or life-threatening SUSARs are to be reported as soon as possible, but no later than after 7 
days. Any additional relevant information must be sent within 8 days of the report. Non-fatal or 
non-life-threatening SUSARs are to be reported as soon as possible but no later than 15 days 
after becoming aware of the reaction. 
 
C8. 
Follow-up Report 
 
If an SAE has not resolved at the time of the initial report, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. All SAEs should be followed until either resolved or stable. 
 
D. 
Medical Emergencies 
 
In medical emergencies, the Investigator should use medical judgment and remove the subject 
from the immediate hazard. The Medical Expert and the IRB/ IEC must be notified regarding the 
type of emergency and course of action taken and the procedures for SAE reporting must be 
followed. 
 
D1. Emergency Sponsor Contact 
 
In emergency situations, the Investigator should contact the Medical Monitor: 
 
 
D2. Emergency Treatment 
 
At present, the threshold and extent of clinical adverse effects are not known as only limited 
information is available in healthy volunteers. It is anticipated in the planned study that any 
effects will be minimal and laboratory measurements will detect study drug effects before they 
become clinically significant. 


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X. 
STUDY ADMINISTRATION 
A. 
Treatment Assignment Methods 
 
This is an open-label study. 
 
B. 
Data Collection and Management 
 
Monitoring and auditing procedures, developed or endorsed by Edison will be followed in order 
to comply with GCP guidelines. Direct access to on-site study documentation including all 
source data, documentation and medical records should be ensured. 
 
The study will be monitored by Edison. Throughout the course of the study, the Study Monitor 
will make frequent contact with the Investigator. This will include telephone calls and on-site 
visits. During the on-site visits, the completed CRF will be compared to the source 
documentation for completeness, accuracy and adherence to the protocol. As part of the data 
audit, source documents must be made available to the Study Monitor for review. The Study 
Monitor will also perform drug accountability checks and will review the Investigator study file 
to assure completeness of documentation in all respects of clinical study conduct. 
 
Upon completion of the study, the Study Monitor will arrange for a final review of the study 
files, after which the files should be secured for the appropriate time period. The Investigator, or 
appointed delegate, will meet with the Study Monitor during the on-site visits and will cooperate 
in providing the documents for inspection and responding to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of Edison or 
the regulatory agencies. 
 
US and other competent regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. Medical records and other 
study documents may be copied during audit or inspection provided that subject names are 
obliterated on the copies to ensure confidentiality. 
 
C. 
Data Quality Assurance 
 
As a final step in the data management process, a 100% audit will be performed on the key 
safety and critical efficacy parameters. In addition, a random subject sample (10%) will be 
selected in order to perform a partial audit of remaining data. The purpose of this audit is to 
detect systematic and random errors. Any errors found from this audit will be corrected and, if 
the error rate is greater than 1 error per 1,000 fields (0.001%), a systematic review of the 
database will be undertaken and corrections will be made to achieve an error rate of less than 
0.001%. 
 
AEs will be coded using MedDRA, version (14.3). Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary, March 2014. 


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D. 
Retention of Study Records 
 
The following records must be retained by the Investigator for a minimum of 2 years after the 
Sponsor has notified the FDA or other competent authority that investigations have been 
discontinued, or after the FDA or other competent authority has approved the new drug 
application. In accordance with European regulatory requirements (Directive 2005/28/EC and 
Annex 17 and 2001/83/EC and Annex1), the Sponsor may request retention for a longer period 
of time. 
1. Signed informed consent documents for all subjects 
2. Subject identification code list, screening log (if applicable), and enrollment log 
3. Record of all communications between the Investigator and the IRB/IEC 
4. Composition of the IRB/IEC or other applicable statement 
5. Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
6. List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in the 
study and their signatures 
7. Copies of CRFs and of documentation of corrections for all subjects 
8. Drug accountability records 
9. Record of any body fluids or tissue samples retained 
10. All other source documents (subject records, hospital records, laboratory records, etc.) 
11. All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. 
 
Normally, these records will be held in the Investigator's archives. If the Investigator is unable to 
meet this obligation, 
or 
must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 
E. 
Confidentiality 
 
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the Sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be told that representatives of the Sponsor, IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection and privacy laws, including the Health Insurance 
Portability and Accountability Act (HIPAA) Guidelines, and the General Data Protection 
Regulation (GDPR). 


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The Investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
F. 
Documentation of Study Results 
 
A CRF will be provided for each enrolled subject. 
 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the CRF. Details of CRF completion and correction will be 
explained to the Investigator. If the Investigator authorizes other persons to make entries in the 
CRF, the names, positions, signatures, and initials of these persons must be supplied to the 
Sponsor. 
 
The Investigator, or designated representative, should complete the CRF pages as soon as 
possible after information is collected, preferably on the same day that a study subject is seen for 
an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
 
By signing the completed CRFs, the Investigator or Subinvestigator attests to the accuracy, 
completeness, legibility, and timeliness of the data collected on the CRF and casebooks. 
 
The Sponsor will retain the originals of all CRFs. The Investigator will retain a copy of all 
completed CRF pages. 
 
G. 
Regulatory and Ethical Considerations 
G1. Risk Assessment 
 
Based on the safety results of Study EPI-589-14-01 as summarized in the Clinical Study Report, 
it is not foreseen that subjects will endure any risks greater than minimal at the 500-mg BID dose 
selected for this study. 
 
G2. Potential Benefits of Trial Participation 
 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 
benefit in subjects with PD. Therefore, we cannot assure that subjects will benefit from treatment 
with EPI-589. Potential benefits may manifest in a variety of ways, such as in disease-related 
parameters, functioning, and quality of life. 
 
G3. Risk-Benefit Assessment 
 
There are no effective and/or approved disease modifying treatments available for PD, although 
a number of clinical interventions are being researched. Based on disease mechanism, EPI-589 
mechanism of action and pre-clinical studies, EPI-589 may hold benefit for patients with PD. 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 


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benefit in subjects with PD. In order to further minimize risks, subjects will be closely monitored 
with a variety of safety measures. 
 
H. 
Informed Consent 
 
Before being enrolled in the clinical study, subjects must provide written consent to participate 
after the nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them. The Investigator will not undertake any measures specifically 
required only for the clinical study until valid consent has been obtained. 
 
An informed consent document that includes both information about the study and the consent 
form will be prepared and given to the subject. This document will contain all the elements 
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements 
required by local regulations and must be in a language understandable to the subject. Where 
required by local law, the person who informs the subject must be a physician. It should be 
signed and dated by all the parties concerned including the subject, legal guardian (where 
applicable), witness (where applicable) and the person obtaining the consent. 
 
A copy of the signed consent document must be given to the subject. The original signed consent 
document will be retained by the Investigator. 
 
The Investigator must inform the subject’s primary physician about the subject’s participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
 
 
 
Space intentionally left blank 


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XI. PUBLICATION 
A. Use of Study Results 
 
All information concerning the product, as well as any matter concerning the operation of Edison 
(such as clinical indications for the drug, its formula, methods of manufacture, and other 
scientific data relating to it, that have been provided by Edison and are unpublished), are 
confidential and must remain the sole property of Edison. The Investigator will agree to use the 
information only for the purposes of carrying out this study and for no other purpose unless prior 
written permission from Edison is obtained. The Sponsor has full ownership of the CRFs 
completed as part of the study. 
 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by Edison. If necessary, the authorities will be notified 
of the Investigator's name, address, qualifications, and extent of involvement. 
 
This Study is part of a multicenter clinical research study. Accordingly, Sponsor will act as 
coordinator and referee with respect to publications of the data generated thereunder. Principal 
Investigator shall not publish or disclose any data, result or information with respect to any 
matters resulting from work performed under this Protocol while this Study is being conducted at 
other center/s. Only after the completion of this Study at all other centers, provision of the data to 
the FDA or EMA for review and comment, and publishing the combined data from all of the 
centers, may the Principal Investigator publish/present the individual results of the Study in 
accordance with this paragraph. 
 
Principal Investigator may publish provided, however, that no publication, abstract, 
announcement or disclosure (“Publication”) shall be made until the Principal Investigator 
submits to Sponsor any proposed Publication for Sponsor’s review. Sponsor shall have a period 
of sixty (60) days to review such Publication. If Sponsor determines during the review period 
that the Publication contains patentable subject matter, then the above sixty (60) days shall be 
extended to one hundred twenty (120) days in order to allow for the preparation of patent 
applications covering said patentable subject matter. Unless Sponsor approves in writing, no 
Publication may contain any Confidential Information (other than data and results generated 
under the Study). 
 
Without limiting the foregoing, Institution and Principal Investigator, and all other study 
investigators in other study institutions, shall give due regard to Sponsor’s legitimate interests, 
such as manuscript authorship, coordinating and maintaining the proprietary nature of 
submissions to health authorities, and coordinating with other ongoing studies in the same field, 
and agree to accept Sponsor’s reasonable comments and suggestions with respect to such 
Publications. 
 
If the Investigator is to be an author of a publication manuscript prepared by Edison, Edison will 
allow the Investigator or CRO 60 days for full review of the manuscript before publication. 


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XII. LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AR 
accumulation ratio 
BDI 
Beck Depression Inventory 
BID 
twice daily 
BSO 
L-buthionine-(S,R)-sulfoximine 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatinine kinase 
CNS 
central nervous system 
CoQ10 
Coenzyme Q 10 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DaT 
dopamine transporters 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EITT 
efficacy intent-to-treat 
EPDA 
European Parkinson’s Disease Association 
EU 
European Union 
%F 
percent fluctuation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GCRC 
good clinical research practice 
GDPR 
General Data Protection Regulation 
GSH 
glutathione 
GSSG 
glutathione disulfide 
HDPE 
high density polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HMPAO 
hexamethylpropylene amine oxime 
ICF 
informed consent form 
ICH 
International Committee on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 
kg 
kilogram 
λz 
apparent terminal constant 


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LFT 
liver function test 
MAD 
multiple ascending (oral) dose 
MADRS 
Montgomery and Asberg Depression rating scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale 
mg 
milligram 
mL 
milliliter 
MoCA 
Montreal Cognitive Assessment 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
MPV 
mean platelet volume 
mtDNA 
mitochondrial DNA 
N/A 
not applicable 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NF 
National Formulary 
nM 
nanomolar 
NMSS 
Non-motor Symptoms Scale 
NOAEL 
no observed adverse effect level 
NQ01 
NAD(P)H Quinone oxidoreductase 1 
OD 
once daily 
OTC 
over-the-counter 
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PO 
by mouth 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 
PVP 
polyvinylpyrrolidone 
QT 
interval between the start of the Q wave and the end of the T wave 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAD 
single ascending (oral) dose 
SAE 
serious adverse event 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
Tmax 
time to peak concentration 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 


Edison Pharmaceuticals, Inc 
Protocol EPI589-15-002 
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Version: Amendment 1.0 
 
 
 
 
XIII. SIGNATURE OF SPONSOR 
 
A. Declaration of Sponsor 
 
This study protocol was subject to critical review and the information it contains is consistent 
with the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP as described in 21 CPR parts 50, 54, 56, and 
312. 
 
The Investigator will be supplied with details of any significant or new findings on EPI-589, 
including AEs. 
 
 
 
 
 
Date: /a S¢  261 J Signature: 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Ave 
Mountain View, CA 94043 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
09 September 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Edison Pharmaceuticals Inc. 
Page 48 of SO 


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XIV. REFERENCES 
 
Ashrafi G, Schlehe JS, LaVoie MJ, Schwartz TL. Mitophagy of damaged mitochondria occurs 
locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014; 1;206(5):655- 
70. 
 
Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces 
features of Parkinson's disease. Nat Neurosci. 2000; 3(12): 1301-1306. 
 
Dauer W and Przedborski S. Parkinson's disease: mechanisms and models, Neuron 2003; 39: 
889–909. 
 
de Lau LM and Breteler MM. Epidemology of Parkinson’s Disease. Lancet Neur.2006; 5: 525- 
35. 
 
EPDA-European Parkinson’s Disease Association. http://www.epda.eu.com/en/resources/life- 
with-parkinsons/part-1/prevalence-of-parkinsons-disease/ (consulted 04 December 2014). 
 
Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, et al. Biochemical and pathological 
characterization of Lrrk2. Ann Neurol. 2006: 59(2): 315-22. 
 
Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, 
environment and mitochondria. Parkinsonism Relat. Disord. 2003; 9 (Suppl 2): S59–S64. 
 
Holmay, MJ, Terpstra M, Coles LD, et al. N-acetylcysteine Boosts Brain and Blood Glutathione 
in Gaucher and Parkinson Diseases. Clin. Neuropharm. 2013; 36, 4: 103-106. 
 
Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, et al. Glutathione Depletion in PC12 Results in 
Selective Inhibition of Mitochondrial Complex I Activity. Implications for Parkinson’s disease. J 
Biol Chem. 2000; 25;275 (34): 26096-101. 
 
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product 
of meperidine-analog synthesis. Science. 1983; 219: 979–980. 
 
Lin MT and Beal FB. Mitochondrial dysfunction and oxidative stress in neurodegenerative 
diseases. Nature. 2006; 443: 787-795. 
 
Maarouf CL, Beach TG, Adler CH, Shill HA, Sabbagh MN, et al. Cerebrospinal fluid 
biomarkers of neuropathologically diagnosed Parkinson's disease subjects. Neurol Res. 2012; 
34:669–676. 
 
Mao P and Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and 
mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and 
therapeutics. Biochim. Biophys. Acta. 2011; 1812: 1359-1370. 


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Narendra, DP and Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and parkin in 
mitochondrial quality control. Antioxi. Redox Signal. 2011; 14: 1929-1938. 
 
The Parkinson’s Disease Foundation. http://www.pdf.org/en/parkinson_statistics (consulted 27 
April 2015). 
 
Pinto M, Pickrell AM, Moraes CT. Regional susceptibilities to mitochondrial dysfunctions in the 
CNS. Biol. Chem. 2012; 393: 275-281. 
 
Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, et al. Transition metals, ferritin, 
glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 1989; Feb;52(2): 515-20. 
 
Winklhofer KF and Haass C. Mytochondrial dysfunction in Parkinson’s disease. Biochimica et 
Biophysica Acta. 2010; 1802: 29-44. 
 
Zhu X, Babar A, Siedlak SL, Yang Q, Ito G, et al. LRRK2 in Parkinson's disease and dementia 
with Lewy bodies. Mol Neurodegener. 2006;1:17. 


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Summary of Changes 
Amendment 1.0 
EPI589-15-002 
A Phase 2A Safety and Biomarker Study of EPI-589 
in Mitochondrial Subtype and Idiopathic Parkinson’s 
Disease Subjects 
 
 
 
 
Protocol Number 
EPI589-15-002 
Original Protocol Date 
27 April 2015 
Amendment 1.0 Date 
09 September 2015 
Study Sponsor 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Sponsor’s Representative 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
The information contained in this document is confidential and will not be disclosed to others without written authorization from Edison 
Pharmaceuticals, except to the extent necessary to obtain informed consent from those persons to whom the drug may be administered or 
for discussions with local regulatory authorities, Ethics Committee/Investigational Review Boards, or people participating in the conduct of 
the study. 
 
 
 


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KEY CHANGES TO THE PROTOCOL 
 
Amendment 1 provides the following changes and their rationales: 
 
Change 
Rationale 
Study title, objectives, and endpoints were 
modified 
Primary endpoint has become safety as 
assessed by drug-related AEs, and biomarker 
assessments have become secondary endpoints. 
CNS and urine biomarker assessments added 
Glutathione will be measured in cerebral spinal 
fluid and urine as well as in blood. 
DaTscan removed from Month-3 visit 
Minimal anticipated measurable changes 
within the short 90-day treatment period do not 
warrant the radiation exposure of a second 
study-required DaTscan. 
The Columbia Suicide Severity Scale has been 
added to the clinical safety assessments 
FDA-DNP determination that assessments of 
suicidality be included in clinical trials of 
drugs for neurological indications. 
DNA genetic analysis has been removed from 
Screening assessments 
Specific testing for Parkinson’s genetic 
subtypes is not necessary as a study procedure 
requirement. 
Mattis Dementia Rating Scale has been 
removed from the efficacy variables 
To minimize redundancy and responder 
burden. 


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DESCRIPTION OF CHANGES TO THE PROTOCOL 
 
Relevant point changes to the protocol by section appear in the table below. Other changes that 
are informational in nature and do not involve implementation of new procedures, may not be 
individually identified, but the modified text appears in the protocol (see appropriate sections of 
interest). These changes may include administrative updates, clarifications, corrections, and 
editorial adjustments to improve clarity and provide consistency. Global changes appearing in 
multiple places throughout protocol may not be identified individually unless they appear within 
the context of other important changes. 
 
In this summary document, bold italic font indicates additions to existing text, and strikethrough 
font indicates deleted text. The actual amended protocol does not include bold or strikethrough 
font to indicate changes. 
 
Protocol 
Section 
Modification (or Explanation) 
Cover page; 
Synopsis; II.F 
A Phase 2A Safety and Biomarker Study of EPI-589 in Mitochondrial Subtype 
and Idiopathic Parkinson’s Disease Subjects 
Synopsis 
Synopsis sections were updated to reflect all changes in the body of the 
protocol. 
I Schedule of 
Assessments 
 
II.B 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 
<100nM ) and efficacy (>80% rescue from oxidative stress-induced cell death) 
in cells derived from patients diagnosed with sporadic idiopathic and familial 
PD genetic subtypes including PINK1, parkin and LRRK2. 
III.A 
A. Primary Efficacy Objective 
The primary objective of this study is to evaluate the effects of EPI-589 safety 
as assessed by occurrence of drug-related serious adverse events on blood 
based glutathione cycle biomarkers in subjects with PD. 
III.B, III.C 
B. Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with 
PD on: 


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1. Central nervous system (CNS)Glutathione cycle biomarkers as 
assessed by magnetic resonance spectroscopy (MRS)measured in 
blood, cerebral spinal fluid, and DaTscanurine 
2. Clinical Ddisease Sstate as assessed by the Movement Disorder 
Society-sponsored revision of the Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale 
(NMSS), PDQ-39 and EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment 
(MoCA) and Mattis Dementia rating scale (DRS 2) 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the 
Montgomery & Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
C. Safety Objectives 
7. To examine the safety of EPI 589 in subjects with PD by examining 
hematology h Hematology, blood chemistry, electrocardiogram 
, and drug related AEs and SAEs. 
IV.A2 
Once eligibility is confirmed, the subject will be enrolled in the study and the 
run-in scans, CNS, blood-based biomarker, urine-based biomarker and clinical 
measurements will be collected. 
IV.A3 
Baseline assessments, scans, blood-based biomarker, urine-based biomarker, 
and clinical measurements will be collected. 
IV.A4 
Blood-based biomarker, urine-based biomarker, and clinical measurements 
will be collected at Day 29 (± 3 days) and Day 85 (± 3 days). 
V.A 
9. Genetic analysis for subjects that have not had prior genetic testing for PD 
mutations (See Section VI.D3.c) 
V.A1 
1. Blood-based Gglutathione cycle biomarkers 
2. CNS biomarkers 
3. Urine biomarkers 
4. MDS-UPDRS 
5. Timed motor tests (for subjects on dopamine therapy) 
6. Concomitant medications review 
V.B1 
The following will be assessed or performed at this visit. 
1. Physical examination including vital signs 
2. Height and weight* 
3. 12-Lead ECG* 
4. Blood-based GSH cycle biomarkers 
5. Urine-based biomarkers 
6. Laboratory assessments for hematology, coagulation and serum 
chemistry* 
7. Urine pregnancy test (females of child bearing potential) 
8. C-SSRS (Columbia Suicide Severity Rating Scale) 
9. MDS-UPDRS 
10. NMSS, PDQ-39, EQ-5D 
11. DRS 2 
BDI, MADRS 


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11. Timed motor tests (for subjects on dopamine therapy) 
12. Concomitant medications review 
V.B2 
The following will be assessed or performed at the Month 1 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum 
chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. MDS-UPDRS 
10. Pharmacokinetics: a full plasma drug concentration profile will be 
obtained from the first 10 subjects to complete 1 month of therapy at 
each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours after dosing. 
11. AE assessments 
12. Concomitant medications review 
V.B2 
The following will be assessed or performed at the Month 3 clinic visit: 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum 
chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. C-SSRS 
7. Blood-based GSH cycle biomarkers 
8. Urine-based biomarkers 
9. CNS biomarkers 
10. MDS-UPDRS 
11. Pharmacokinetics: a full plasma drug concentration profile will be 
obtained from the first 10 subjects to complete 1 month of therapy at 
each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours after dosing. 
12. AE assessments 
13. Concomitant medications review 
14. MRI and MRS 
15. DaTscan 
14. MoCA 
15. NMSS, PDQ-39, EQ-5D 
16. DRS 2 
16. BDI, MADRS 
17. Timed motor tests (for subjects on dopamine therapy) 
VI. A 
A. Primary Efficacy Endpoint 
Change from baseline in blood based glutathione cycle biomarkers in subjects 
with PD. 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of drug- 


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related serious adverse events in subjects with PD. 
VI. B 
B. Secondary Efficacy Endpoints (Efficacy) 
1. Blood-based biomarkers 
2. CNS-based biomarkers 
3. MRS, DaTscan 
3. Urine-based biomarkers 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. DRS 2 
8. MoCA 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine 
therapy) 
12. Pharmacokinetics 
VI.C 
C. Safety Secondary Endpoints (Safety) 
VI.D3.c 
c. DNA sample 
1. 1.5 mL EDTA blood sample for DNA extraction for genetic testing for 
PD subtypes at screening if not done previously. 
VI.D4 
D.4 Columbia Suicide Severity Rating Scale (C SSRS) 
The C-SSRS is a semi-structured tool for assessing suicidal ideation 
(Questions 1-5) and behavior (Questions 6-10) through a series of questions. 
VI.E 
Fasting bBlood, urine, and cerebral spinal fluid samples will be collected for 
determination of levels of GSH cycle markers. A contract laboratory will 
receive samples via courier in order to test GSH cycle components and to 
perform the pharmacokinetic analysis. Additional information about the 
collection, handling, storage, and shipment of the GSH cycle marker samples 
will be provided separately prior to start of the study. 
Blood samples for clinical laboratory measurements should be collected and 
processed according to the site’s laboratory’s standard procedure. 
VI.F1 
Blood, urine, and CNS levels of oxidized and reduced GSH as well as GSH 
metabolites will be used to evaluate EPI-589 target engagement and ability to 
correct a key biochemical aspect of disease pathology. 
VI.F2 
MRS will be used to measure GSH and other metabolites in the basal ganglia. 
Extent of cortical and basal degeneration will be assessed by MRI. Dopamine 
uptake will be measured by DaTscan. 
VI.F.8 
F8. Mattis Dementia Rating Scale (DRS 2) 
The DRS 2 is an instrument used in screening for dementia designed for adults 
with cognitive impairment aged 56 and older. It provides a composite score and 
five subscale scores in Attention, Initiation Perseveration, Construction, 
Conceptualization, and Memory. 
VII.A 
In this a within subject,-controlled, open-label study the incidence of drug 
related SAEs in addition to changes from baseline to Month 3 for disease- 
relevant peripheral and CNS biomarkers as well as clinical measures will be 


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calculated for each subject. 
VII.B1 
VII.B2 
B1. Primary Efficacy Variables 
The primary efficacy variable is GSH cycle biomarkers (at baseline, Day 29 
and Day 85). 
B1B.2 Secondary Efficacy Endpoints Variables 
1. Blood-based glutathione cycle biomarkers 
2. CNS biomarkers 
3. Urine-based biomarkers 
4. Brain MRS, DaTscan 
4. MDS-UPDRS 
5. NMSS 
6. PDQ-39 
7. EQ-5D 
8. MoCA 
9.  DRS 2 
9. BDI 
10. MADRS 
11. Timed motor tests in ON and OFF state (for subjects on dopamine 
therapy) 
12. Pharmacokinetics 
VII.C. 
The primary objective of this study is to evaluate the effects of EPI-589 
safety as assessed by occurrence of drug-related serious adverse events in 
subjects with PD. 
Assessment of safety will include calculating the overall number of subjects 
(by absolute number and percentage) with a particular AE. Safety will also be 
evaluated through examining clinical laboratory data (including chemistry and 
hematology and coagulation information) and physical examination findings, 
including vital signs obtained throughout the course of the study. A medical 
monitor will provide study oversight. 
VII.D 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 
PD drug-naïve subjects). Under an adaptive design strategy, additional 
subjects (up to 20) may be added to increase the number of biomarker 
responsive idiopathic PD subjects. 
XII 
XII. LIST OF ABBREVIATIONS 
 
 
End of Document 
#### 


 
 
 
 
 
 
EPI589-15-002 
A Phase 2A Biomarker Study of 
EPI-589 in Subjects with 
Parkinson’s Disease 
 
 
 
Original Protocol: 27 April 2015 
 
 
Edison Pharmaceuticals, Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
 
 
 
 
 
The information contained in this document is confidential and will not be disclosed to others without 
written authorization from Edison, except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the study. 


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Table of Contents 
PROTOCOL SYNOPSIS ........................................................................................................ 6 
I. SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE ................................. 11 
II. BACKGROUND INFORMATION AND RATIONALE............................................. 12 
A. Introduction ................................................................................................................. 12 
B. Rationale for the Study of EPI-589 in Parkinson’s Disease .................................... 13 
C. Name and Description of Investigational Product ................................................... 13 
D. Findings from Non-Clinical and Clinical Studies .................................................... 14 
D1. Non-Clinical Studies .................................................................................................. 14 
D2. Clinical Studies .......................................................................................................... 16 
E. Human Pharmacokinetics ............................................................................................ 16 
F. 
Clinical Study .............................................................................................................. 17 
G. Selection of Drugs and Dosages .................................................................................. 17 
H. Compliance Statement ................................................................................................ 17 
I. 
Relevant Literature and Data .................................................................................... 17 
III. STUDY OBJECTIVES ................................................................................................... 18 
A. Primary Efficacy Objective ....................................................................................... 18 
B. Secondary Objectives .................................................................................................. 18 
C. Safety Objectives ......................................................................................................... 18 
IV. INVESTIGATIONAL PLAN ......................................................................................... 19 
A. General Schema of Study Design .............................................................................. 19 
A1. Screening Phase ......................................................................................................... 19 
A2. 30-Day Run-in Phase ................................................................................................. 19 
A3. Baseline ...................................................................................................................... 19 
A4. Treatment Phase ........................................................................................................ 19 
A5. End of Study ............................................................................................................... 19 
B. Randomization and Blinding ..................................................................................... 20 
C. Study Duration, Enrollment and Number of Sites .................................................. 20 
C1. Duration of Subject Treatment ................................................................................... 20 
C2. Total Number of Study Sites/Total Number of Subjects Projected ............................ 20 
D. Study Population ......................................................................................................... 20 
D1. Inclusion Criteria ....................................................................................................... 20 


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D2. Exclusion Criteria ...................................................................................................... 21 
V. STUDY PROCEDURES ................................................................................................. 23 
A. Screening Visit ............................................................................................................ 23 
A1. Run-in Assessments .................................................................................................... 23 
B. Treatment Phase ......................................................................................................... 24 
B1. Baseline Assessments ................................................................................................. 24 
B2. Study Visit Assessments .............................................................................................. 24 
B3. Pharmacokinetics ....................................................................................................... 26 
B4. Early Termination Study Visit .................................................................................... 26 
C. End of Study Visit ....................................................................................................... 26 
D. Unscheduled Visits ...................................................................................................... 26 
E. Concomitant Medication ............................................................................................ 26 
F. 
Prohibited Medications .............................................................................................. 26 
G. Subject Withdrawals ................................................................................................... 27 
VI. STUDY ENDPOINTS AND EVALUATIONS .............................................................. 28 
A. Primary Efficacy Endpoint ........................................................................................ 28 
B. Secondary Efficacy Endpoints ................................................................................... 28 
C. Safety Endpoints ......................................................................................................... 28 
D. Screening and Baseline Evaluation ........................................................................... 28 
D1. Physical Examination ................................................................................................ 28 
D2. Height and Weight ..................................................................................................... 29 
D3. Laboratory Evaluations ............................................................................................. 29 
E. Sample Collection Procedures, Bioanalytical Methods and Sample Shipment .... 30 
F. 
Efficacy Evaluations ................................................................................................... 30 
F1. Glutathione Cycle Biomarkers .................................................................................... 30 
F2. Neuroradiology .......................................................................................................... 31 
F3. Parkinson’s Disease Rating (MDS-UPDRS) ............................................................. 31 
F4. Non-motor Symptoms (NMSS) ................................................................................... 31 
F5. Parkinson’s Disease Questionnaire (PDQ-39) .......................................................... 31 
F6. EQ-5D ........................................................................................................................ 31 
F7. Montreal Cognitive Assessment (MoCA) ................................................................... 31 
F8. Mattis Dementia Rating Scale (DRS-2) ..................................................................... 32 


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F9. Beck Depression Inventory (BDI) .............................................................................. 32 
F10. Montgomery and Asberg Depression rating scale (MADRS) ................................. 32 
F11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) ........ 32 
VII. STATISTICAL CONSIDERATIONS........................................................................... 33 
A. Statistical Analysis ...................................................................................................... 33 
A1. Analysis Populations .................................................................................................. 33 
B. Efficacy Analysis ......................................................................................................... 33 
B1. Primary Efficacy Variables ........................................................................................ 33 
B2. Secondary Endpoints ................................................................................................. 33 
C. Safety Analysis ............................................................................................................ 33 
D. Sample Size .................................................................................................................. 34 
VIII. 
STUDY MEDICATION .......................................................................................... 35 
A. Description ................................................................................................................... 35 
B. Packaging .................................................................................................................... 35 
B1. Labeling ..................................................................................................................... 35 
B2. Dosage Form ............................................................................................................. 35 
B3. Dispensing .................................................................................................................. 35 
C. Treatment Compliance and Adherence .................................................................... 35 
D. Drug Accountability ................................................................................................... 35 
IX. SAFETY MANAGEMENT ............................................................................................ 37 
A. Clinical Adverse Events ............................................................................................. 37 
B. Adverse Event Reporting ............................................................................................ 37 
B1. Safety Guidance ......................................................................................................... 37 
C. Definition of an Adverse Event .................................................................................. 37 
C1. Adverse Event ............................................................................................................ 37 
C2. Definition of a Serious Adverse Event (SAE) ............................................................. 38 
C3. Non-serious Adverse Event ........................................................................................ 39 
C4. Definition of Relationship to Study Medication .......................................................... 39 
C5. Definition of Severity ................................................................................................. 39 
C6. Definition of Unexpected Adverse Event.................................................................... 40 
C7. Notification of SAEs ................................................................................................... 40 
C8. Follow-up Report ....................................................................................................... 41 


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D. Medical Emergencies .................................................................................................. 41 
D1. Emergency Sponsor Contact ...................................................................................... 41 
D2. Emergency Treatment ................................................................................................. 42 
X. STUDY ADMINISTRATION ........................................................................................ 43 
A. Treatment Assignment Methods ............................................................................... 43 
B. Data Collection and Management ............................................................................. 43 
C. Data Quality Assurance .............................................................................................. 43 
D. Retention of Study Records ....................................................................................... 44 
E. Confidentiality ............................................................................................................. 44 
F. 
Documentation of Study Results ............................................................................... 45 
G. Regulatory and Ethical Considerations .................................................................... 45 
G1. Risk Assessment ......................................................................................................... 45 
G2. Potential Benefits of Trial Participation .................................................................... 45 
G3. Risk-Benefit Assessment .............................................................................................. 46 
H. Informed Consent ....................................................................................................... 46 
XI. PUBLICATION ............................................................................................................... 47 
A. Use of Study Results ................................................................................................... 47 
XII. LIST OF ABBREVIATIONS ......................................................................................... 48 
XIII. 
SIGNATURE OF SPONSOR ................................................................................. 50 
A. Declaration of Sponsor ............................................................................................... 50 
XIV. 
REFERENCES ........................................................................................................ 51 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Title of study 
A Phase 2A Biomarker Study of EPI-589 in Subjects with 
Parkinson’s Disease 
Protocol number 
EPI589-15-002 
IND number 
EudraCT number 
TBD 
2015-001786-10 
Investigative Drug 
EPI-589 
Study Sponsor 
Edison Pharmaceuticals Inc. 
350 North Bernardo Avenue 
Mountain View, CA 94043 
Investigators and 
Investigative Sites 
• 
USA 
• 
UK 
Study population 
Approximately 40 subjects with Parkinson’s disease (PD) 
including 20 subjects with genetically-defined subtypes 
Rationale for Study 
Mitochondrial pathophysiology 
It is now well appreciated that defects in mitochondrial function 
contribute to the pathophysiology of PD both in subjects with 
defined genetic defects as well as those with idiopathic forms of 
the disease. 
High morbidity 
Despite the available therapies for symptomatic relief, PD 
remains a highly morbid disease. There are no approved 
treatments for PD capable of modifying disease progression. 
Pre-clinical efficacy data 
EPI-589 is a redox active molecule that has demonstrated 
potency (EC50 < 100nM) and efficacy (>80% rescue from 
oxidative stress-induced cell death) in cells derived from 
patients diagnosed with sporadic and familial PD subtypes 
including PINK1, parkin and LRRK2. 
Study objectives 
Primary Efficacy Objective 
To evaluate the effects of EPI-589 on blood-based glutathione 
cycle biomarkers in subjects with PD. 


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Secondary Efficacy Objectives 
To evaluate the effects of EPI-589 in subjects with PD on: 
1. Central nervous system (CNS) biomarkers as assessed 
by magnetic resonance spectroscopy (MRS) and 
DaTscan 
2. Clinical Disease State as assessed by the Movement 
Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor 
Symptoms Scale (NMSS), PDQ-39 and EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive 
Assessment (MoCA) and Mattis Dementia rating scale 
(DRS-2) 
5. Mood as assessed by the Beck Depression Inventory 
(BDI) and the Montgomery and Asberg Depression 
rating scale (MADRS) 
6. Pharmacokinetics 
Safety Objectives 
To examine the safety of EPI-589 in subjects with PD by 
examining hematology, blood chemistry, electrocardiogram, 
and drug-related adverse events (AEs) and serious adverse 
events (SAEs). 
Study design 
Open-label study with 30-day run-in phase and adaptive design 
component to include more subjects if deemed appropriate by 
investigators. 
Planned number of 
subjects 
Approximately 40 subjects (20 with genetically-defined 
subtypes of PD and 20 drug-naïve idiopathic PD subjects). 
Study duration 
3 months of study treatment preceded by a 1-month baseline 
parameter run-in period. 
Test product, mode of 
administration, and 
dose 
Test product 
EPI-589 in a tablet formulation at a strength of 250 mg 
Mode of Administration 
Oral with meal 
Dose 
EPI-589 500-mg BID 


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Reference therapy, 
dose, and mode of 
administration 
None 
Safety monitoring 
Clinical 
1. Physical exam and vital signs 
2. Evaluation of adverse events 
3. 12-lead Electrocardiogram 
Laboratory 
1. Routine serum chemistries 
2. Routine hematology tests and coagulation tests 
Inclusion criteria 
1. Hoehn and Yahr stage ≤ 2.5 
2. Ambulatory with or without assistance 
3. Agreement to use contraception if within reproductive 
years 
4. Willingness and ability to comply with study procedures 
5. Stable regimen of dietary supplements for 30 days prior 
to enrollment 
6. Abstention from use of other investigative or non- 
approved drugs for the duration of the trial 
For Idiopathic Subjects 
7. For idiopathic subjects: a diagnosis of early idiopathic 
PD confirmed by the presence of bradykinesia plus one 
or both of the following symptoms: rigidity or resting 
tremor; and with an abnormal DaTscan consistent with a 
dopaminergic deficit 
8. For idiopathic subjects: must not yet require 
symptomatic medications for PD and not expected to 
require such treatment before the end of the study 
9. For idiopathic subjects: age 40 to 75 years 
10. For idiopathic subjects: within 5 years of diagnosis of 
Parkinson’s disease 
For Genetic Subtype Subjects 
11. For genetic subtype subjects: a confirmed diagnosis of 
PD plus a genetic diagnosis consistent with PD, 
specifically PINK1, parkin, LARK2 or other 
mitochondrial genetic subtype 


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12. For genetic subtype subjects: age 21 to 75 years 
13. For genetic subtype subjects: stable medication regimen 
of PD drugs for 30 days (except 60 days for rasagiline) 
prior to enrollment 
Exclusion criteria 
1. Allergy to EPI-589 or other components of the EPI-589 
tablet formulation 
2. Use of antioxidant supplements, specifically vitamins E 
and C beyond the recommended daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic 
disease that will confound the assessment of effect of 
study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 
3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times 
normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of 
study in a trial of a device, drug or other therapy for PD 
For Idiopathic Subjects 
16. For idiopathic subjects: use of any MAO inhibitors, 
amantadine or other drugs prescribed for core symptoms 
of Parkinson’s disease for idiopathic subjects 
17. For idiopathic subjects: use of nortriptyline or 
fluvoxamine 60 days prior to enrollment 
Treatment 
Following study enrollment, baseline assessments will be 
performed. Subjects will participate in a 30-day run-in phase to 
establish biomarker and clinical baseline measurements. 
EPI-589 will then be administered for up to 3 months unless 


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discontinued for safety or tolerability issues. Under an adaptive 
design strategy, additional subjects (up to 20) may be added to 
increase the number of biomarker responsive idiopathic PD 
subjects. 
Efficacy variables 
1. Blood-based glutathione biomarkers 
2. Brain MRS, DaTscan 
3. MDS-UPDRS 
4. Non-motor Symptoms Scale (NMSS) 
5. PDQ-39 
6. EQ-5D 
7. Montreal Cognitive Assessment (MoCA) 
8. Mattis Dementia rating scale (DRS-2) 
9. Beck Depression Inventory (BDI) 
10. Montgomery & Asberg Depression rating scale 
(MADRS) 
11. Timed motor tests in ON and OFF state (for subjects 
on dopamine therapy) 
Safety variables 
Clinical 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
Laboratory 
1. Routine serum chemistries with liver function tests 
2. Routine hematology tests with coagulation tests 
Statistical 
Considerations 
Data Analysis 
This is a within-subject, controlled open-label study seeking to 
determine if EPI-589 can alter the biochemical signature of PD 
as assessed by peripheral blood biomarkers and brain imaging 
biomarkers. In addition, data on a number of disease-relevant 
clinical measures will be collected. 
 
 
 
 
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I. 
SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE 
 
Tests 
-2 to -1 Months 
Day 0 
Month 1 
Month 2 
Month 3 
End of Study 
Screening 
Run-in 
(± 30 days) 
Baseline 
Day 29 
(± 3 days) 
Day 57e 
(± 3 days) 
Day 85 
(± 3 days) 
Informed consent 
 
Inclusion/Exclusion criteria 
 
Past Medical history 
 
Previous genetic testing review 
 
Physical exam & Vital signs 
 
 
 
 
Height & weight 
 
a 
 
 
12-lead ECG 
 
a 
 
 
Hematology (including 
coagulation panel) 
 
a 
 
 
Serum Chemistry 
 
a 
 
 
Pregnancy testb 
 
 
 
 
Genetic analysisc 
c 
Montreal Cognitive Assessment 
 
 
DaTscan 
 
 
Revised Hamilton Rating Scale 
for Depression 
 
Subject enrolls in study 
X 
MRI & MRS 
 
 
Glutathione cycle biomarkers 
 
 
 
 
MDS-UPDRS 
 
 
 
 
Timed motor tests (for subjects on 
dopamine therapy) 
 
 
 
NMSS, PDQ-39, EQ-5D 
 
 
DRS-2, BDI, MADRS 
 
 
Drug plasma concentrationd 
d 
d 
AE/SAE assessment 
 
e 
e 
Concomitant medications 
assessment 
 
 
 
 
e 
e 
a. Screening values can be used if done within one month of baseline. 
b. Female subjects of childbearing potential must have a negative pregnancy test. 
c. Subject should have genetic testing for PD genetic subtypes at screening if not done previously. 
d. Full plasma concentration profile will be obtained at Time = 0, and 0.5, 1, 2, 4, 6, 8, and 12 hours after dosing 
from the first 10 subjects to complete 1 month of therapy at each site. 
e. Month 2 assessments can be done by telephone. Any new AEs and associated concomitant medications 
reported at Month 3 must be followed for 30 days; this follow up may be conducted by telephone. 
Dosing Schedule 
Month 1 
Month 2 
Month 3 
EPI-589 500-mg BID 
 
 
 


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II. 
BACKGROUND INFORMATION AND RATIONALE 
A. 
Introduction 
 
Parkinson’s disease (PD) is a highly morbid neurodegenerative movement disorder that has a 
number of neuromuscular, cognitive and neuropsychiatric manifestations as well as non- 
neurological symptoms. PD is the second most common neurodegenerative disorder with an 
estimated prevalence of 6.3 million people worldwide (EPDA). 
 
PD has long been considered a non-genetic (idiopathic) disease; however, about 5% of patients 
have an identifiable mutation. Disease onset typically occurs after age 50, however, in a subset of 
patients, disease onset can occur at a younger age. The primary motor symptoms result from 
death of dopamine-producing cells in the pars compacta region of the substantia nigra. However, 
the mechanisms underlying this cell death and disease pathology remain poorly understood. 
There is no approved treatment for PD capable of modifying disease progression. Current 
therapies partially address disease motor symptoms through levodopa or dopamine agonists or 
other agents, and other disease symptoms (e.g. neuropsychiatric symptoms), but disability tends 
to increase over time despite these treatments. 
 
The association of PD with mitochondrial pathology and high levels of oxidative stress are well 
established. Increased levels of oxidative stress have been consistently measured in post-mortem 
specimens from PD patients (Maarouf 2012, Reale 2012). The occurrence of PD-like symptoms 
in heroin addicts exposed to MPTP in the 1980s established a first link between PD and 
mitochondrial injury (Langston 1983, Dauer and Przedborski 2003). MPTP inhibits complex 1 of 
the mitochondrial respiratory chain and induces degeneration of dopaminergic cells through 
oxidative stress-mediated injury. The link between mitochondrial injury and PD was further 
strengthened by the induction of PD symptoms following exposure to another neurotoxic 
complex 1 inhibitor, rotenone (Betarbet et al 2000, Greenamyre et al. 2003), which like MPTP 
has come to be used in pre-clinical testing for its phenotypic similarities to PD. 
 
Furthermore, the identification of genetic mutations such as PINK1, parkin, LRRK2 and others 
in mitochondrial genes in familial PD patients provided the strongest link between the 
mitochondria and PD (Winklhofer and Haass 2010). Normally these genes influence oxidative 
balance and provide neural protection of the dopaminergic neurons that are affected by PD. 
PINK1 and parkin are involved in protecting against oxidative stress (OS) and overabundant 
reactive oxygen species (ROS), and are implicated in cell morphology and dynamics, as well as 
in the preferential degradation of dysfunctional mitochondria or “mitophagy” (Ashrafi et al. 
2014). Mutant LRRK2 leads to the accumulation of misfolding intracellular protein 
accumulations, cell stress and apoptosis (Giasson et al. 2006, Zhu et al. 2006). 
 
The importance of oxidative stress in PD pathology is further substantiated by the measurement 
of decreased levels of reduced glutathione in the brains of patients with PD (Holmay et al. 2013). 
Glutathione levels are low at very early stages of PD and correlate with disease severity 
(Riederer et al. 1989), and experimental induction of glutathione depletion leads to mitochondrial 
complex I dysfunction (Jha et al, 2000;). Reduced glutathione is an essential intermediary 


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metabolite that serves as the primary native cellular antioxidant. In a state of high oxidative 
stress, elevated levels of ROS outstrip the supply of glutathione (GSH) resulting in depletion of 
GSH and ROS-mediated cell death. 
 
Given the important role of oxidative stress and mitochondrial pathology in PD, a redox-active 
therapy that could target key pathways in cellular OS response pathways may hold promise for 
the treatment of PD. 
 
B. 
Rationale for the Study of EPI-589 in Parkinson’s Disease 
 
EPI-589 is a redox active molecule that has demonstrated potency (EC50 <100nM ) and efficacy 
(>80% rescue from oxidative stress-induced cell death) in cells derived from patients diagnosed 
with sporadic and familial PD genetic subtypes including PINK1, parkin and LRRK2. 
In these cell-based assays, primary fibroblasts from patients (and control) were pre-incubated 
with and without test compound, then treated with L-buthionine-(S,R)-sulfoximine (BSO), a 
GSH synthesis inhibitor, to initiate depletion of cellular GSH. GSH depletion has been shown to 
lead to OS and disruption of calcium homeostasis resulting in loss of the mitochondrial 
membrane potential and cell death. Under these conditions, the control cells are resistant to the 
stress and the fibroblast cells from patients with disease indications die within 36 to 48 hours. 
Pretreatment of cells with EPI-589 prior to initiation of GSH depletion potently protected against 
oxidative stress-mediated cell death, with EC50 response concentrations of 16 to 52 nM.(Table 
1). 
Table 1: 
Cell Line Rescue with EPI-589 in Parkinson’s Disease Genetic Subtypes 
 
EPI-589 
EC50 (nM range) 
PINK1 
26-36 
LRRK2 
16-18 
parkin 
42-52 
 
C. 
Name and Description of Investigational Product 
The IUPAC name of EPI-589 is: 
(R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanamide. 
 
A common chemical name of EPI-589 is (R)-troloxamide quinone. EPI-589 is derived from 
resolved (R)-Trolox®, a derivative of vitamin E in the form of a pale yellow to yellow solid. The 
EPI-589 drug product will be provided in a 250-mg tablet formulation. 


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The Investigator will ensure that all study drugs are stored and dispensed in accordance with the 
Food and Drug Administration (FDA) and local regulations concerning the storage and 
administration of investigational drugs. 
 
D. 
Findings from Non-Clinical and Clinical Studies 
D1. Non-Clinical Studies 
 
EPI-589 is an orally available compound that has been demonstrated in vitro and in vivo to cross 
the blood-brain-barrier. In 28-day and 91-day repeat-dose toxicity studies in rat and cynomolgus 
monkey, the no observed adverse effect level (NOAEL) was 300 mg/kg/day, corresponding to 
combined mean Cmax values of 37,717 to 56,500 ng/mL (rat) and 14,300 to 16,417 ng/mL 
(monkey), and a combined mean area under the plasma concentration-time curve from time zero 
to the last measurable concentration (AUClast) value of 149,495 to 297,000 ng.h/mL (rat) and 
47,300 to 67,656 ng.h/mL (monkey) (Studies 1660-038, 1660-039, 1660-063, and 1660-064). 
 
A phase 1 clinical study demonstrated that healthy subjects administered 500 mg EPI-589 BID 
for 14 days showed a mean Cmax value of 1,890 ng/mL and a mean AUClast value of 5,240 
ng.h/mL (Study EPI589-14-01). These plasma concentrations are well below the mean exposure 
values in monkey associated with the NOAEL in the toxicity studies, corresponding to safety 
margins of approximately 7- to 8-fold for the mean Cmax and 9- to 12-fold for the mean AUC. 
 
During the 28-day repeat-dose toxicity studies, rat and monkey were exposed to up to 1,000 
mg/kg/day EPI-589 PO (Studies 1660-039 and 1660-038). The NOAEL for both studies was 300 
mg/kg/day. Rats exposed to 1,000 mg/kg/day exhibited adverse test-article related effects on 
hematology parameters consistent with hemolysis and bone marrow regeneration, mild to 
moderately enlarged spleens, and increased organ weights with some organs showing 
corresponding microscopic pathology. The majority of these findings were resolved following 
the 28-day recovery period. Monkeys exposed to 1,000 mg/kg/day showed significant test-article 
related morbundidity that resulted in half the animals in the high dose group being euthanized on 
Days 3 and 4 and the remaining animals being euthanized on Day 9. These animals exhibited 
significant elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
values, and microscopic findings in the kidney, liver, skeletal muscle, heart, and lymphoid 
tissues. In several of the animals the primary cause of morbidity was determined to be test-article 
related renal tubular degeneration/necrosis. 
 
During the 91-day repeat-dose toxicity studies, rat and monkey were exposed to up to 300 
mg/kg/day EPI-589 PO (Studies 1660-063 and 1660-064). The NOAEL for the rat study was 300 
mg/kg/day and the no observed effect level (NOEL) for the monkey study was 300 mg/kg/day. 
rats exposed to 300 mg/kg/day and 
rats exposed to ≥ 100 mg/kg/day exhibited mild 
test-article related effects on hematology parameters consistent with hemolysis and bone marrow 
regeneration. These findings were not considered adverse. 
 
Development and reproductive toxicology studies were conducted in rat and rabbit at doses up to 
1,000 mg/kg/day EPI-589 PO (Studies 1660-069, 1660-067, and 1660-068). The NOAEL for 
reproductive toxicity in rat was demonstrated to be 1,000 mg/kg/day (1660-069). The NOAEL 


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for developmental toxicity in rat and rabbit during the embryofetal studies was deemed to be 300 
mg/kg/day (Studies 1660-067 and 1660-068). Rats exposed to 1,000 mg/kg/day exhibited 
decreased maternal body weights, decreased food consumption, and decreased fetal body 
weights. There was no teratogenic potential in rat at doses up to 1,000 mg/kg/day. Rabbits 
exposed to 1,000 mg/kg/day exhibited decreased maternal body weights, decreased food 
consumption, decreased number of viable fetuses, decreased litter size, increased 
postimplantation loss, increased resorptions (early and late), and increased fetal skeletal 
malformations. The margin of exposure between healthy humans exposed to 500 mg BID EPI- 
589 (relevant clinical dose) for 14 days (Study EPI589-14-01) and rabbits exposed to 1,000 and 
300 mg/kg/day EPI-589 is approximately 179- to 236-fold and 47- to 50-fold, respectively. 
Based on these data, EPI-589 is not anticipated to increase the risk of adverse developmental or 
reproductive outcomes in humans when used in accordance with dosing information. 
 
EPI-589 was negative for mutagenic response in the in vitro Ames bacterial reverse mutation 
assay (Study AD58AS.502ICH.BTL); equivocal for the induction of structural and negative for 
the induction of numerical chromosomal aberrations in the in vitro chromosome aberration assay 
in Chinese hamster ovary (CHO) cells (Study AD58AS.331ICH.BTL); and negative in the in 
vivo micronucleus assay in rat (Study AD58AS.125012ICH.BTL). These data indicate a low 
clinical mutagenicity risk. 
 
Primary pharmacodynamics studies demonstrated that EPI-589 is a potent rescue agent in 
cellular models of diseases of energy metabolism and oxidative stress. In vitro cellular models 
utilizing primary human fibroblasts from patients with ALS, Parkinson’s disease and other 
diseases characterized by high levels of oxidative stress, or striatal cells derived from mouse 
models of Huntingdon’s disease were used to assess the potential of EPI-589 to mitigate the 
harmful effects of oxidative stress (Studies EPI-BA-000216, EPI-BA-000363, and EPI-BA- 
000362). Pretreatment of patient cells with EPI-589 potently protected against oxidative stress- 
mediated cell death in a concentration dependent manner. Furthermore, EPI-589 normalized 3- 
nitrosotyrosine (3NT) levels, a biomarker of oxidative stress, and increased glutathione levels in 
mouse striatal cells under oxidative stress conditions. 
 
In secondary pharmacodynamics in vitro receptor/ion channel binding studies, EPI-589 did not 
significantly affect off-target molecular targets (Study EPI-BA-159). In safety pharmacology 
studies, EPI-589 did not significantly affect ion channel current in the hERG assay (Study 
130719.FEK); did not affect ECG parameters during the 28-day and 3-month repeat-dose 
toxicology studies in monkey at doses up to 1,000 mg/kg/day (only Day 1 data collected for 
animals administered 1,000 mg/kg/day and up to Day 91 data collected for animals administered 
up to 300 mg/kg/day) (Studies 1660-038 and 1660-064); and did not change respiratory function 
or adversely impact neurobehavioral function in rat at doses up to 1,000 mg/kg (Studies 1660- 
051, 1660-050, and 1660-063). 
 
In single dose exposure PK studies, EPI-589 was absorbed rapidly in rat, dog, and monkey, with 
mean Tmax values ranging from .08 to 1 hour and mean T1/2 values ranging from 3.7 to 5.0 
hours (Studies EPI-BA-53, EPI-BA-59, EPI-BA-72, and EPI-BA-302). EPI-589 does not 
significantly induce cytochrome P450 (CYP) enzymes and appears to be metabolized by 


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reductases in the liver cytosol and microsomal subcellular fractions and to a lesser extent by the 
family of CYP enzymes (Studies MC12M-0037 and MC14M-0018). 
 
EPI-589 exhibited weak direct inhibition of CYP2B6, CYP2C8, CYP2C9, and CYP3A4/5 (both 
midazolam and testosterone as probe substrates) with estimated IC50 (µM) values and R values 
based on free plasma concentrations (shown in parentheses) of 28 (1.25), 40 (1.18), 92 (1.08), 34 
(1.21), and 53 (1.13), respectively (Study MC14M-0020)Based on these data, EPI-589 is not 
anticipated to increase the risk of adverse developmental or reproductive outcomes in humans 
when used in accordance with dosing information. 
 
D2. Clinical Studies 
 
Phase I Study EPI589-13-022 evaluated the pharmacokinetics, safety and tolerability of single 
ascending oral doses (SADs) of EPI-589 in healthy subjects and a preliminary evaluation of 
safety and tolerability data was performed. Sixteen AEs were reported in the 36 subjects who 
received administration of EPI-589. Ten subjects (27.8%) who received EPI-589 (and 2 subjects, 
20% on placebo) reported AEs that were assessed as related. All were mild and resolved during 
the study, with the exception of a common cold (1 subject) and cold sore (1 subject). None of the 
vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant change 
compared to baseline. From all preliminary data available from this SAD study it may be 
concluded that there is no objection to proceed with treatment with 50 mg, 100 mg, 250 mg or 
500 mg of EPI-589. 
 
Phase I Study EPI589-14-01 evaluated the pharmacokinetics, safety and tolerability of multiple 
ascending oral doses (MAD) of EPI-589 in healthy subjects, and an evaluation of safety and 
tolerability data was performed. No severe or serious adverse events were observed. Twenty-six 
subjects (65.0%) on EPI-589, and 8 subjects (80%) on placebo reported AEs. Twenty-four of 34 
AEs were considered by the Investigator to be related to EPI-589. Nineteen subjects (47.5%) on 
EPI-589, and 6 subjects (60%) on placebo reported AEs that were assessed as related. All 
adverse events were mild, except for 1 AE which was moderate (unrelated brain contusion). All 
AEs were resolved during the study, with the exception of one, which was a common cold. None 
of the vital signs, ECG parameters or clinical laboratory test results showed a clinically relevant 
change compared to baseline. From all preliminary data available from the MAD study it may be 
concluded that there is no objection to proceed with treatment with 250-mg, or 500-mg doses of 
EPI-589. 
 
E. 
Human Pharmacokinetics 
 
EPI-589 was fast absorbed following oral administration in SAD Study EPI589-13-022. The 
median Cmax was attained approximately within 1 hour under fasted conditions after dosing. The 
median Tmax values were attained in 0.50 to 1.00 hours over the dose range of 50 to 1000 mg 
under fasted conditions and 3.01 hours at the 500 mg dose level under fed conditions. Mean half- 
life ranged from 5.55 to 10.7 hours over the dose range of 50 to 1000 mg under fasted conditions 
and 4.91 hours at the 500 mg dose level under fed conditions. Half-life was independent of the 
dose levels over the dose range of 50 to 1000 mg under fasted conditions. The rate of EPI-589 
absorption, as measured by Cmax, was decreased by 24.07% under fed conditions at the 500 mg 


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dose level. The extent of absorption as measured by AUCs (AUC0-t or AUC0-inf) was not affected 
under fed conditions in the 500 mg dose groups. 
 
In MAD study EPI589-14-01, EPI-589 was rapidly absorbed following oral administration and 
the median Cmax was attained within 1 hour (0.50 to 0.76 hours) under fasted conditions after 
single or multiple dosing among these five cohorts. The mean half-life of EPI-589 ranged from 
5.64 to 8.47 hours among these five cohorts. In general, the mean values of the time to peak 
concentration (Tmax), half-life (t½), apparent terminal constant (λz), accumulation ratio (AR), 
percent fluctuation (%F) and accumulation index (AI) of EPI-589 were similar among the five 
cohorts of various ages and smoking status. No significant effects of age or smoking on EPI-589 
pharmacokinetics were observed in this study. Dose proportionality existed in the exposures 
(AUC0-tau, Cmax, Cmin and Cavg) over the dose range of 250 to 500-mg BID EPI-589 under fasted 
conditions. 
 
F. 
Clinical Study 
 
EPI589-15-002: A Phase 2A Biomarker Study of EPI-589 in Subjects with Parkinson’s Disease. 
 
G. 
Selection of Drugs and Dosages 
 
The study drug in this trial is EPI-589: common chemical name (R)-troloxamide quinone. 
 
Each tablet contains 250 mg of EPI-589. The study dose is 500-mg BID, to be maintained in the 
absence of treatment-emergent toxicity. EPI-589 tablets must be taken with meals. 
 
H. 
Compliance Statement 
 
This study will be conducted in full accordance with all applicable research policies and 
procedures, the EU Clinical Trials Directive, all applicable EU and US federal and local laws 
and regulations including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312 and 314, and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonization (ICH). Any episode of noncompliance will be documented. 
 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
will report AEs in accordance with local institutional policies and procedures and all EU and US 
federal requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the study. 
 
I. 
Relevant Literature and Data 
 
Literature references have been provided in Section XIV. Additional information can be found in 
the Investigator’s Brochure. 


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III. STUDY OBJECTIVES 
A. 
Primary Efficacy Objective 
 
The primary objective of this study is to evaluate the effects of EPI-589 on blood-based 
glutathione cycle biomarkers in subjects with PD. 
 
B. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with PD on: 
1. Central nervous system (CNS) biomarkers as assessed by magnetic resonance 
spectroscopy (MRS) and DaTscan 
2. Clinical Disease State as assessed by the Movement Disorder Society-sponsored 
revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
3. Disease morbidity as assessed by the Non-motor Symptoms Scale (NMSS), PDQ-39 
and EQ-5D 
4. Cognitive function as assessed by Montreal Cognitive Assessment (MoCA) and Mattis 
Dementia rating scale (DRS-2) 
5. Mood as assessed by the Beck Depression Inventory (BDI) and the Montgomery & 
Asberg Depression rating scale (MADRS) 
6. Pharmacokinetics 
 
C. 
Safety Objectives 
 
To examine the safety of EPI-589 in subjects with PD by examining hematology, blood 
chemistry, electrocardiogram, and drug-related AEs and SAEs. 
 
 
 
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IV. INVESTIGATIONAL PLAN 
A. 
General Schema of Study Design 
 
Following study enrollment, baseline assessments will be performed. Subjects will participate in 
a 30-day run-in phase to establish biomarker and clinical baseline measurements. EPI-589 will 
then be administered for up to 3 months unless discontinued for safety or tolerability issues. 
 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. 
 
A1. 
Screening Phase 
 
Suitable candidates for the trial will receive a short overview of the study by the Investigator’s 
staff and, if interested, will undergo Screening. The Investigator will inform each prospective 
subject of the nature and details of the study, explain the potential risks and must obtain written 
informed consent from the subject or their legally authorized representative prior to performing 
any study related procedures. 
 
A2. 
30-Day Run-in Phase 
 
Once eligibility is confirmed, the subject will be enrolled in the study and the run-in scans, 
biomarker and clinical measurements will be collected. 
 
A3. 
Baseline 
 
Baseline assessments, scans, biomarker and clinical measurements will be collected. 
 
A4. 
Treatment Phase 
 
EPI-589 dosing will start on Day 1. Subjects will self-administer EPI-589 at a dose of 500-mg 
BID. 
 
Scans, biomarker and clinical measurements will be collected at Day 29 (± 3 days) and Day 85 
(± 3 days). 
 
A5. 
End of Study 
 
End of study data will be collected at the last study visit Day 85 (± 3 days). 
 
AEs reported as ongoing at Day 85, any associated concomitant medications associated with 
such events, and any events occurring within 30 days of last dose will be followed for 30 days. 


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B. 
Randomization and Blinding 
 
This is an open-label study. 
 
C. 
Study Duration, Enrollment and Number of Sites 
C1. Duration of Subject Treatment 
 
Subjects will participate in a 30 day run-in phase to establish biomarker and clinical baseline 
measurements. EPI-589 will then be administered for 3 months unless discontinued for safety or 
tolerability issues. 
 
C2. Total Number of Study Sites/Total Number of Subjects Projected 
 
This study will be conducted at two study sites: 
 
• 
UK 
• 
USA. 
 
Approximately 40 subjects with PD are projected: 
 
• 
20 with genetically-defined subtypes 
• 
20 PD drug-naïve 
 
Under an adaptive design strategy, additional subjects (up to 20) may be added to increase the 
number of biomarker responsive idiopathic PD subjects. 
 
D. 
Study Population 
D1. Inclusion Criteria 
 
1. Hoehn and Yahr stage ≤ 2.5 
2. Ambulatory with or without assistance 
3. Agreement to use contraception if within reproductive years 
4. Willingness and ability to comply with study procedures 
5. Stable regimen of dietary supplements for 30 days prior to enrollment 
6. Abstention from use of other investigative or non-approved drugs for the duration of the 
trial 
 
For Idiopathic Subjects 


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7. For idiopathic subjects: a diagnosis of early idiopathic PD confirmed by the presence of 
bradykinesia plus one or both of the following symptoms: rigidity or resting tremor; and 
with an abnormal DaTscan consistent with a dopaminergic deficit 
8. For idiopathic subjects: must not yet require symptomatic medications for PD and not 
expected to require such treatment before the end of the study 
9. For idiopathic subjects: age 40 to 75 years 
10. For idiopathic subjects: within 5 years of diagnosis of Parkinson’s disease 
 
For Genetic Subtype Subjects 
 
11. For genetic subtype subjects: a confirmed diagnosis of PD plus a genetic diagnosis 
consistent with PD, specifically PINK1, parkin, LARK2 or other mitochondrial genetic 
subtype 
12. For genetic subtype subjects: age 21 to 75 years 
13. For genetic subtype subjects: stable medication regimen of PD drugs for 30 days (except 
60 days for rasagiline) prior to enrollment 
 
D2. Exclusion Criteria 
 
1. Allergy to EPI-589 or other components of the EPI-589 tablet formulation 
2. Use of antioxidant supplements, specifically vitamins E and C beyond the recommended 
daily allowance 
3. Other Parkinsonian disorders 
4. MoCA score of <24 
5. Revised Hamilton Rating Scale for Depression ≥ 11 
6. Parkinsonism due to drugs or toxins 
7. Diagnosis of any other clinically significant neurologic disease that will confound the 
assessment of effect of study drug on disease progression 
8. Malignancy within past two years 
9. Pregnant or plans to become pregnant or breast feeding 
10. History of stroke 
11. History of brain surgery 
12. Hepatic insufficiency with liver function tests (LFTs) > 3 times upper limit of normal 
13. Renal insufficiency as defined by creatinine > 1.5 times normal 
14. End stage cardiac failure 
15. Participation within past 3 months and for duration of study in a trial of a device, drug or 
other therapy for PD 


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For Idiopathic Subjects 
 
16. For idiopathic subjects: use of any MAO inhibitors, amantadine or other drugs prescribed 
for core symptoms of Parkinson’s disease for idiopathic subjects 
17. For idiopathic subjects: use of nortriptyline or fluvoxamine 60 days prior to enrollment 
 
 
 
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V. 
STUDY PROCEDURES 
A. 
Screening Visit 
 
Screening evaluations will be performed within two months of first dose. The Investigator will 
inform each prospective subject of the nature of the study, explain the potential risks, and must 
obtain written informed consent from the subject prior to performing any study-related 
procedures and prior to the administration of study drug. Screening evaluations consist of the 
following: 
 
1. Assessment of eligibility 
2. Medical history, chart review 
3. Receipt and review of previous testing including genetic tests 
4. Physical examination including vital signs 
5. Height and weight 
6. 12-lead ECG 
7. Laboratory assessments for hematology, coagulation, and serum chemistry (See Sections 
VI.D3.a and VI.D3.b) 
8. Urine pregnancy test (women of childbearing potential must have a negative urine 
pregnancy test; see Section VI.D3.d) 
9. Genetic analysis for subjects that have not had prior genetic testing for PD mutations (See 
SectionVI.D3.c) 
10. MoCA 
11. DaTscan 
12. Revised Hamilton Rating Scale for Depression 
13. Concomitant medications assessment (last 60 days prior to enrollment) 
 
A1. 
Run-in Assessments 
 
If the subject is eligible for the study following all screening procedures and is still willing to 
participate in the study, the subject must return to the clinic within one month for Run-in 
assessments. These will be performed 30 days (± 3 days) prior to baseline after eligibility is 
confirmed and subject is enrolled in the study. Run-in evaluations consist of the following: 
 
1. Glutathione cycle biomarkers 
2. MRI and MRS 
3. MDS-UPDRS 
4. Timed motor tests (for subjects on dopamine therapy) 


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5. Concomitant medications review 
 
B. 
Treatment Phase 
 
After the Run-in phase, the subject must return to the clinic within 30 days (± 3 days) for 
baseline assessments. In-clinic study visits are scheduled at Month 1 and Month 3. The Month 2 
study assessments can be conducted via telephone. End of Study assessments will be conducted 
at the Month 3 study visit. Pharmacokinetic sampling takes place at Month 1 and Month 3. 
 
B1. 
Baseline Assessments 
 
The following will be assessed or performed at this visit. 
 
1. Physical examination including vital signs 
2. Height and weight* 
3. 12-Lead ECG* 
4. GSH cycle biomarkers 
5. Laboratory assessments for hematology, coagulation and serum chemistry* 
6. Urine pregnancy test (females of child bearing potential) 
7. MDS-UPDRS 
8. NMSS, PDQ-39, EQ-5D 
9. DRS-2 
10. BDI, MADRS 
11. Timed motor tests (for subjects on dopamine therapy) 
12. Concomitant medications review 
 
* Screening results for these assessments may be used if obtained within 1 month of Baseline. 
 
B2. 
Study Visit Assessments 
 
• 
Month 1 Clinic Visit (Day 29 ± 3 days): 
 
The following will be assessed or performed at the Month 1 clinic visit: 
 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 


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6. GSH cycle biomarkers 
7. MDS-UPDRS 
8. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
9. AE assessments 
10. Concomitant medications review 
 
• 
Month 2 Visit (Day 57 ± 3 days) 
 
Month 2 assessments can be conducted by telephone and must include review of: 
 
1. Concomitant medication 
2. AEs 
 
• 
Month 3 Clinic Visit (Day 85 ± 3 days) 
 
The following will be assessed or performed at the Month 3 clinic visit: 
 
1. Physical examination including vital signs 
2. Height and weight 
3. 12-lead ECG 
4. Laboratory assessments for hematology, coagulation, and serum chemistry 
5. Urine pregnancy test (females of child bearing potential) 
6. GSH cycle biomarkers 
7. MDS-UPDRS 
8. Pharmacokinetics: a full plasma drug concentration profile will be obtained from the first 
10 subjects to complete 1 month of therapy at each site at: Time = 0, and 0.5, 1, 2, 4, 6, 8, 
and 12 hours after dosing. 
9. AE assessments 
10. Concomitant medications review 
11. MRI and MRS 
12. DaTscan 
13. MoCA 
14. NMSS, PDQ-39, EQ-5D 
15. DRS-2 
16. BDI, MADRS 


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17. Timed motor tests (for subjects on dopamine therapy) 
 
B3. 
Pharmacokinetics 
 
Plasma concentration samples will be collected from the first 10 subjects to complete 1 month of 
therapy at each site, at the following time points: 
 
• 
Month 1 (Day 29 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
• 
Month 3 (Day 85 ± 3 days): 0 hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose 
 
B4. 
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 study visit assessments completed as soon as possible. 
 
C. 
End of Study Visit 
 
End of Study visit takes place at Month 3 (Day 85 ± 3 days) and includes the assessments listed 
in Section VB2 Study Visit Assessments. 
 
Subjects who have an ongoing AE at the time of study completion will be followed for up to 30 
days, until the event resolves, or until the Sponsor and the Investigator agree that further follow- 
up is not medically necessary. 
 
D. 
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 case report form (CRF) using the supplemental visit CRF pages. 
 
E. 
Concomitant Medication 
 
Any medication taken by a subject ≤ 60 days prior to enrollment and during the course of the 
study and the reason for use of the medication will be recorded on the 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 [OTC] medications) without consulting the Investigator. 
 
F. 
Prohibited Medications 
 
The following are prohibited while the subject is on study treatment: 
1. Use of antioxidants, specifically vitamins E and C beyond the recommended daily 
allowance 


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2. Participation 3 months prior to and for the duration of the study in a trial of a device, drug 
or other therapy for PD 
3. Use of MAO inhibitors, amantadine or other drugs prescribed for core symptoms of 
Parkinson’s disease for idiopathic subjects 
4. Use of nortriptyline or fluvoxamine 
 
G. 
Subject Withdrawals 
 
Subjects may be withdrawn from the study at any time for reasons including the following: 
 
1. At their own request or at the request of their legally authorized representative 
2. If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
subject’s well-being 
3. At the specific request of the Sponsor (or designee) 
4. Additional protocol specific reasons 
 
In all cases, the reason for withdrawal must be recorded in the 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 
IX.B. 
 
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. 
 
Every effort will be made to follow subjects who have an ongoing AE at the time of withdrawal 
until the event resolves, or until the Sponsor and the Investigator agree that further follow-up is 
not medically necessary. 
 
 
 
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VI. STUDY ENDPOINTS AND EVALUATIONS 
A. 
Primary Efficacy Endpoint 
 
Change from baseline in blood-based glutathione cycle biomarkers in subjects with PD. 
 
B. 
Secondary Efficacy Endpoints 
 
1. MRS, DaTscan 
2. MDS-UPDRS 
3. NMSS 
4. PDQ-39 
5. EQ-5D 
6. MoCA 
7. DRS-2 
8. BDI 
9. MADRS 
10. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
 
C. 
Safety Endpoints 
 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Routine serum chemistries with liver function tests 
4. Routine hematology tests with coagulation tests 
5. Electrocardiogram 
 
D. 
Screening and Baseline Evaluation 
D1. Physical Examination 
 
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. 
 
Vital sign measurements (pulse rate, blood pressure and respiration rate) will be obtained in the 
sitting position (after the subject has been sitting for five minutes). 


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Medical history and demographics including age, gender, race, height and weight will be 
collected at Screening. 
 
D2. Height and Weight 
 
Weight (kg) will be measured in ordinary indoor clothing (i.e., street clothes, scrubs, etc.) with 
shoes off. Height will be recorded in centimeters (cm). 
 
If clinically significant findings, as determined by the Investigator, are recorded for a particular 
symptom, sign or abnormal measurement, that measurement will be repeated at medically 
appropriate intervals until the value returns to an acceptable range, a specific diagnosis is 
established, or the condition is otherwise explained. 
 
D3. Laboratory Evaluations 
 
Subjects will have less than 100 mL of blood drawn over the course of the study. 
The following variables will be collected at various times (as detailed in Section I). 
a. 
Hematology 
 
1. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), red cell distribution width (RDW) 
2. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) reported as absolute values 
3. Platelets: platelet count, mean platelet volume (MPV) 
4. Coagulation: prothrombin time (PT) with INR, partial thromboplastin time (PTT), 
activated (aPTT) 
 
b. Serum chemistry 
 
1. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase 
[SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total and 
direct), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH) 
2. Renal: blood urea nitrogen (BUN), and creatinine 
3. Electrolytes: sodium, potassium, chloride, and carbon dioxide (CO2) as bicarbonate 
4. General: creatine phosphokinase (CPK), creatine kinase (CK), and troponin (at baseline 
only); total protein, albumin, calcium, magnesium, glucose, phosphate 
5. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL) cholesterol, cholesterol/HDL Ratio (calculated), non-HDL cholesterol 
(calculated), and triglycerides 


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c. 
DNA sample 
 
1. 1.5 mL EDTA blood sample for DNA extraction for genetic testing for PD subtypes at 
screening if not done previously. 
 
d. Urine pregnancy test 
1. Human chorionic gonadotropin (HCG) beta subunit will be measured on all female 
subjects of childbearing potential. 
 
Laboratory tests that result in significantly abnormal values should be repeated for verification. 
Additional tests and other evaluations required to establish the significance or etiology of an 
abnormal result, or to monitor the course of an AE, should be obtained when clinically indicated. 
In particular, if a clinically significant abnormal result is observed that is not resolved by the 
final study visit, repeat tests should be performed to document resolution or stability of the 
abnormality. 
 
Diagnoses associated with any NIH Common Terminology Criteria for Adverse Events (CTC 
v4.03) Grade 3 or 4 laboratory abnormalities will be recorded as SAEs on the CRF. Repeated 
and verified ≥ Grade 3 laboratory tests will be reported as an SAE to the Sponsor and the IRB 
per institutional requirements. The recorded event should indicate the underlying abnormality or 
diagnosis (e.g., renal insufficiency) if known, as opposed to the observed deviation in laboratory 
results (e.g., elevated creatinine). Any additional relevant laboratory results obtained by the 
Investigator during the study will be supplied to the Sponsor. 
 
E. 
Sample Collection Procedures, Bioanalytical Methods and Sample Shipment 
 
Subject samples will be identified by unique sample codes. 
 
Fasting blood samples will be collected for determination of levels of GSH cycle markers. A 
contract laboratory will receive samples via courier in order to test GSH cycle components and 
to perform the pharmacokinetic analysis. Additional information about the collection, handling, 
storage, and shipment of the GSH cycle marker samples will be provided separately prior to start 
of the study. 
 
Blood samples for clinical laboratory measurements should be collected and processed according 
to the site’s laboratory’s standard procedure. 
 
F. 
Efficacy Evaluations 
F1. 
Glutathione Cycle Biomarkers 
 
Plasma levels of oxidized and reduced GSH as well as GSH metabolites will be used to evaluate 
EPI-589 target engagement and ability to correct a key biochemical aspect of disease pathology. 


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F2. 
Neuroradiology 
 
MRS will be used to measure GSH and other metabolites in the basal ganglia. Extent of cortical 
and basal degeneration will be assessed by MRI. Dopamine uptake will be measured by 
DaTscan. 
 
F3. 
Parkinson’s Disease Rating (MDS-UPDRS) 
 
The MDS-UPDRS is a tool for monitoring the impact of PD, the degree of disability caused, and 
complications from treatment. Part I evaluates nonmotor experiences of daily living; Part II 
evaluates motor experiences of daily living; Part III is a motor examination and includes the 
Hoehn and Yahr scale; Part IV examines motor complications (e.g., motor fluctuations and 
dyskinesias). 
 
Several questions from Part I and all questions from Part II are designed to be amenable to a 
patient/caregiver questionnaire format; the remaining interview (Part I and Part III) and 
examination (Part IV) are designed with the expectation they can be completed within 30 
minutes. Each item is measured on a five-point scale. 
 
F4. 
Non-motor Symptoms (NMSS) 
 
Non-motor symptoms are evaluated using the NMSS which is divided into 30 questions in 9 
different domains including such symptoms as dribbling saliva, constipation, depression, sleep 
disorders, apathy, hallucinations and dementia. Symptoms are quantified based on their severity 
(using a scale of 0 to 3) and frequency (using a scale of 0 to 4). The final cumulative scores are 
derived from adding up the product of the frequency score times severity score for each of the 30 
questions. 
 
F5. 
Parkinson’s Disease Questionnaire (PDQ-39) 
 
PDQ-39 is a self-administered questionnaire for patients with PD that has 39 questions relating 
to eight key areas of health and daily activities, including both motor and non-motor symptoms. 
It is scored on a scale of 0 to 100, with lower scores indicating better health, and high scores 
more severe symptoms. 
 
F6. 
EQ-5D 
 
EQ-5D is a questionnaire designed to provide measures of health-related quality of life states, 
consisting in five domains (mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression). 
 
F7. 
Montreal Cognitive Assessment (MoCA) 
 
MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive 
domains: attention and concentration, executive functions, memory, language, visuo- 


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constructional skills, conceptual thinking, calculations, and orientation. Severity ranges are 
approximately: 26 to 30 normal; 18 to 26 mild cognitive impairment; 10-17 moderate cognitive 
impairment; < 10 severe cognitive impairment. 
 
F8. 
Mattis Dementia Rating Scale (DRS-2) 
 
The DRS-2 is an instrument used in screening for dementia designed for adults with cognitive 
impairment aged 56 and older. It provides a composite score and five subscale scores in 
Attention, Initiation-Perseveration, Construction, Conceptualization, and Memory. 
 
F9. 
Beck Depression Inventory (BDI) 
 
The BDI is a self-reporting inventory that measures characteristic attitudes and symptoms of 
depression, including physical symptoms. Twenty-one questions have four responses each (rated 
0 to 3) with a total cumulative score scale ranging from 1-10 considered normal) > 40 (extreme 
depression). 
 
F10. Montgomery and Asberg Depression rating scale (MADRS) 
 
The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. 
Ten core symptoms and cognitive features are rated on a severity scale of 0 to 6. Higher scores 
indicate increasing depressive symptoms. 
 
F11. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
 
Timed motor tests are simple, objective, quantitative measures for the assessment of Parkinson’s 
disease. They include, in an on-medication and an off-medication state, timed recorded physical 
movements. 
 
 
 
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VII. STATISTICAL CONSIDERATIONS 
A. 
Statistical Analysis 
 
In this a within-subject, controlled open-label study changes from baseline to Month 3 will be 
calculated for each subject. 
 
A1. 
Analysis Populations 
 
Demographic characteristics and baseline efficacy data will be presented and summarized by 
treatment group for all subjects in the efficacy intent to treat (EITT) population. Demographic 
information will also be summarized by treatment group for the Safety population. No formal 
statistical comparisons will be made for either the EITT or Safety populations. 
 
B. 
Efficacy Analysis 
B1. 
Primary Efficacy Variables 
 
The primary efficacy variable is GSH cycle biomarkers (at baseline, Day 29 and Day 85). 
 
B2. 
Secondary Endpoints 
 
1. Brain MRS, DaTscan 
2. MDS-UPDRS 
3. NMSS 
4. PDQ-39 
5. EQ-5D 
6. MoCA 
7. DRS-2 
8. BDI 
9. MADRS 
10. Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
 
C. 
Safety Analysis 
 
Assessment of safety will include calculating the overall number of subjects (by absolute number 
and percentage) with a particular AE. Safety will also be evaluated through examining clinical 
laboratory data (including chemistry and hematology and coagulation information) and physical 
examination findings, including vital signs obtained throughout the course of the study. A 
medical monitor will provide study oversight. 


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D. 
Sample Size 
 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 PD drug-naïve 
subjects). 
 
 
 
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VIII. STUDY MEDICATION 
A. 
Description 
 
EPI-589 is presented as an immediate release film-coated tablet. Each tablet contains 250 mg of 
EPI-589 and the following compendial excipients: lactose, microcrystalline cellulose, 
polyvinylpyrrolidone, crospovidone and magnesium stearate. Each tablet is film-coated with 
Opadry® II yellow. The tablets are yellow-colored and oval-shaped with a total target weight of 
824 mg. The tablets are packaged at 28 tablets per bottle in high-density polyethylene (HDPE) 
pharmaceutical wide mouth containers, induction sealed, and closed with a child-resistant 
closure. Each container is labeled with appropriate product information meeting current 
regulatory requirements. 
 
B. 
Packaging 
B1. 
Labeling 
 
Each container is labeled with appropriate product information meeting current regulatory 
requirements, in compliance with 21 CRF 312.6. 
 
B2. 
Dosage Form 
 
The EPI-589 drug product will be provided in a 250-mg tablet formulation. 
 
B3. 
Dispensing 
 
Tablets are packaged in white round HPDE wide mouth containers. Each container holds 28 
tablets without desiccant. Each container is sealed with an induction seal held in place with a 
child-resistant closure. The packaged tablets are stored at controlled room temperature 20° to 
25°C (68° to 77°F). (See United States Pharmacopeia [USP]). 
 
C. 
Treatment Compliance and Adherence 
 
Study medication will be counted to assess compliance during each scheduled clinic visit. 
Subjects who take ≥ 80 percent of the prescribed doses and no more than 100 percent will be 
considered compliant. Subjects who fall outside the boundaries of these thresholds will be 
counseled and re-instructed on proper dosing procedures. Medication compliance will be 
recorded on the CRF for each visit after verification with subject-completed diary cards and 
returned used drug supply. 
 
D. 
Drug Accountability 
 
Dosing information will be captured on a subject Dosing Diary Form. This form is part of the 
source documentation and will be utilized as a source for the completion of CRFs associated 
with dosing and for reconciliation of study drug administered and returned to the study site for 
accounting and destruction. Adequate records of study drug receipt and disposition should be 


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maintained by pharmacy records of receipts, investigational drug orders, dispensing records, and 
disposition forms. The Study Monitor will also assess drug accountability and will 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 either be returned to the Sponsor or designee 
or destroyed per study site guidelines for destruction of investigational product immediately after 
drug accountability is performed by the study monitor. 
 
 
 
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IX. SAFETY MANAGEMENT 
A. 
Clinical Adverse Events 
 
Clinical AEs will be monitored throughout the study. All AEs, whether observed by the 
Investigator, reported by the subject, from clinically significant laboratory findings, or other 
means, will be recorded in the CRF. 
 
B. 
Adverse Event Reporting 
 
All SAEs will be reported to the IRB in accordance with the IRB policies and as detailed below. 
AEs that are not serious will be summarized in narrative or other format and submitted to the 
IRB at the time of continuing review. 
 
B1. 
Safety Guidance 
 
Based on the known clinical manifestations of Parkinson’s disease, we expect that many AEs 
could occur during the course of the trial that are well documented to occur as the results of the 
natural history of this disease. These include, but are not limited to worsening neuromuscular 
function, depression, decline in cognitive function, loss of vision and other ophthalmological 
symptoms, loss of coordination and loss of speech. 
 
Edison Pharmaceuticals 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, Edison Pharmaceuticals should be provided with a copy 
of any post-mortem findings, including histopathology. 
 
C. 
Definition of an Adverse Event 
C1. Adverse Event 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
 
The AE may be: 
 
1. A new illness 
2. Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 
3. An effect of the study medication, including comparator 


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4. A combination of 2 or more of these factors 
 
No causal relationship with the study medication or with the clinical study itself is implied by the 
use of the term “adverse event” or “AE”. 
 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an AE. Planned surgical 
measures permitted by the clinical study protocol and the condition(s) leading to these measures 
are not AEs. 
 
Adverse events fall into the categories “non-serious” and “serious”. 
 
C2. Definition of a Serious Adverse Event (SAE) 
 
An SAE is one that at any dose results in any of the following: 
 
1. Death; 
2. A life-threatening adverse drug experience; 
3. Inpatient hospitalization or prolongation of existing hospitalization; 
4. A persistent or significant disability/incapacity; or 
5. A congenital anomaly/birth defect. 
 
ICH guidance also recommends that important medical events that may or may not be 
immediately life-threatening or result in death or hospitalization should also be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the serious definition. 
 
The term ”life-threatening” in the definition of “serious” refers to an event in which the subject 
was at immediate risk of death at the time of the SAE. It does not refer to an SAE which 
hypothetically might have caused death if it were more severe. 
 
Medical and scientific judgment should be exercised in deciding whether other AEs, such as 
important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject, require intervention to prevent one of the other 
outcomes listed 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. 
 
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 
has received 
study drug, 
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. While pregnancy itself is not considered an 


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AE or SAE, all pregnancies should be reported using the same process as for SAEs. Any 
pregnancy complications or an outcome other than a healthy, normal outcome will be recorded 
as an AE or SAE. 
 
Clarification on the difference in meaning between “severe” and “serious”: The term “severe” is 
often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe 
myocardial infarction); the event itself, however, may be of relatively minor medical significance 
(such as severe headache). This is not the same as “serious,” which is based on the outcome or 
action criteria usually associated with events that pose a threat to life or functioning. Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
 
C3. 
Non-serious Adverse Event 
 
A non-serious AE is any AE not meeting the SAE criteria. 
 
C4. Definition of Relationship to Study Medication 
 
Association or relatedness to the study medication will be graded as either “probably”, 
“possibly”, or “unlikely”. Determination of relatedness includes: 
 
PROBABLY – The adverse event: 
 
1. Follows a reasonable temporal sequence from drug administration 
2. Abates upon discontinuation of the drug and reappears with re-introduction of the drug 
3. Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state 
 
POSSIBLY – The adverse event: 
 
1. Follows a reasonable temporal sequence from drug administration 
2. Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
UNLIKELY – The adverse event: 
 
1. Does not follow a reasonable temporal sequence from drug administration 
2. Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
C5. Definition of Severity 
 
All AEs will be graded if possible by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. The severity of AEs that cannot be graded by CTCAE v4.03 will be categorized 
as follows: 


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Grade 1 – Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy indicated. 
 
Grade 2 – Moderate limitation in activity, some assistance may be needed; minimal noninvasive 
medical intervention/therapy indicated. 
 
Grade 3 – Severe limitation in activity, assistance usually required; medical intervention/therapy 
required; hospitalization or prolongation of hospitalization indicated; disabling. 
 
Grade 4 – Extreme limitation in activity, significant assistance required; urgent medical 
intervention/therapy required; life-threatening consequences. 
 
Grade 5 – Death 
 
C6. Definition of Unexpected Adverse Event 
 
Any AE, the specificity or severity of which is not consistent with those listed in the current 
investigator’s brochure is considered “unexpected.” 
 
C7. Notification of SAEs 
 
The Investigator is responsible for promptly notifying the IRB/IEC of all study on-site SAEs and 
other unanticipated problems related to research. 
 
External SAEs that are unexpected and related to the study intervention should be reported as 
they are received using the MedWatch or CIOMs form (as appropriate). 
 
SAEs (whether unexpected or expected AEs) must be documented on the designated SAE form. 
The SAE must be reported to the medical expert and appropriate Edison or Edison-assigned 
pharmacovigilance staff within 24 hours, according to regulatory, Sponsor, or ICH-E6 Good 
Clinical Practice, followed by the SAE form within two calendar days. The designated SAE form 
and the instructions are provided in the Investigator’s site file. 
 
The SAE contact information will be provided separately from the protocol. 
 
The Investigator and/or Medical Expert must also inform the Study Monitor and the Sponsor in 
all cases. Any SAEs must also be reported to the IRB/IEC. The Sponsor or designee will ensure 
that all legal reporting requirements are met. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and the 
study medication. 
 
Information not available at the time of the initial report (e.g., an end date for the AE or 
laboratory values received after the report) must be documented on a follow-up SAE forms. 


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The instructions to sites for the completion of SAE reports give detailed guidance on the 
reporting of SAEs and AEs initially reported as non-serious that become serious. When a non- 
serious event becomes serious, details must be forwarded immediately to the Medical expert and 
Edison or Edison-assigned pharmacovigilance staff first for assessment and then submitted to the 
Sponsor on the designated SAE form within 24 hours. 
 
All relevant information about suspected unexpected serious adverse reactions (SUSARs) that 
are fatal or life-threatening are to be recorded and reported to the relevant competent authorities. 
 
In the US, all fatal or life-threatening suspected unexpected serious adverse events assessed as 
possibly or probably related to study drug by the Sponsor must be reported to the FDA as soon as 
possible (i.e., by telephone or facsimile transmission), but no later than 7 calendar days after first 
knowledge by the Sponsor that a report qualifies as a suspected unexpected fatal or life- 
threatening reaction. All unexpected serious adverse events, other than fatal or life-threatening, 
assessed as possibly or probably related to study drug by the Sponsor must be reported to the 
FDA within 15 calendar days from the day the Sponsor determines that the information qualifies 
as a SUSAR. 
 
In the UK, the Sponsor or trial investigator must act immediately or at least within 24 hours after 
becoming aware of a SUSAR by informing the MHRA’s Clinical Trial Unit by telephone. The 
MHRA must then be informed in writing within 3 days of the incident. All SUSARs originating 
in the UK or originating outside the UK involving the same medicinal product are to be reported. 
Fatal or life-threatening SUSARs are to be reported as soon as possible, but no later than after 7 
days. Any additional relevant information must be sent within 8 days of the report. Non-fatal or 
non-life-threatening SUSARs are to be reported as soon as possible but no later than 15 days 
after becoming aware of the reaction. 
 
C8. Follow-up Report 
 
If an SAE has not resolved at the time of the initial report, a follow-up report including all 
relevant new or reassessed information (e.g., concomitant medication, medical history) should be 
submitted to the IRB. All SAEs should be followed until either resolved or stable. 
 
D. 
Medical Emergencies 
 
In medical emergencies, the Investigator should use medical judgment and remove the subject 
from the immediate hazard. The Medical Expert and the IRB/ IEC must be notified regarding the 
type of emergency and course of action taken and the procedures for SAE reporting must be 
followed. 
 
D1. Emergency Sponsor Contact 
 
In emergency situations, the Investigator should contact the Medical Monitor: 
 


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D2. Emergency Treatment 
 
At present, the threshold and extent of clinical adverse effects are not known as only limited 
information is available in healthy volunteers. It is anticipated in the planned study that any 
effects will be minimal and laboratory measurements will detect study drug effects before they 
become clinically significant. 
 
 
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X. 
STUDY ADMINISTRATION 
A. 
Treatment Assignment Methods 
 
This is an open-label study. 
 
B. 
Data Collection and Management 
 
Monitoring and auditing procedures, developed or endorsed by Edison will be followed in order 
to comply with GCP guidelines. Direct access to on-site study documentation including all 
source data, documentation and medical records should be ensured. 
 
The study will be monitored by Edison. Throughout the course of the study, the Study Monitor 
will make frequent contact with the Investigator. This will include telephone calls and on-site 
visits. During the on-site visits, the completed CRF will be compared to the source 
documentation for completeness, accuracy and adherence to the protocol. As part of the data 
audit, source documents must be made available to the Study Monitor for review. The Study 
Monitor will also perform drug accountability checks and will review the Investigator study file 
to assure completeness of documentation in all respects of clinical study conduct. 
 
Upon completion of the study, the Study Monitor will arrange for a final review of the study 
files, after which the files should be secured for the appropriate time period. The Investigator, or 
appointed delegate, will meet with the Study Monitor during the on-site visits and will cooperate 
in providing the documents for inspection and responding to inquiries. In addition, the 
Investigator will permit inspection of the study files by authorized representatives of Edison or 
the regulatory agencies. 
 
US and other competent regulatory authorities, the IRB/IEC, and an auditor authorized by the 
Sponsor may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. Medical records and other 
study documents may be copied during audit or inspection provided that subject names are 
obliterated on the copies to ensure confidentiality. 
 
C. 
Data Quality Assurance 
 
As a final step in the data management process, a 100% audit will be performed on the key 
safety and critical efficacy parameters. In addition, a random subject sample (10%) will be 
selected in order to perform a partial audit of remaining data. The purpose of this audit is to 
detect systematic and random errors. Any errors found from this audit will be corrected and, if 
the error rate is greater than 1 error per 1,000 fields (0.001%), a systematic review of the 
database will be undertaken and corrections will be made to achieve an error rate of less than 
0.001%. 
 
AEs will be coded using MedDRA, version (14.3). Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary, March 2014. 


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D. 
Retention of Study Records 
 
The following records must be retained by the Investigator for a minimum of 2 years after the 
Sponsor has notified the FDA or other competent authority that investigations have been 
discontinued, or after the FDA or other competent authority has approved the new drug 
application. In accordance with European regulatory requirements (Directive 2005/28/EC and 
Annex 17 and 2001/83/EC and Annex1), the Sponsor may request retention for a longer period 
of time. 
 
1. Signed informed consent documents for all subjects 
2. Subject identification code list, screening log (if applicable), and enrollment log 
3. Record of all communications between the Investigator and the IRB/IEC 
4. Composition of the IRB/IEC or other applicable statement 
5. Record of all communications between the Investigator and Sponsor (or Contract 
Research Organization [CRO]) 
6. List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in the 
study and their signatures 
7. Copies of CRFs and of documentation of corrections for all subjects 
8. Drug accountability records 
9. Record of any body fluids or tissue samples retained 
10. All other source documents (subject records, hospital records, laboratory records, etc.) 
11. All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
 
The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. 
 
Normally, these records will be held in the Investigator's archives. If the Investigator is unable to 
meet this obligation, 
or 
must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 
E. 
Confidentiality 
 
Subject names will not be supplied to the Sponsor. Only the subject number and subject initials 
will be recorded in the CRF, and if the subject name appears on any other document (e.g., 
pathologist report), it must be redacted before a copy of the document is supplied to the Sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be told that representatives of the Sponsor, IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 


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accordance with local data protection and privacy laws, including the Health Insurance 
Portability and Accountability Act (HIPAA) Guidelines, and the General Data Protection 
Regulation (GDPR). 
 
The Investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
F. 
Documentation of Study Results 
 
A CRF will be provided for each enrolled subject. 
 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the CRF. Details of CRF completion and correction will be 
explained to the Investigator. If the Investigator authorizes other persons to make entries in the 
CRF, the names, positions, signatures, and initials of these persons must be supplied to the 
Sponsor. 
 
The Investigator, or designated representative, should complete the CRF pages as soon as 
possible after information is collected, preferably on the same day that a study subject is seen for 
an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
 
By signing the completed CRFs, the Investigator or Subinvestigator attests to the accuracy, 
completeness, legibility, and timeliness of the data collected on the CRF and casebooks. 
 
The Sponsor will retain the originals of all CRFs. The Investigator will retain a copy of all 
completed CRF pages. 
 
G. 
Regulatory and Ethical Considerations 
G1. Risk Assessment 
 
Based on the safety results of Study EPI-589-14-01 as summarized in the Clinical Study Report, 
it is not foreseen that subjects will endure any risks greater than minimal at the 500-mg BID dose 
selected for this study. 
 
G2. Potential Benefits of Trial Participation 
 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 
benefit in subjects with PD. Therefore, we cannot assure that subjects will benefit from treatment 
with EPI-589. Potential benefits may manifest in a variety of ways, such as in disease-related 
parameters, functioning, and quality of life. 


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G3. Risk-Benefit Assessment 
 
There are no effective and/or approved disease modifying treatments available for PD, although 
a number of clinical interventions are being researched. Based on disease mechanism, EPI-589 
mechanism of action and pre-clinical studies, EPI-589 may hold benefit for patients with PD. 
This is the first study to better understand EPI-589 target engagement and potential therapeutic 
benefit in subjects with PD. In order to further minimize risks, subjects will be closely monitored 
with a variety of safety measures. 
 
H. 
Informed Consent 
 
Before being enrolled in the clinical study, subjects must provide written consent to participate 
after the nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them. The Investigator will not undertake any measures specifically 
required only for the clinical study until valid consent has been obtained. 
 
An informed consent document that includes both information about the study and the consent 
form will be prepared and given to the subject. This document will contain all the elements 
required by the ICH E6 Guideline for Good Clinical Practice and any additional elements 
required by local regulations and must be in a language understandable to the subject. Where 
required by local law, the person who informs the subject must be a physician. It should be 
signed and dated by all the parties concerned including the subject, legal guardian (where 
applicable), witness (where applicable) and the person obtaining the consent. 
 
A copy of the signed consent document must be given to the subject. The original signed consent 
document will be retained by the Investigator. 
 
The Investigator must inform the subject’s primary physician about the subject’s participation in 
the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
 
 
 
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Protocol EPI589-15-002 
EPI-589 
Version: Original 
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27 April 2015 
Edison Pharmaceuticals Inc. 
Page 47 of 52 
 
 
 
XI. PUBLICATION 
A. Use of Study Results 
 
All information concerning the product, as well as any matter concerning the operation of Edison 
(such as clinical indications for the drug, its formula, methods of manufacture, and other 
scientific data relating to it, that have been provided by Edison and are unpublished), are 
confidential and must remain the sole property of Edison. The Investigator will agree to use the 
information only for the purposes of carrying out this study and for no other purpose unless prior 
written permission from Edison is obtained. The Sponsor has full ownership of the CRFs 
completed as part of the study. 
 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by Edison. If necessary, the authorities will be notified 
of the Investigator's name, address, qualifications, and extent of involvement. 
 
This Study is part of a multicenter clinical research study. Accordingly, Sponsor will act as 
coordinator and referee with respect to publications of the data generated thereunder. Principal 
Investigator shall not publish or disclose any data, result or information with respect to any 
matters resulting from work performed under this Protocol while this Study is being conducted at 
other center/s. Only after the completion of this Study at all other centers, provision of the data to 
the FDA or EMA for review and comment, and publishing the combined data from all of the 
centers, may the Principal Investigator publish/present the individual results of the Study in 
accordance with this paragraph. 
 
Principal Investigator may publish provided, however, that no publication, abstract, 
announcement or disclosure (“Publication”) shall be made until the Principal Investigator 
submits to Sponsor any proposed Publication for Sponsor’s review. Sponsor shall have a period 
of sixty (60) days to review such Publication. If Sponsor determines during the review period 
that the Publication contains patentable subject matter, then the above sixty (60) days shall be 
extended to one hundred twenty (120) days in order to allow for the preparation of patent 
applications covering said patentable subject matter. Unless Sponsor approves in writing, no 
Publication may contain any Confidential Information (other than data and results generated 
under the Study). 
 
Without limiting the foregoing, Institution and Principal Investigator, and all other study 
investigators in other study institutions, shall give due regard to Sponsor’s legitimate interests, 
such as manuscript authorship, coordinating and maintaining the proprietary nature of 
submissions to health authorities, and coordinating with other ongoing studies in the same field, 
and agree to accept Sponsor’s reasonable comments and suggestions with respect to such 
Publications. 
 
If the Investigator is to be an author of a publication manuscript prepared by Edison, Edison will 
allow the Investigator or CRO 60 days for full review of the manuscript before publication. 


Edison Pharmaceuticals, Inc 
Protocol EPI589-15-002 
EPI-589 
Version: Original 
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27 April 2015 
Edison Pharmaceuticals Inc. 
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XII. LIST OF ABBREVIATIONS 
 
 
AE 
adverse event 
AI 
accumulation index 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AR 
accumulation ratio 
BDI 
Beck Depression Inventory 
BID 
twice daily 
BSO 
L-buthionine-(S,R)-sulfoximine 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatinine kinase 
CNS 
central nervous system 
CoQ10 
Coenzyme Q 10 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DaT 
dopamine transporters 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EITT 
efficacy intent-to-treat 
EPDA 
European Parkinson’s Disease Association 
EU 
European Union 
%F 
percent fluctuation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GCRC 
good clinical research practice 
GDPR 
General Data Protection Regulation 
GSH 
glutathione 
GSSG 
glutathione disulfide 
HDPE 
high density polyethylene 
hERG 
human Ether-a-go-go Related Gene 
HCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HMPAO 
hexamethylpropylene amine oxime 
ICF 
informed consent form 
ICH 
International Committee on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUPAC 
International Union of Pure and Applied Chemistry 
kg 
kilogram 
λz 
apparent terminal constant 


Edison Pharmaceuticals, Inc 
Protocol EPI589-15-002 
EPI-589 
Version: Original 
27 April 2015 
 
 
 
 
 
LFT 
liver function test 
MAD 
multiple ascending (oral) dose 
MADRS 
Montgomery and Asberg Depression rating scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS-UPDRS 
Movement Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale 
mg 
milligram 
mL 
milliliter 
MoCA 
Montreal Cognitive Assessment 
MPTP 
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 
MPV 
mean platelet volume 
MRS 
magnetic resonance spectroscopy 
mtDNA 
mitochondrial DNA 
N/A 
not applicable 
NADPH 
nicotinamide adenine dinucleotide phosphate 
NF 
National Formulary 
nM 
nanomolar 
NMSS 
Non-motor Symptoms Scale 
NOAEL 
no observed adverse effect level 
NQ01 
NAD(P)H Quinone oxidoreductase 1 
OD 
once daily 
OTC 
over-the-counter 
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PO 
by mouth 
PT 
Prothrombin Time 
PTT 
Partial Prothrombin Time 
PVP 
polyvinylpyrrolidone 
QT 
interval between the start of the Q wave and the end of the T wave 
RBC 
red blood cell 
RDW 
red cell distribution width 
SAD 
single ascending (oral) dose 
SAE 
serious adverse event 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
Tmax 
time to peak concentration 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
 
 
 
 
 
 
Confidential 
Edison Pharmaceuticals Inc. 
Page 49 of 52 


Edison Pharmaceuticals, Inc 
Protocol EPCS89-15-002 
EPI-589 
Version: Original 
27 April 2015 
 
 


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Protocol EPI589-15-002 
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XIV. REFERENCES 
 
Ashrafi G, Schlehe JS, LaVoie MJ, Schwartz TL. Mitophagy of damaged mitochondria occurs 
locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol. 2014; 1;206(5):655- 
70. 
 
Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces 
features of Parkinson's disease. Nat Neurosci. 2000; 3(12): 1301-1306. 
 
Dauer W and Przedborski S. Parkinson's disease: mechanisms and models, Neuron 2003; 39: 
889–909. 
 
de Lau LM and Breteler MM. Epidemology of Parkinson’s Disease. Lancet Neur.2006; 5: 525- 
35. 
 
EPDA-European Parkinson’s Disease Association. http://www.epda.eu.com/en/resources/life- 
with-parkinsons/part-1/prevalence-of-parkinsons-disease/ (consulted 04 December 2014). 
 
Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, et al. Biochemical and pathological 
characterization of Lrrk2. Ann Neurol. 2006: 59(2): 315-22. 
 
Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, 
environment and mitochondria. Parkinsonism Relat. Disord. 2003; 9 (Suppl 2): S59–S64. 
 
Holmay, MJ, Terpstra M, Coles LD, et al. N-acetylcysteine Boosts Brain and Blood Glutathione 
in Gaucher and Parkinson Diseases. Clin. Neuropharm. 2013; 36, 4: 103-106. 
 
Jha N, Jurma O, Lalli G, Liu Y, Pettus EH, et al. Glutathione Depletion in PC12 Results in 
Selective Inhibition of Mitochondrial Complex I Activity. Implications for Parkinson’s disease. J 
Biol Chem. 2000; 25;275 (34): 26096-101. 
 
Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product 
of meperidine-analog synthesis. Science. 1983; 219: 979–980. 
 
Lin MT and Beal FB. Mitochondrial dysfunction and oxidative stress in neurodegenerative 
diseases. Nature. 2006; 443: 787-795. 
 
Maarouf CL, Beach TG, Adler CH, Shill HA, Sabbagh MN, et al. Cerebrospinal fluid 
biomarkers of neuropathologically diagnosed Parkinson's disease subjects. Neurol Res. 2012; 
34:669–676. 
 
Mao P and Reddy PH. Aging and amyloid beta-induced oxidative DNA damage and 
mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and 
therapeutics. Biochim. Biophys. Acta. 2011; 1812: 1359-1370. 


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Page 52 of 52 
 
 
 
Narendra, DP and Youle RJ. Targeting mitochondrial dysfunction: role for PINK1 and parkin in 
mitochondrial quality control. Antioxi. Redox Signal. 2011; 14: 1929-1938. 
 
The Parkinson’s Disease Foundation. http://www.pdf.org/en/parkinson_statistics (consulted 27 
April 2015). 
 
Pinto M, Pickrell AM, Moraes CT. Regional susceptibilities to mitochondrial dysfunctions in the 
CNS. Biol. Chem. 2012; 393: 275-281. 
 
Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, et al. Transition metals, ferritin, 
glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 1989; Feb;52(2): 515-20. 
 
Winklhofer KF and Haass C. Mytochondrial dysfunction in Parkinson’s disease. Biochimica et 
Biophysica Acta. 2010; 1802: 29-44. 
 
Zhu X, Babar A, Siedlak SL, Yang Q, Ito G, et al. LRRK2 in Parkinson's disease and dementia 
with Lewy bodies. Mol Neurodegener. 2006;1:17. 

SAP_001.pdf: 
EPI589-15-002  
16.1 Study Information 
V1.0 
PTC Therapeutics Inc. - Confidential 
Page 1 of 1 
9 
STATISTICAL METHODS INTERIM ANALYSIS PLAN 
Document Date 
Document Name 
03 August 2018 
EPI589-15-002 Statistical Analysis Plan Version 1.0 
NCT# NCT02462603


BioElectron Technology Corporation 
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Protocol No.: EPI589-15-002 
 
 
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A Phase 2A Safety and Biomarker Study of EPI-589 in 
Mitochondrial Subtype and Idiopathic Parkinson’s Disease 
Subjects 
 
Protocol No.: EPI589-15-002 
STATISTICAL ANALYSIS PLAN 
 
Version: 1.0 
Date: 03-Aug-2018 
Biostatistician: 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is the property of BioElectron Technology Corporation, and may not-in full or part-be passed on, reproduced, 
distributed to any person, or submitted to any regulatory authorities without prior written permission of BioElectron 
Technology Corporation. 




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TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................................................... 4 
2. 
STUDY OBJECTIVE ........................................................................................................ 4 
3. 
STUDY DESIGN ................................................................................................................ 4 
3.1 SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE .............................................. 5 
3.2 PRIMARY ENDPOINT ...................................................................................................... 6 
3.3 SECONDARY ENDPOINTS .............................................................................................. 6 
4. 
GENERAL STATISTICAL ISSUES ................................................................................ 6 
4.1 CONTINUOUS ENDPOINTS ............................................................................................. 6 
4.2 CATEGORICAL ENDPOINTS ............................................................................................ 7 
4.3 SAMPLE SIZE ESTIMATION AND POWER ......................................................................... 7 
5. 
DATA HANDLING PROCEDURES ................................................................................ 7 
5.1 CODING SYSTEM ........................................................................................................... 7 
5.2 MISSING DATA HANDLING ............................................................................................. 7 
5.3 EARLY TERMINATION DATA HANDLING .......................................................................... 7 
6. 
ANALYSIS OF STUDY POPULATIONS ....................................................................... 7 
6.1 EFFICACY INTENT-TO-TREAT (EITT) POPULATION ....................................................... 8 
6.2 SAFETY POPULATION .................................................................................................... 8 
7. 
DISPOSITION OF PATIENTS AND STUDY COMPLETION ..................................... 8 
8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ....................... 8 
8.1 MEDICAL HISTORY ......................................................................................................... 8 
9. 
EFFICACY ANALYSIS ..................................................................................................... 8 
9.1 PRIMARY EFFICACY VARIABLE ...................................................................................... 8 
9.2 SECONDARY EFFICACY VARIABLES .............................................................................. 9 
10. 
EXTENT OF EXPOSURE AND DRUG COMPLIANCE ........................................... 11 
11. 
SAFETY ANALYSIS ....................................................................................................... 12 
11.1 ADVERSE EVENTS ..................................................................................................... 12 
11.2 SERIOUS ADVERSE EVENT........................................................................................ 14 
11.3 LABORATORY EVALUATIONS ...................................................................................... 14 
11.4 VITAL SIGNS AND PHYSICAL EXAMINATION ............................................................... 16 
11.5 OTHER VARIABLES RELATED TO SAFETY ................................................................. 16 
12. 
COMPUTER METHODS ................................................................................................ 17 


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1. INTRODUCTION 
This is a phase 2a safety and biomarker study of EPI-589 in mitochondrial subtype and 
idiopathic Parkinson’s disease (PD) subjects. Approximately 40 subjects with PD including 
20 subjects with genetically-defined subtypes and 20 subjects with drug-naïve idiopathic 
PD will be enrolled. 
 
This statistical analysis plan (SAP) is based on protocol amendment 2.0, dated 
04-Jan-2016. The SAP provides details of data handling procedures and statistical analysis 
methods for efficacy and safety evaluations. It also outlines statistical programming 
specifications for tables and listings, and other details on the analyses not provided in the 
study protocol. It is noted that in case there is discrepancy between the SAP and the 
protocol then the SAP will supersede the protocol.  
 
This SAP will include efficacy and safety analysis only. The pharmacokinetic (PK) analysis 
plan is not part of this SAP. 
 
2. STUDY OBJECTIVE 
Primary Objective 
The primary objective is to evaluate the effects of EPI-589 on safety as assessed by 
occurrence of drug-related serious adverse events in subjects with PD. 
 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with PD on: 
(1) Redox biomarkers as measured in blood, cerebral spinal fluid, and urine 
(2) Clinical disease state as assessed by the Movement Disorder Society-sponsored 
revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) 
(3) Disease morbidity as assessed by the Non-motor Symptoms Scale (NMSS), PDQ-39 
and EQ-5D 
(4) Cognitive function as assessed by Montreal Cognitive Assessment (MoCA) 
(5) Mood as assessed by the Beck Depression Inventory (BDI) and the Montgomery and 
Asberg Depression rating scale (MADRS) 
(6) Pharmacokinetics 
(7) Hematology, blood chemistry, electrocardiogram 
 
3. STUDY DESIGN 


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This is an open-label, subject-controlled study. Following study enrollment, baseline clinical 
and biomarker assessments will be performed. Subjects will participate in a 30-day run-in 
phase to establish biomarker and clinical baseline measurement. EPI-589 will then be 
administered at a dose of 500-mg twice a day (BID) from Day 1 and up to 3 months (85 
days ± 3 days) unless discontinued for safety or tolerability issues. A post-treatment 
follow-up will be conducted at least 10 days and up to 30 days after last dose to assess for 
possible adverse events. 
3.1 Schedule of Assessments and Dosing Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
  
 
 
 
 
 
 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 


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3.2 Primary Endpoint 
To evaluate the effects of EPI-589 on safety as assessed by occurrence of drug-related 
serious adverse events in subjects with PD. 
 
3.3 Secondary Endpoints  
Secondary Endpoints (Efficacy) 
(1) Blood-based biomarkers 
(2) CNS-based biomarkers 
(3) Urine-based biomarkers 
(4) MDS-UPDRS 
(5) NMSS 
(6) PDQ-39 
(7) EQ-5D 
(8) MoCA 
(9) BDI 
(10) MADRS 
(11) Timed motor tests in ON and OFF state (for subjects on dopamine therapy) 
(12) Pharmacokinetics 
 
Secondary Endpoints (Safety) 
(1) Routine assessments of AEs and SAEs 
(2) Dose limiting toxicities 
(3) Routine serum chemistries with liver function tests 
(4) C-SSRS 
(5) Routine hematology tests with coagulation tests 
(6) Electrocardiogram 
 
4. GENERAL STATISTICAL ISSUES 
For data listings, all raw data will be displayed exactly as provided. For summaries of 
quantitative data, the median, minimum and maximum value will be reported exactly as the 
raw data are reported; measures of central tendency (means will be reported as one 
decimal more than the raw data and measure of standard deviation (SD) will be reported as 
the two decimals more than the raw data.) Baseline will be defined as the last value prior to 
study drug dosing. 
 
4.1 Continuous endpoints 


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Continuous variables, such as age, will be presented as number of observations (n), mean, 
median, standard deviation (SD), minimum and maximum for the raw data as well as 
change from baseline.  
 
4.2 Categorical endpoints 
Categorical variables, such as gender, will be presented and summarized as counts and 
percentages.  
 
4.3 Sample size estimation and power 
Approximately 40 subjects (20 with genetically-defined subtypes of PD and 20 PD 
drug-naïve subjects). Under an adaptive design strategy, additional subjects (up to 20) may 
be added to increase the number of biomarker-responsive idiopathic PD subjects to 
achieve a higher number of subjects in whom we could understand the biochemical effects 
of the investigative drug and its potential clinical impact as assessed by the same study 
protocol and outcome metrics. 
 
5. DATA HANDLING PROCEDURES 
5.1 Coding System 
The Adverse Events and Serious Adverse Events will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 14.3 or higher, and be reported by System Organ 
Class and Preferred Term.  
Concomitant medications will be coded according to the World Health Organization (WHO) 
Drug Dictionary, March 2014 or higher. 
 
5.2 Missing Data Handling 
For missing data related to a safety or efficacy endpoint, no missing data method will be 
performed. 
 
5.3 Early Termination Data Handling 
For early termination data, it will combine to Month 3 measurements. 
 
6. ANALYSIS OF STUDY POPULATIONS 
In this study, there will be two populations, efficacy intent-to-treat (EITT) population and 


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safety population. The EITT population will be used in the efficacy analysis, and the safety 
population will be used in the safety analysis. Demographic characteristics and baseline 
efficacy data will be presented and summarized by treatment group for all subjects in the 
EITT population and safety population. No formal statistical comparisons will be made for 
either the EITT or Safety populations. The populations for analysis applied in this study are 
defined as follows: 
 
6.1 Efficacy Intent-to-treat (EITT) Population  
The efficacy intent-to-treat (EITT) population will consist of any subject receiving at least 
one dose of EPI-589 and has minimum of the month 3 assessment. 
 
6.2 Safety Population 
The safety population will consist of any subject receiving at least one dose of EPI-589. 
 
The analysis of study population will be summarized as Table 14.1.1. Besides, subjects 
excluded from the analysis will be listed as Listing 16.2.3. 
 
7. DISPOSITION OF PATIENTS AND STUDY COMPLETION 
A total of 40 subjects are anticipated to be enrolled. Data on the completion status and 
primary reason for study discontinuation will be listed in Listing 16.2.1.1 and Listing 
16 2.1.2. All subjects’ disposition and completion status will be summarized in Table 14.1.1. 
Subject eligibility will be listed in Listing 16.2.1.3. All protocol deviation(s) will be listed in 
Listing 16.2.2. 
 
8. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Subject demographics will be listed in Listing 16.2.4.1. Demographics and baseline 
characteristics will be summarized by treatment group in Table 14.1.2. 
 
8.1 Medical History 
Medical history and concurrent medical conditions data will be listed by subject in Listing 
16 2.4.2. 
 
9. EFFICACY ANALYSIS 
9.1 Primary Efficacy Variable 
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The primary endpoint of this study is to evaluate the effects of EPI-589 on safety as 
assessed by occurrence of drug-related serious adverse events in subjects with PD. No 
primary efficacy variable is defined on protocol.  
 
9.2 Secondary Efficacy Variables 
Secondary efficacy endpoints included: 
(1) Blood-based biomarkers 
Individual subject Blood-based redox biomarkers will be listed in Listing 16.2.6.1 and the 
results at Baseline, Month 1, Month 3 / End of Treatment and change from baseline will be 
summarized in Table 14.2.1. 
 
(2) CNS-based biomarkers 
Individual subject CNS-based redox biomarkers will be listed in Listing 16.2.6.2 and the 
results at Month 3 / End of Treatment will be summarized in Table 14.2.2. 
 
(3) Urine-based biomarkers 
Individual subject Urine-based redox biomarkers will be listed in Listing 16.2.6.3 and the 
results at Baseline, Month 1, Month 3 / End of Treatment and change from baseline will be 
summarized in Table 14.2.3. 
 
(4) Parkinson's Disease Rating (MDS-UPDRS) 
The MDS-UPDRS is a tool for monitoring the impact of PD, the degree of disability caused, 
and complications from treatment. Part I evaluates non-motor experiences of daily living 
and will be listed in Listing 16.2.6.4; Part II evaluates motor experiences of daily living and 
will be listed in Listing 16.2.6.5; Part III is a motor examination including the Hoehn and 
Yahr scale and will be listed in Listing 16.2.6.6; Part IV examines motor complications (e.g., 
motor fluctuations and dyskinesias) and will be listed in Listing 16.2.6.7. Total score for all 
parts of MDS-UPDRS at Baseline, Month 1, Month 3 / End of Treatment and changed from 
baseline will be summarized in Table 14.2.4. 
 
(5) Non-motor Symptoms (NMSS) 
Totally 30 questions in the NMSS are listed by subject and 9 different domains including 
such symptoms as dribbling saliva, constipation, depression, sleep disorders, apathy, 
hallucinations and dementia in Listing 16.2.6.8. Symptoms are quantified based on their 
severity (using a scale of 0 to 3) and frequency (using a scale of 0 to 4). The final 
cumulative scores are derived from adding up the product of the frequency score times 
severity score for each of the 30 questions at Baseline, Month 3 / End of Treatment and 


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changed from baseline will be summarized in Table 14.2.5. 
(6) Parkinson's Disease Questionnaire (PDQ-39) 
PDQ-39 is a self-administered questionnaire for patients with PD that has 39 questions 
relating to eight key areas of health and daily activities, including both motor and non-motor 
symptoms. It is scored on a scale of 0 to 100, with lower scores indicating better health, and 
high scores more severe symptoms. 
 
Individual subject PDQ-39 score will be listed in Listing 16.2.6.9 and total score of 39 
questions at Baseline, Month 1 and change from baseline will be summarized in Table 
14 2.6.  
 
(7) EQ-5D 
EQ-5D is a questionnaire designed to provide measures of health-related quality of life 
states, consisting in five domains (mobility, self-care, usual activities, pain/discomfort and 
anxiety/ depression). 
 
Health status measured in terms of five dimensions (5D) and the Visual analogue scale 
(VAS) scored on a scale of 0 to 100 for each subject will be listed in Listing 16.2.6.10. The 
health state involves having no problem will score 1, some problems score 2, and extreme 
score 3. The ‘Total score’, which simply adds up the levels on each dimension and the VAS 
score at Baseline, Month 3 / End of Treatment and change from baseline will be 
summarized in Table 14.2.7. 
 
(8) Montreal Cognitive Assessment (MoCA) 
MoCA is a 30-point questionnaire for cognitive dysfunction. It assesses different cognitive 
domains: 
attention 
and 
concentration, 
executive 
functions, 
memory, 
language, 
visuoconstructional skills, conceptual thinking, calculations, and orientation. Severity 
ranges are approximately: 26 to 30 normal; 18 to 26 mild cognitive impairment; 10-17 
moderate cognitive impairment; < 10 severe cognitive impairment. 
 
Individual subject MoCA report will be listed in Listing 16.2.6.11 and total score of 30-point 
questionnaire at Month 3 will be summarized in Table 14.2.8.  
 
(9) Beck Depression Inventory (BDI) 
The BDI is a self-reporting inventory that measures characteristic attitudes and symptoms 
of depression, including physical symptoms. Twenty-one questions have four responses 
each (rated 0 to 3) with a total cumulative score scale ranging from 1-10 considered normal) 
> 40 (extreme depression). 
1111 


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Individual subject BDI report will be listed in Listing 16.2.6.12 and total score at Baseline, 
Month 3 / End of Treatment and change from baseline will be summarized in Table 14.2.9. 
 
(10) Montgomery and Asberg Depression Rating Scale (MADRS) 
The MADRS is a clinician-rated tool for measuring changes in depressive symptom severity. 
Ten core symptoms and cognitive features are rated on a severity scale of 0 to 6. Higher 
scores indicate increasing depressive symptoms. 
 
Individual subject MADRS report will be listed in Listing 16.2.6.13 and the cumulative 
scores for 10 questions at Baseline, Month 3 / End of Treatment and change from baseline 
will be summarized in Table 14.2.10. 
 
(11) Timed Motor Tests in ON and OFF State (for Subjects on Dopamine Therapy) 
Timed motor tests are simple, objective, quantitative measures for the assessment of 
Parkinson’s disease. They include, in on-medication and off-medication state, timed 
recorded physical movements. 
 
Time Up and Go Test (TUG) is one of timed motor tests which is used to assess a person’s 
mobility and requires both static and dynamic balance. Listing 16.2.6.14 will list the 
measurement of the time in seconds for a subject to complete TUG test and checking 
records of subject’s postural stability, gait, stride length, and sway. The total time will be 
summarized under ON and OFF state by group with subjects on dopamine therapy for 
Baseline, Month 3 / End of Treatment and change from baseline in Table 14.2.11. While 
subjects on dopamine therapy is defined as the answer ‘Yes’ to question ‘3c Is the patient 
on Levodopa’.  
 
 
No formal statistical comparisons will be made for all secondary efficacy variables. All 
secondary endpoints will be summarized descriptively as number of observation, mean, 
median, standard deviation, minimum and maximum for continuous variables; and count 
and percentages for categorical variables.  
 
10. EXTENT OF EXPOSURE AND DRUG COMPLIANCE 
The dosing compliance and missed dose data be listed by subject in Listing 16.2.5.1 and 
Listing 16.2.5.2. 
Listing 16.2.5.1: Dosing Compliance 


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Listing 16.2.5.2: Missed Dose 
Besides, the drug concentration data will be listed in Listing 16.2.5.4. 
 
 
11. SAFETY ANALYSIS 
11.1 Adverse Events 
Clinical AEs will be monitored throughout the study. All AEs, whether observed by the 
Investigator, reported by the subject, from clinically significant laboratory findings, or other 
means, will be recorded in the CRF. The listing of all AEs will be provided in Listing 16.2.7.1. 
The listing of all AEs leading to discontinuation will be provided in Listing 16.2.7.4. 
All AEs will be graded if possible by Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03. The severity of AEs that cannot be graded by CTCAE v4.03 will be 
categorized as follows: 
Grade 1 – Transient of mild discomfort; no limitation in activity; no medical 
intervention/therapy indicated. 
Grade 2 – Moderate limitation in activity, some assistance may be needed; minimal 
noninvasive medical intervention/therapy indicated. 
Grade 3 – Severe limitation in activity, assistance usually required; medical 
intervention/therapy required; hospitalization or prolongation of hospitalization indicated; 
disabling. 
Grade 4 – Extreme limitation in activity, significant assistance required; urgent medical 
intervention/therapy required; life-threatening consequences. 
Grade 5 – Death 
 
Association or relatedness to the study medication will be graded as either “probably”, 
“possibly”, or “unlikely”. Determination of relatedness includes:  
 
PROBABLY – The adverse event:  
1. Follows a reasonable temporal sequence from drug administration  
2. Abates upon discontinuation of the drug and reappears with re-introduction of the drug 
3. Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state  
 


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POSSIBLY – The adverse event:  
1. Follows a reasonable temporal sequence from drug administration  
2. Could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject  
 
UNLIKELY – The adverse event:  
1. Does not follow a reasonable temporal sequence from drug administration  
2. Is readily explained by the subject’s clinical state or by other modes of therapy 
administered to the subject 
 
All AEs will be coded by system organ class and preferred term for analysis. 
Treatment-emergent adverse event (TEAE) is defined as AEs occur after the first 
administration of study drug, or AEs occur before the first administration of study drug and 
worsen in severity after first dose. Unless otherwise specified, all adverse event summaries 
will include the TEAEs only. For purposes of the summary tables, AEs will be classified as 
either related or not related to study drug. The drug-related AEs are assessed as ' Probably', 
or 'Possibly' related to study treatment. This summary will present the number and 
percentage of subjects, as well as number of events. 
 
A general summary of all TEAEs will be provided in Table 14.3.1.1.1 according to the 
following categories: 
 
Subject with any AE  
 
Subject with any SAE  
 
Subject with any drug-related AE 
 
Subject with any drug-related SAE 
 
Also, a general summary of all TEAEs with the most severity and most causal relationship 
will be applied while combined multiple AEs for analysis will be provided in Table 14.3.1.1.2 
according to the following categories: 
 
CTCAE Grade 
 
Relationship to Study Medication 
 
Serious AE 
 
Alternate Causality 
 
Action Taken with Study Medication 
 
Dose Limiting Toxicity 
 
Medication Given for AE 
 
Outcome 


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Other summary tables for adverse events will include: 
Table 14.3.1.2: Treatment-Emergent Adverse Events - MedDRA 
Table 14.3.1.3: Treatment-Emergent Adverse Events by Severity - MedDRA 
Table 14.3.1.4: Treatment-Emergent Adverse Events by Severity and Relationship to Study 
Drug - MedDRA 
Table 14.3.1.5: Treatment-Emergent Adverse Events Leading to Discontinuation 
 
11.2 Serious Adverse Event 
A serious adverse event (SAE) is one that at any dose results in any of the following:  
1. Death  
2. A life-threatening adverse drug experience  
3. Inpatient hospitalization or prolongation of existing hospitalization  
4. A persistent or significant disability/incapacity  
5. A congenital anomaly/birth defect  
 
A listing of all serious adverse events will be provided in Listing 16.2.7.2 and Listing 
16 2.7.3, and the summary of SAEs will be presented: 
Table 14.3.1.6: Treatment-Emergent Serious Adverse Events - MedDRA 
Table 14.3.1.7: Treatment-Emergent Serious Adverse Events by Severity and Relationship 
to Study Drug - MedDRA 
  
11.3 Laboratory Evaluations 
Clinical laboratory tests, including standard hematology, serum chemistry, urinalysis, 
pregnancy test and genetic analysis: 
 
Hematology 
1. Erythrocytes: red blood cell (RBC) count, hematocrit, hemoglobin, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), red cell distribution width (RDW)  
2. Leukocytes: white blood cell count (WBC) and differential (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils) reported as absolute values and percentage. 
3. Platelets: platelet count, mean platelet volume (MPV)  
4. Coagulation: prothrombin time (PT) with INR, partial thromboplastin time (PTT), 
activated (aPTT) 
 
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Serum Chemistry  
1. Liver: Alkaline Phosphatase (ALP), ALT (serum glutamic-pyruvic transaminase [SGPT]), 
AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total, and direct), 
gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH)  
2. Renal: blood urea nitrogen (BUN), creatinine  
3. Electrolytes: sodium, potassium, chloride, and carbon dioxide (CO2) as bicarbonate  
4. General: creatine phosphokinase (CPK), creatine kinase (CK), and troponin (at baseline 
only); total protein, albumin, calcium, magnesium, glucose, phosphate  
5. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 
lipoprotein (LDL) cholesterol, cholesterol/HDL Ratio (calculated), non-HDL cholesterol 
(calculated) and triglycerides  
 
The cholesterol/HDL Ratio is calculated as cholesterol (total)/ high-density lipoprotein (HDL) 
cholesterol; and non-HDL cholesterol is calculated as cholesterol (total) - high-density 
lipoprotein (HDL) cholesterol. 
 
Urinalysis 
The urinalysis items included: Color, Clarity, Specify Gravity, pH, Leukocytes, Blood, Nitrite, 
Ketones, Billrubin, Urobillinogen, Protein and Glucose. 
 
Urine Pregnancy Test  
Human chorionic gonadotropin (HCG) beta subunit will be measured on all female subjects 
of childbearing potential. 
 
Genetic Analysis 
Mutation will be recorded for subjects with genetically diagnosed. 
 
By-subject listings of measured values for clinical laboratory test data (hematology,  
chemistry and urinalysis) will be prepared in Listing 16.2.8.3 to Listing 16.2.8.5. A listing of 
pregnancy test and genetic analysis will be provided in Listing 16.2.8.6 and Listing 16.2.8.7.  
Observations outside the normal range will be flagged. The abnormal values will be 
recorded as ‘Low’ for values below the lower limit of the laboratory’s normal range, ‘High’ for 
values above the upper limit of the laboratory’s normal range or ‘Normal’ for values within 
laboratory’s normal range. All clinically significant laboratory results will be marked as well. 
All original and repeated values will be listed. 
 
Abnormal laboratory values of hematology, serum chemistry, urinalysis, urine pregnancy 


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test and genetic analysis will be listed in Listing 16.2.8.1. The record with observed value of 
clinical laboratory data below or above the detection limit will be imputed with the detection 
limit for analysis. The summary results of laboratory assessment (hematology and 
chemistry) will be presented as Table 14.3.5.1 and Table 14.3.5.2, respectively. The shift 
table with the counts and percentages of the actual number of subjects whose judgments 
including ‘Normal’, ‘Abnormal NCS’, and ‘Abnormal CS’ shifted among categories will be 
presented as Table 14.3.5.3. 
 
11.4 Vital Signs and Physical Examination 
Vital Signs 
Individual subject vital signs (Height, Weight, Systolic Body Pressure, Diastolic Blood 
Pressure, Heart Rate and Respirations) will be listed in Listing 16.4.1. 
The observed value of vital signs at Baseline, Month 1, Month 3 / End of Treatment and 
change from baseline values will be summarized in Table 14.3.6.1. The shift table with the 
counts and percentages of the actual number of subjects whose judgments including 
‘Normal’ and ‘Abnormal’ shifted among categories will be presented as Table 14.3.6.2. 
 
Physical Exam 
Physical exam data (HEENT, Skin, Respiratory, Abdominal/GI, Pulmonary, Cardiovascular, 
Endocrine, Musculoskeletal, Neurologic/CNS, Psychiatric, Immunologic/Allergy and 
Gynecologic/Urologic) will be listed in Listing 16.4.2, and will be summarized for Baseline, 
Month 1, Month 3 in Table 14.3.7.1. The shift table with the counts and percentages of the 
actual number of subjects whose judgments including ‘Normal’, ‘Abnormal NCS’, and 
‘Abnormal CS’ shifted among categories will be presented as Table 14.3.7.2. 
 
11.5 Other Variables Related to Safety 
Concomitant Medications 
Individual subject concomitant medications will be listed in Listing 16.2.5.3.  
 
12-Lead ECG 
Individual subject 12-Lead ECG data (Ventricular rate, PR interval, RR interval, QRS 
duration, QT, QTc (Bazette) and Overall Interpretation) will be listed in Listing 16.4.3, and 
will be summarized at Baseline, Month 1, Month 3 / End of Treatment and change from 
baseline in Table 14.3.8.1. The shift table with the counts and percentages of the actual 
number of subjects whose judgments including ‘Normal’, ‘Abnormal NCS’, and ‘Abnormal 
CS’ shifted among categories for overall Interpretation will be presented as Table 14.3.8.2. 


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DaTscan 
Individual subject DaTscan data will be listed in Listing 16.4.5. 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Individual subject Columbia Suicide Severity Rating Scale (C-SSRS) data will be listed in 
Listing 16.4.6, and will be summarized as suicidal ideation and suicidal behavior in Table 
14 3.9. 
 
Revised Hamilton Rating Scale (RHRSD) 
Individual subject RHRSD report will be listed in Listing 16.4.7. 
 
Telephone Contact 
Individual subject telephone Contact data will be listed in Listing 16.4.8.  
 
12. COMPUTER METHODS 
All statistical analyses will be conducted using SAS® software, Version 9.3 of the SAS 
System for Windows 7. Copyright© 2013 SAS Institute Inc. SAS and all other SAS Institute 
Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc., 
Cary, NC, USA. 
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